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Erythema extent predicts death in cutaneous GVHD
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
Maintenance therapies boost MM survival rates
These results, published in The Lancet Oncology, are not yet practice-changing, but they add to a growing body of evidence supporting this approach.
“Bearing in mind that ATLAS trial data come from unplanned interim analysis, we found that the benefit of combination therapy (KRd) is clearly seen, especially for standard risk patients. We think that, since there are no vast differences in toxicities, there is quite convincing data for considering KRd maintenance for the post autologous stem cell transplantation treatment of MM patients,” ATLAS study coauthor Andrzej Jakubowiak, MD, professor of medicine at the University of Chicago, said in an interview.
Among patients receiving KRd (n = 93), median PFS was 59 months (95% confidence interval) compared with 41 months in the R group (hazard ratio, 0.51, P = .012). These results come from data collected between 2016 and 2020, from 12 academic and clinical centers in the United States and Poland. The cohort included 180 adults randomly assigned to each study arm, (47% were female, median age 59 years) The most common adverse events were neutropenia 48% vs. 60%, thrombocytopenia 13% vs. 7%, and lower respiratory tract infections 8% vs. 1% in the KRd and R groups, respectively. Serious adverse events were reported in 30% of patients in the KRd arm (including one death due to severe pneumonia) and 22% in the R group.
“As expected, there is a slightly higher toxicity in the KRd arm but mostly low-grade events occurred. We believe in KRd maintenance because it provides a longer remission for a relatively small price. The longer a patient is in remission, the better chance that, if relapse does occur, there will be more therapeutic options available to return to remission,” said Dr. Jakubowiak.
Although all patients in the trial received stem cell therapy, the induction therapies were varied.
“We designed the study similarly to the CALGB maintenance trial, one of the key phase 3 trials leading to the approval of lenalidomide as post transplantation maintenance. With so many changes currently occurring MM therapies, having a fixed induction can be its own limitation. Importantly, with our study design we found that all comers may benefit from KRd maintenance,” he said.
It is important to note that KRd treatment occurred for 36 cycles unless a patient withdrew, died, or achieved minimal residual disease (MRD) status.
“Per study design, the duration of KRd treatment was shortened to eight cycles for patients without high-risk cytogenetics who achieved MRD-negativity after cycle six. For these patients, treatment was converted from KRd to R maintenance as of cycle nine. Despite treatment deescalation, this subset of patients (44% of all KRd patients) contributed strongly to KRd PFS. While this approach will need to be validated in a randomized setting, the results provide a proof of concept that if you achieve MRD-negative status and have standard risk cytogenetics, you don’t have to go on a long KRd treatment,” said Dr. Jakubowiak.
Urvi Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, noted the importance of the study as “the first randomized phase-3 trial suggesting progression free survival superiority of an alternative maintenance therapy to lenalidomide alone.”
Dr. Shah did have concerns about the applicability of the study, especially regarding the use of varied induction regimens, saying, “Only 11%-13% of patients in this study got lenalidomide during induction and 4%-6% got carfilzomib induction. Therefore, most patients were getting new drugs during maintenance different from their induction agents, which has the downside of leaving fewer options for patients when they relapse.”
Asked about these concerns, Dr. Jakubowiak responded, “Our team’s perspective is to ‘buy’ the longest remission possible using the most effective available treatment strategy. If we do this, there is a good chance that when the patient relapses, we will have availability of new drugs.”
He added the caveat: “There’s a small proportion of patients who will be progressing while on treatment and will be potentially more challenging to treat if already given KRd. It has been proposed that KRd maintenance might be primarily considered for patients with high-risk cytogenetics. However, at this interim analysis, there were not enough events in high-risk patients to comment on KRd’s usefulness as a maintenance therapy in this population.”
The KRd arm of the ATLAS trial had a high dropout-rate for reasons other than toxicity and death, but “because consent for collecting data was discontinued, we can’t really dig deeper into explaining why they dropped out, but half of the patients who discontinued in the KRd arm did so after already completing KRd treatment and were already on R maintenance. Once taking this into consideration, the dropout rates in both arms are similar, and the data does not appear skewed,” said Dr. Jakubowiak.
In conclusion, Dr. Jakubowiak noted that the phase-2 FORTE trial, also published recently in The Lancet Oncology, provides supportive data for maintenance therapy with KR versus K.
“It is quite important that the results of both trials be presented to public so that people know that KR or KRd could be reasonably considered for posttransplant maintenance,” he said.
Dr. Shah opined that as yet, the results of neither study were practice changing for maintenance therapy in the United States. She said she would consider using KR maintenance for select patients with high-risk myeloma who received these drugs as induction therapy and where there was concern about early progression, given that this aggressive treatment allows for a longer time in remission.
Dr. Shah noted that in these trials, overall survival data on dual maintenance is still being awaited, and that those results would be important when considering whether to switch patients to a more expensive, toxic, and involved therapy that required regular infusion visits for maintenance.
What Dr. Shah found the most groundbreaking and applicable aspect of the study was that “in the ATLAS trial, they’re adapting treatments to disease response, and if patients achieve MRD negativity, which we know is the best kind of response, therapy was deescalated to lenalidomide single agent. I think this is something that we will see more of in newer study designs and this will help individualize patient treatments to their response.”
Dr. Jakubowiak disclosed consulting fees and honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gracell, GlaxoSmithKline, Janssen, and Sanofi-Aventis. Dr. Shah disclosed ties with Sanofi, Bristol Myers Squibb and Janssen.
These results, published in The Lancet Oncology, are not yet practice-changing, but they add to a growing body of evidence supporting this approach.
“Bearing in mind that ATLAS trial data come from unplanned interim analysis, we found that the benefit of combination therapy (KRd) is clearly seen, especially for standard risk patients. We think that, since there are no vast differences in toxicities, there is quite convincing data for considering KRd maintenance for the post autologous stem cell transplantation treatment of MM patients,” ATLAS study coauthor Andrzej Jakubowiak, MD, professor of medicine at the University of Chicago, said in an interview.
Among patients receiving KRd (n = 93), median PFS was 59 months (95% confidence interval) compared with 41 months in the R group (hazard ratio, 0.51, P = .012). These results come from data collected between 2016 and 2020, from 12 academic and clinical centers in the United States and Poland. The cohort included 180 adults randomly assigned to each study arm, (47% were female, median age 59 years) The most common adverse events were neutropenia 48% vs. 60%, thrombocytopenia 13% vs. 7%, and lower respiratory tract infections 8% vs. 1% in the KRd and R groups, respectively. Serious adverse events were reported in 30% of patients in the KRd arm (including one death due to severe pneumonia) and 22% in the R group.
“As expected, there is a slightly higher toxicity in the KRd arm but mostly low-grade events occurred. We believe in KRd maintenance because it provides a longer remission for a relatively small price. The longer a patient is in remission, the better chance that, if relapse does occur, there will be more therapeutic options available to return to remission,” said Dr. Jakubowiak.
Although all patients in the trial received stem cell therapy, the induction therapies were varied.
“We designed the study similarly to the CALGB maintenance trial, one of the key phase 3 trials leading to the approval of lenalidomide as post transplantation maintenance. With so many changes currently occurring MM therapies, having a fixed induction can be its own limitation. Importantly, with our study design we found that all comers may benefit from KRd maintenance,” he said.
It is important to note that KRd treatment occurred for 36 cycles unless a patient withdrew, died, or achieved minimal residual disease (MRD) status.
“Per study design, the duration of KRd treatment was shortened to eight cycles for patients without high-risk cytogenetics who achieved MRD-negativity after cycle six. For these patients, treatment was converted from KRd to R maintenance as of cycle nine. Despite treatment deescalation, this subset of patients (44% of all KRd patients) contributed strongly to KRd PFS. While this approach will need to be validated in a randomized setting, the results provide a proof of concept that if you achieve MRD-negative status and have standard risk cytogenetics, you don’t have to go on a long KRd treatment,” said Dr. Jakubowiak.
Urvi Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, noted the importance of the study as “the first randomized phase-3 trial suggesting progression free survival superiority of an alternative maintenance therapy to lenalidomide alone.”
Dr. Shah did have concerns about the applicability of the study, especially regarding the use of varied induction regimens, saying, “Only 11%-13% of patients in this study got lenalidomide during induction and 4%-6% got carfilzomib induction. Therefore, most patients were getting new drugs during maintenance different from their induction agents, which has the downside of leaving fewer options for patients when they relapse.”
Asked about these concerns, Dr. Jakubowiak responded, “Our team’s perspective is to ‘buy’ the longest remission possible using the most effective available treatment strategy. If we do this, there is a good chance that when the patient relapses, we will have availability of new drugs.”
He added the caveat: “There’s a small proportion of patients who will be progressing while on treatment and will be potentially more challenging to treat if already given KRd. It has been proposed that KRd maintenance might be primarily considered for patients with high-risk cytogenetics. However, at this interim analysis, there were not enough events in high-risk patients to comment on KRd’s usefulness as a maintenance therapy in this population.”
The KRd arm of the ATLAS trial had a high dropout-rate for reasons other than toxicity and death, but “because consent for collecting data was discontinued, we can’t really dig deeper into explaining why they dropped out, but half of the patients who discontinued in the KRd arm did so after already completing KRd treatment and were already on R maintenance. Once taking this into consideration, the dropout rates in both arms are similar, and the data does not appear skewed,” said Dr. Jakubowiak.
In conclusion, Dr. Jakubowiak noted that the phase-2 FORTE trial, also published recently in The Lancet Oncology, provides supportive data for maintenance therapy with KR versus K.
“It is quite important that the results of both trials be presented to public so that people know that KR or KRd could be reasonably considered for posttransplant maintenance,” he said.
Dr. Shah opined that as yet, the results of neither study were practice changing for maintenance therapy in the United States. She said she would consider using KR maintenance for select patients with high-risk myeloma who received these drugs as induction therapy and where there was concern about early progression, given that this aggressive treatment allows for a longer time in remission.
Dr. Shah noted that in these trials, overall survival data on dual maintenance is still being awaited, and that those results would be important when considering whether to switch patients to a more expensive, toxic, and involved therapy that required regular infusion visits for maintenance.
What Dr. Shah found the most groundbreaking and applicable aspect of the study was that “in the ATLAS trial, they’re adapting treatments to disease response, and if patients achieve MRD negativity, which we know is the best kind of response, therapy was deescalated to lenalidomide single agent. I think this is something that we will see more of in newer study designs and this will help individualize patient treatments to their response.”
Dr. Jakubowiak disclosed consulting fees and honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gracell, GlaxoSmithKline, Janssen, and Sanofi-Aventis. Dr. Shah disclosed ties with Sanofi, Bristol Myers Squibb and Janssen.
These results, published in The Lancet Oncology, are not yet practice-changing, but they add to a growing body of evidence supporting this approach.
“Bearing in mind that ATLAS trial data come from unplanned interim analysis, we found that the benefit of combination therapy (KRd) is clearly seen, especially for standard risk patients. We think that, since there are no vast differences in toxicities, there is quite convincing data for considering KRd maintenance for the post autologous stem cell transplantation treatment of MM patients,” ATLAS study coauthor Andrzej Jakubowiak, MD, professor of medicine at the University of Chicago, said in an interview.
Among patients receiving KRd (n = 93), median PFS was 59 months (95% confidence interval) compared with 41 months in the R group (hazard ratio, 0.51, P = .012). These results come from data collected between 2016 and 2020, from 12 academic and clinical centers in the United States and Poland. The cohort included 180 adults randomly assigned to each study arm, (47% were female, median age 59 years) The most common adverse events were neutropenia 48% vs. 60%, thrombocytopenia 13% vs. 7%, and lower respiratory tract infections 8% vs. 1% in the KRd and R groups, respectively. Serious adverse events were reported in 30% of patients in the KRd arm (including one death due to severe pneumonia) and 22% in the R group.
“As expected, there is a slightly higher toxicity in the KRd arm but mostly low-grade events occurred. We believe in KRd maintenance because it provides a longer remission for a relatively small price. The longer a patient is in remission, the better chance that, if relapse does occur, there will be more therapeutic options available to return to remission,” said Dr. Jakubowiak.
Although all patients in the trial received stem cell therapy, the induction therapies were varied.
“We designed the study similarly to the CALGB maintenance trial, one of the key phase 3 trials leading to the approval of lenalidomide as post transplantation maintenance. With so many changes currently occurring MM therapies, having a fixed induction can be its own limitation. Importantly, with our study design we found that all comers may benefit from KRd maintenance,” he said.
It is important to note that KRd treatment occurred for 36 cycles unless a patient withdrew, died, or achieved minimal residual disease (MRD) status.
“Per study design, the duration of KRd treatment was shortened to eight cycles for patients without high-risk cytogenetics who achieved MRD-negativity after cycle six. For these patients, treatment was converted from KRd to R maintenance as of cycle nine. Despite treatment deescalation, this subset of patients (44% of all KRd patients) contributed strongly to KRd PFS. While this approach will need to be validated in a randomized setting, the results provide a proof of concept that if you achieve MRD-negative status and have standard risk cytogenetics, you don’t have to go on a long KRd treatment,” said Dr. Jakubowiak.
Urvi Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, noted the importance of the study as “the first randomized phase-3 trial suggesting progression free survival superiority of an alternative maintenance therapy to lenalidomide alone.”
Dr. Shah did have concerns about the applicability of the study, especially regarding the use of varied induction regimens, saying, “Only 11%-13% of patients in this study got lenalidomide during induction and 4%-6% got carfilzomib induction. Therefore, most patients were getting new drugs during maintenance different from their induction agents, which has the downside of leaving fewer options for patients when they relapse.”
Asked about these concerns, Dr. Jakubowiak responded, “Our team’s perspective is to ‘buy’ the longest remission possible using the most effective available treatment strategy. If we do this, there is a good chance that when the patient relapses, we will have availability of new drugs.”
He added the caveat: “There’s a small proportion of patients who will be progressing while on treatment and will be potentially more challenging to treat if already given KRd. It has been proposed that KRd maintenance might be primarily considered for patients with high-risk cytogenetics. However, at this interim analysis, there were not enough events in high-risk patients to comment on KRd’s usefulness as a maintenance therapy in this population.”
The KRd arm of the ATLAS trial had a high dropout-rate for reasons other than toxicity and death, but “because consent for collecting data was discontinued, we can’t really dig deeper into explaining why they dropped out, but half of the patients who discontinued in the KRd arm did so after already completing KRd treatment and were already on R maintenance. Once taking this into consideration, the dropout rates in both arms are similar, and the data does not appear skewed,” said Dr. Jakubowiak.
In conclusion, Dr. Jakubowiak noted that the phase-2 FORTE trial, also published recently in The Lancet Oncology, provides supportive data for maintenance therapy with KR versus K.
“It is quite important that the results of both trials be presented to public so that people know that KR or KRd could be reasonably considered for posttransplant maintenance,” he said.
Dr. Shah opined that as yet, the results of neither study were practice changing for maintenance therapy in the United States. She said she would consider using KR maintenance for select patients with high-risk myeloma who received these drugs as induction therapy and where there was concern about early progression, given that this aggressive treatment allows for a longer time in remission.
Dr. Shah noted that in these trials, overall survival data on dual maintenance is still being awaited, and that those results would be important when considering whether to switch patients to a more expensive, toxic, and involved therapy that required regular infusion visits for maintenance.
What Dr. Shah found the most groundbreaking and applicable aspect of the study was that “in the ATLAS trial, they’re adapting treatments to disease response, and if patients achieve MRD negativity, which we know is the best kind of response, therapy was deescalated to lenalidomide single agent. I think this is something that we will see more of in newer study designs and this will help individualize patient treatments to their response.”
Dr. Jakubowiak disclosed consulting fees and honoraria for lectures and presentations from AbbVie, Amgen, Celgene (Bristol Myers Squibb), Gracell, GlaxoSmithKline, Janssen, and Sanofi-Aventis. Dr. Shah disclosed ties with Sanofi, Bristol Myers Squibb and Janssen.
FDA calls for withdrawal of multiple myeloma drug Pepaxto
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
(melphalan flufenamide), the company announced in a press release.
The drug was granted an accelerated approval by the FDA in February 2021, for use in combination with dexamethasone in adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy.
However, the phase 3 OCEAN study raised concerns about safety, as it showed a higher mortality associated with melphalan flufenamide in the experimental arm, compared with pomalidomide (Pomalyst).
The FDA already flagged this issue in July 2021, issuing a safety alert flagging the increased risk for death observed in the OCEAN trial among patients receiving melphalan flufenamide versus pomalidomide (47.6% vs. 43.4%) and a 5.3-month shorter overall survival.
The issue was also discussed in September 2022 by FDA’s Oncologic Drugs Advisory Committee, which voted 14-to-2 against maintaining the accelerated approval, citing an unfavorable risk/benefit profile.
The company stopped marketing the drug in the United States in October 2021 at the FDA’s request but continued to make it available for patients already undergoing treatment.
However, in March 2022, Oncopeptides rescinded the letter that voluntarily withdrew the agent from market, after further review of overall survival data from the OCEAN trial led the company to reconsider its decision. Notably, marketing efforts were still discontinued while the company worked with the FDA to interpret the data, it stated in the press release.
That review of the data showed that progression-free survival was 42% higher with melphalan flufenamide versus pomalidomide and overall response rates were 32.1% versus 26.5%, respectively.
Now, the FDA has requested that the company withdraw its U.S. marketing authorization.
“We respect FDA’s accelerated approval regulations,” Jakob Lindberg, CEO of Oncopeptides commented in the press release.
However, he also added, “multiple myeloma remains an incurable disease, and the treatment options for patients with triple-class refractory disease will ultimately become exhausted. The OCEAN study demonstrated clinical benefit for multiple myeloma patients, in particular for nontransplanted elderly patients where the unmet medical need remains very high.”
Commercialization of the drug in Europe, under the brand name Pepaxti, is ongoing.
“Pepaxti has a full approval from the European Medicines Agency, EMA, since Aug. 18, 2022, and was approved by the Medicines and Healthcare Products Regulatory Agency, MHRA, in the U.K. on Nov 11, 2022,” the company noted.
A version of this article first appeared on Medscape.com.
Multiple myeloma diagnosed more via emergency care during COVID
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
‘Exciting’ responsiveness to talquetamab for r/r MM
“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.
The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.
It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.
“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.
Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.
“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.
The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.
The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
MonumenTAL study
Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.
In the phase 1 dose-escalation study published in NEJM, the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
Three cohorts, two doses
The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.
There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.
The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.
The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
Phase 2 results
The overall response rate (ORR) among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).
The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.
The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).
The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
Safety profile
Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.
Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.
Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.
Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases with dose reductions.
Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
What’s next?
At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)
Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.
Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.
A version of this article first appeared on Medscape.com.
“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.
The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.
It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.
“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.
Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.
“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.
The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.
The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
MonumenTAL study
Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.
In the phase 1 dose-escalation study published in NEJM, the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
Three cohorts, two doses
The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.
There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.
The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.
The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
Phase 2 results
The overall response rate (ORR) among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).
The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.
The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).
The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
Safety profile
Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.
Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.
Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.
Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases with dose reductions.
Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
What’s next?
At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)
Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.
Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.
A version of this article first appeared on Medscape.com.
“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.
The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.
It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.
“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.
Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.
“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.
The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.
The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
MonumenTAL study
Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.
In the phase 1 dose-escalation study published in NEJM, the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
Three cohorts, two doses
The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.
There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.
The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.
The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
Phase 2 results
The overall response rate (ORR) among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).
The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.
The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).
The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
Safety profile
Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.
Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.
Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.
Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases with dose reductions.
Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
What’s next?
At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)
Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.
Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.
A version of this article first appeared on Medscape.com.
AT ASH 2022
Blenrep for multiple myeloma withdrawn from U.S. market
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
Teclistamab for MM: Lifesaver or 'cause of death'?
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
FDA OKs teclistamab for relapsed/refractory multiple myeloma
The results made the case for “teclistamab as a monotherapy for eligible patients with heavily pretreated multiple myeloma, in need of new treatment options,” investigator Maria-Victoria Mateos, MD, PhD, a hematologist at the University Hospital of Salamanca (Spain) said in a June press release from drug maker Janssen/Johnson & Johnson.
The approval was based on the phase 1-2 single-arm MajesTEC-1 trial. The MajesTEC-1 findings, published in August in the New England Journal of Medicine, included 165 patients with relapsed or refractory multiple myeloma after at least three therapy lines – including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. These patients received a weekly subcutaneous 1.5 mg/kg injection of teclistamab after stepping up from 0.06 mg and 0.3 mg/kg doses.
According to the FDA announcement, the overall response rate was nearly 62%. And the estimated duration of response rate among responders was 90.6% at 6 months and 66.5% at 9 months.
The NEJM results also indicated that almost 40% of patients had a complete response to the therapy, over a median follow-up of 14.1 months. More than a quarter of patients (26.7%) had no minimal residual disease.
The study investigators concluded that “teclistamab resulted in a high rate of deep and durable response in patients with triple-class exposed relapsed or refractory multiple myeloma.”
In a press release, Michael Andreini, president and CEO of the Multiple Myeloma Research Foundation, commented that “teclistamab is an important new treatment option for patients who have faced multiple relapses.”
The recommended dose for teclistamab is 0.06 mg/kg via subcutaneous injection on day 1, 0.3 mg/kg on day 4, and 1.5 mg/kg on day 7, followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity.
The FDA noted, however, that the prescribing information for teclistamab comes with a Boxed warning for “life-threatening or fatal cytokine-release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity (ICANS).”
CRS was reported in 72.1% of patients (grade 3 in one patient but no grade 4 cases), neurologic toxicity in 57%, and ICANS in 6%. Other common adverse events in the NEJM report included neutropenia in 71% of subjects (grade 3 or 4 in 64%); anemia in 52% (grade 3 or 4 in 37%), and thrombocytopenia in 40% (grade 3 or 4 in 21%). Overall, 45% of patients developed grade 3 or 4 infections.
“Because of the risks of CRS and neurologic toxicity, including ICANS, teclistamab-cqyv is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS,” according to the FDA’s press release.
Teclistamab is a T-cell–bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen (BCMA) expressed on the surface of myeloma cells, activating T-cells to kill cancer cells that express the antigen.
Three BCMA-directed therapies are already on the market in the United States that carry teclistamab’s indication: the antibody-drug conjugate belantamab mafodotin (Blenrep) and two chimeric antigen receptor (CAR) T-cell therapies, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti).
The overall response rate is approximately 31% with belantamab mafodotin, 67% for idecabtagene vicleucel, and 83% for ciltacabtagene autoleucel.
Pfizer also has a bispecific BCMA-CD3–targeted antibody in development, elranatamab, for triple-class refractory multiple myeloma that is expected to compete with teclistamab.
MajesTEC-1 was funded by Janssen. Dr. Mateos is a paid speaker and consultant for the company.
A version of this article first appeared on Medscape.com.
The results made the case for “teclistamab as a monotherapy for eligible patients with heavily pretreated multiple myeloma, in need of new treatment options,” investigator Maria-Victoria Mateos, MD, PhD, a hematologist at the University Hospital of Salamanca (Spain) said in a June press release from drug maker Janssen/Johnson & Johnson.
The approval was based on the phase 1-2 single-arm MajesTEC-1 trial. The MajesTEC-1 findings, published in August in the New England Journal of Medicine, included 165 patients with relapsed or refractory multiple myeloma after at least three therapy lines – including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. These patients received a weekly subcutaneous 1.5 mg/kg injection of teclistamab after stepping up from 0.06 mg and 0.3 mg/kg doses.
According to the FDA announcement, the overall response rate was nearly 62%. And the estimated duration of response rate among responders was 90.6% at 6 months and 66.5% at 9 months.
The NEJM results also indicated that almost 40% of patients had a complete response to the therapy, over a median follow-up of 14.1 months. More than a quarter of patients (26.7%) had no minimal residual disease.
The study investigators concluded that “teclistamab resulted in a high rate of deep and durable response in patients with triple-class exposed relapsed or refractory multiple myeloma.”
In a press release, Michael Andreini, president and CEO of the Multiple Myeloma Research Foundation, commented that “teclistamab is an important new treatment option for patients who have faced multiple relapses.”
The recommended dose for teclistamab is 0.06 mg/kg via subcutaneous injection on day 1, 0.3 mg/kg on day 4, and 1.5 mg/kg on day 7, followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity.
The FDA noted, however, that the prescribing information for teclistamab comes with a Boxed warning for “life-threatening or fatal cytokine-release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity (ICANS).”
CRS was reported in 72.1% of patients (grade 3 in one patient but no grade 4 cases), neurologic toxicity in 57%, and ICANS in 6%. Other common adverse events in the NEJM report included neutropenia in 71% of subjects (grade 3 or 4 in 64%); anemia in 52% (grade 3 or 4 in 37%), and thrombocytopenia in 40% (grade 3 or 4 in 21%). Overall, 45% of patients developed grade 3 or 4 infections.
“Because of the risks of CRS and neurologic toxicity, including ICANS, teclistamab-cqyv is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS,” according to the FDA’s press release.
Teclistamab is a T-cell–bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen (BCMA) expressed on the surface of myeloma cells, activating T-cells to kill cancer cells that express the antigen.
Three BCMA-directed therapies are already on the market in the United States that carry teclistamab’s indication: the antibody-drug conjugate belantamab mafodotin (Blenrep) and two chimeric antigen receptor (CAR) T-cell therapies, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti).
The overall response rate is approximately 31% with belantamab mafodotin, 67% for idecabtagene vicleucel, and 83% for ciltacabtagene autoleucel.
Pfizer also has a bispecific BCMA-CD3–targeted antibody in development, elranatamab, for triple-class refractory multiple myeloma that is expected to compete with teclistamab.
MajesTEC-1 was funded by Janssen. Dr. Mateos is a paid speaker and consultant for the company.
A version of this article first appeared on Medscape.com.
The results made the case for “teclistamab as a monotherapy for eligible patients with heavily pretreated multiple myeloma, in need of new treatment options,” investigator Maria-Victoria Mateos, MD, PhD, a hematologist at the University Hospital of Salamanca (Spain) said in a June press release from drug maker Janssen/Johnson & Johnson.
The approval was based on the phase 1-2 single-arm MajesTEC-1 trial. The MajesTEC-1 findings, published in August in the New England Journal of Medicine, included 165 patients with relapsed or refractory multiple myeloma after at least three therapy lines – including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. These patients received a weekly subcutaneous 1.5 mg/kg injection of teclistamab after stepping up from 0.06 mg and 0.3 mg/kg doses.
According to the FDA announcement, the overall response rate was nearly 62%. And the estimated duration of response rate among responders was 90.6% at 6 months and 66.5% at 9 months.
The NEJM results also indicated that almost 40% of patients had a complete response to the therapy, over a median follow-up of 14.1 months. More than a quarter of patients (26.7%) had no minimal residual disease.
The study investigators concluded that “teclistamab resulted in a high rate of deep and durable response in patients with triple-class exposed relapsed or refractory multiple myeloma.”
In a press release, Michael Andreini, president and CEO of the Multiple Myeloma Research Foundation, commented that “teclistamab is an important new treatment option for patients who have faced multiple relapses.”
The recommended dose for teclistamab is 0.06 mg/kg via subcutaneous injection on day 1, 0.3 mg/kg on day 4, and 1.5 mg/kg on day 7, followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity.
The FDA noted, however, that the prescribing information for teclistamab comes with a Boxed warning for “life-threatening or fatal cytokine-release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity (ICANS).”
CRS was reported in 72.1% of patients (grade 3 in one patient but no grade 4 cases), neurologic toxicity in 57%, and ICANS in 6%. Other common adverse events in the NEJM report included neutropenia in 71% of subjects (grade 3 or 4 in 64%); anemia in 52% (grade 3 or 4 in 37%), and thrombocytopenia in 40% (grade 3 or 4 in 21%). Overall, 45% of patients developed grade 3 or 4 infections.
“Because of the risks of CRS and neurologic toxicity, including ICANS, teclistamab-cqyv is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS,” according to the FDA’s press release.
Teclistamab is a T-cell–bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen (BCMA) expressed on the surface of myeloma cells, activating T-cells to kill cancer cells that express the antigen.
Three BCMA-directed therapies are already on the market in the United States that carry teclistamab’s indication: the antibody-drug conjugate belantamab mafodotin (Blenrep) and two chimeric antigen receptor (CAR) T-cell therapies, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti).
The overall response rate is approximately 31% with belantamab mafodotin, 67% for idecabtagene vicleucel, and 83% for ciltacabtagene autoleucel.
Pfizer also has a bispecific BCMA-CD3–targeted antibody in development, elranatamab, for triple-class refractory multiple myeloma that is expected to compete with teclistamab.
MajesTEC-1 was funded by Janssen. Dr. Mateos is a paid speaker and consultant for the company.
A version of this article first appeared on Medscape.com.
CAR T-cell therapy neurotoxicity linked to NfL elevations
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
FROM JAMA ONCOLOGY
Novel approach brings hospice-bound MM patient into remission
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
FROM THE JOURNAL OF HEMATOLOGY & ONCOLOGY