Multiple Myeloma

Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.

Zffoto/Thinkstock

Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.

The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.

“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.

A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.

To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.

They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.

They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.

The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.

“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.

In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.

“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.

The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.

SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.

Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.

Zffoto/Thinkstock

Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.

The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.

“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.

A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.

To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.

They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.

They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.

The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.

“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.

In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.

“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.

The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.

SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.

Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.

Zffoto/Thinkstock

Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.

The investigators implicate aberrant editing of adenosine to inosine (A-to-I) in malignant plasma cells, and its effects on NEIL1, a gene that encodes proteins involved in base excision repair of DNA, as important mechanisms in multiple myeloma pathogenesis.

“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.

A-to-I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several different cancer types, the investigators noted.

To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.

They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.

They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.

The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.

“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.

In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.

“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.

The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.

SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.

Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.

But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.

The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.

At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.

During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.

The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.

Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.

Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.

But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.

The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.

At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.

During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.

The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.

Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.

Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.

But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.

The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.

At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.

During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.

The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.

Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.

Allowed costs for patients with blood cancer averaged almost $157,000 in the year after diagnosis, with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).

Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.

The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.

Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.

OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.

The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
 

[email protected]

Allowed costs for patients with blood cancer averaged almost $157,000 in the year after diagnosis, with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).

Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.

The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.

Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.

OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.

The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
 

[email protected]

Allowed costs for patients with blood cancer averaged almost $157,000 in the year after diagnosis, with costs for acute leukemia almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS).

Total allowed cost – the average amount paid by the insurer and patient combined – for acute leukemia was more than $463,000 for the 12 months after initial diagnosis. Averages for the other four cancers included in the analysis came in at $214,000 for multiple myeloma, $134,000 for bone marrow disorders, $131,000 for lymphoma, and $89,000 for chronic leukemia, the LLS said.

The cost figures are drawn from claims data for 2,332 patients diagnosed in 2014.

Differences in out-of-pocket (OOP) costs were smaller, with the average for all patients at almost $3,900 in the year after diagnosis and acute leukemia coming in the highest at $5,100. Over time, however, OOP costs for multiple myeloma patients became the highest, totaling $9,100 for the 3 years after diagnosis, compared with $8,800 for acute leukemia and an average of less than $7,800 for the other blood cancers, the LLS said in the report, which was prepared by the actuarial firm Milliman.

OOP costs also varied by the type of plan. Patients in high-deductible plans averaged nearly $5,400 for the first year after diagnosis, compared with $3,300 for those with traditional insurance, the LLS noted. For acute leukemia, the OOP costs of high-deductible plans were more than twice as high as those of traditional plans.

The study was based on data for adults aged 18-64 years from the Truven Health MarketScan commercial claims databases for the years from 2013 to 2016. The LLS received support for the study from Pfizer, Genentech, and Amgen.
 

[email protected]

Robinson of MUSC

Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).

The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.

The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.

They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”

“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.

“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”

Dr. Dolloff and his colleagues reported their discovery in Leukemia.

The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.

On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.

The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.

This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.

In vivo activity

To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ^−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.

E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.

In another experiment, two of eight mice achieved a complete response.

After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.

Molecular target of E61

Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.

Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.

Anti-MM activity of E64FC26

The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.

E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.

E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.

The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.

The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.

Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).

The investigators observed similar effects in a human xenotransplant MM model.

These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.

E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.

Single-agent bortezomib increased survival by 6 days (P=0.0007).

And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).

The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.

“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.

“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”

“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”

Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.

The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program. 

Robinson of MUSC

Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).

The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.

The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.

They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”

“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.

“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”

Dr. Dolloff and his colleagues reported their discovery in Leukemia.

The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.

On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.

The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.

This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.

In vivo activity

To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ^−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.

E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.

In another experiment, two of eight mice achieved a complete response.

After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.

Molecular target of E61

Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.

Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.

Anti-MM activity of E64FC26

The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.

E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.

E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.

The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.

The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.

Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).

The investigators observed similar effects in a human xenotransplant MM model.

These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.

E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.

Single-agent bortezomib increased survival by 6 days (P=0.0007).

And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).

The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.

“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.

“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”

“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”

Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.

The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program. 

Robinson of MUSC

Researchers say they have identified a new class of protein disulfide isomerase (PDI) inhibitors that sensitize multiple myeloma (MM) cells to proteasome inhibitors (PIs).

The investigators screened approximately 20,000 compounds spanning multiple chemical libraries and found the compound E61 to be a “striking hit,” with a six-fold increase in bortezomib cytotoxicity and the ability to re-sensitize PI activity at low micromolar concentrations.

The researchers then synthesized and evaluated 150 E61 derivatives and discovered the lead candidate, E64FC26, which was highly synergistic with PIs at concentrations as low as 200 nM.

They reported that E64FC26 has “several advantages over previously reported PDI inhibitors, including superior potency and a pan-style mode of inhibition.”

“PDI is an attractive target in oncology, but good PDI inhibitors have been hard to find,” said Nathan G. Dolloff, PhD, of the Medical University of South Carolina (MUSC) in Charleston.

“The compounds we discovered have a lot of advantages, including high potency and good drug-like properties. We hope that those strengths translate into an effective new drug that can ultimately help patients.”

Dr. Dolloff and his colleagues reported their discovery in Leukemia.

The investigators detected the synergistic effects of E61 in combination with next-generation PIs, including carfilzomib, ixazomib, and oprozomib in both PI-sensitive and -resistant MM cell lines.

On the other hand, E61 had no effect on dexamethasone activity in dexamethasone-resistant cells. And E61 did not affect lenalidomide or doxorubicin cytotoxicity in PI-resistant cells.

The researchers also determined that E61 was only active in MM cells. E61 did not enhance the cytotoxic effects of PIs in normal cells.

This selective toxicity suggests that E61 may have “a wide therapeutic index in vivo,” the investigators wrote.

In vivo activity

To investigate the anti-MM activity and tolerability of E61 in vivo, the researchers treated a NOD-SCID IL2Rγ^−/− mouse model with E61 at a continuous dose of 50 mg/kg/day.

E61 prolonged survival by 11 days in the treated mice (P=0.0007), and four of the 11 treated mice survived to the experiment’s end.

In another experiment, two of eight mice achieved a complete response.

After continuous dosing for 40 or more days, E61 was well tolerated, the investigators reported. The mice showed no overt signs of distress and did not lose weight.

Molecular target of E61

Using click (Cu(I)-catalyzed azide-alkyne cycloaddition) chemistry and a proteomics approach, the researchers then confirmed that PDI family members are the molecular target of E61.

Functional studies indicated that E61 inhibited PDI reductase activity in vitro. E61 also enhanced the accumulation of ubiquitinylated proteins and produced strong endoplasmic reticulum (ER) and oxidative stress responses when combined with PIs.

Anti-MM activity of E64FC26

The investigators used a structure activity relationship program to narrow the candidate molecules down to E64FC26.

E64FC26 demonstrated pan-inhibition in that it inhibited all members of the PDI family tested, including PDIA3, PDIA4, TXNDC5, and PDIA6.

E64FC26 also had greater in vitro potency against PDIA1 and the other PDI isoforms. It was the only compound to sensitize MM cells to PIs, with an average increase in PI sensitivity ranging from six- to seven-fold.

The researchers also noted that E64FC26 was superior to other PDI inhibitors they tested in activating ER stress.

The investigators tested the activity of E64FC26 in vivo using Vk*MYC transgenic mice, a model that closely resembles human MM.

Mice treated with E64FC26 had an immediate anti-MM response. Serum M-protein decreased in all mice by an average of 33 ± 7.9% (P=0.0135).

The investigators observed similar effects in a human xenotransplant MM model.

These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.

E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.

Single-agent bortezomib increased survival by 6 days (P=0.0007).

And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).

The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.

“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.

“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”

“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”

Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.

The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program. 

PixCell Medical

The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.

This portable hematology analyzer is used to perform a complete blood count at the point of care.

HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.

HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.

Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.

“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.

He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.

HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.

PixCell Medical

The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.

This portable hematology analyzer is used to perform a complete blood count at the point of care.

HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.

HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.

Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.

“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.

He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.

HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.

PixCell Medical

The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance for PixCell Medical’s HemoScreen™.

This portable hematology analyzer is used to perform a complete blood count at the point of care.

HemoScreen requires a single drop of blood and uses disposable cartridges that provide automatic sample preparation.

HemoScreen can analyze 20 standard complete blood count parameters and produces results within 5 minutes.

Study results suggested that HemoScreen provides results comparable to those of another hematology analyzer, Sysmex XE-2100. This study was published in the Journal of Clinical Pathology in 2016.

“The HemoScreen delivers lab-accurate results,” said Avishay Bransky, PhD, chief executive officer of PixCell Medical.

He added that HemoScreen “would be especially useful” in physicians’ offices, emergency rooms, intensive care units, oncology clinics, and remote locations.

HemoScreen makes use of a technology called viscoelastic focusing, which employs microfluidics and machine vision algorithms to analyze cells.

Patients with multiple myeloma who did not respond to treatment with lenalidomide and a proteasome inhibitor had a significantly lower risk of progression or death when receiving elotuzumab plus pomalidomide and dexamethasone, compared with pomalidomide and dexamethasone alone (hazard ratio, 0.54; 95% confidence interval, 0.34-0.86; P = .008), according to results of a multicenter, randomized, open-label, phase 2 trial published in the New England Journal of Medicine 2018 Nov 7. doi: 10.1056/NEJMoa1805762.

Study results of ELOQUENT-3 were presented earlier this year at the Annual Congress of the European Hematology Association.

[email protected]

Patients with multiple myeloma who did not respond to treatment with lenalidomide and a proteasome inhibitor had a significantly lower risk of progression or death when receiving elotuzumab plus pomalidomide and dexamethasone, compared with pomalidomide and dexamethasone alone (hazard ratio, 0.54; 95% confidence interval, 0.34-0.86; P = .008), according to results of a multicenter, randomized, open-label, phase 2 trial published in the New England Journal of Medicine 2018 Nov 7. doi: 10.1056/NEJMoa1805762.

Study results of ELOQUENT-3 were presented earlier this year at the Annual Congress of the European Hematology Association.

[email protected]

Patients with multiple myeloma who did not respond to treatment with lenalidomide and a proteasome inhibitor had a significantly lower risk of progression or death when receiving elotuzumab plus pomalidomide and dexamethasone, compared with pomalidomide and dexamethasone alone (hazard ratio, 0.54; 95% confidence interval, 0.34-0.86; P = .008), according to results of a multicenter, randomized, open-label, phase 2 trial published in the New England Journal of Medicine 2018 Nov 7. doi: 10.1056/NEJMoa1805762.

Study results of ELOQUENT-3 were presented earlier this year at the Annual Congress of the European Hematology Association.

[email protected]

The Food and Drug Administration has approved elotuzumab (Empliciti) in combination with pomalidomide and dexamethasone for adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is already approved in combination with lenalidomide and dexamethasone to treat adult myeloma patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from ELOQUENT-3. This phase 2 trial enrolled multiple myeloma patients who had refractory or relapsed disease and had received both lenalidomide and a proteasome inhibitor.

In the trial, patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n = 60) or pomalidomide and dexamethasone (Pd, n = 57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P = .0029); the rate of complete response or stringent complete response was 8.3% and 1.8%, respectively.


Median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (P = .0078).

Serious adverse events occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious adverse events were pneumonia and respiratory tract infection.

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available on the Empliciti website.

Bristol-Myers Squibb and AbbVie are codeveloping elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

[email protected]

The Food and Drug Administration has approved elotuzumab (Empliciti) in combination with pomalidomide and dexamethasone for adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is already approved in combination with lenalidomide and dexamethasone to treat adult myeloma patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from ELOQUENT-3. This phase 2 trial enrolled multiple myeloma patients who had refractory or relapsed disease and had received both lenalidomide and a proteasome inhibitor.

In the trial, patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n = 60) or pomalidomide and dexamethasone (Pd, n = 57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P = .0029); the rate of complete response or stringent complete response was 8.3% and 1.8%, respectively.


Median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (P = .0078).

Serious adverse events occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious adverse events were pneumonia and respiratory tract infection.

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available on the Empliciti website.

Bristol-Myers Squibb and AbbVie are codeveloping elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

[email protected]

The Food and Drug Administration has approved elotuzumab (Empliciti) in combination with pomalidomide and dexamethasone for adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is already approved in combination with lenalidomide and dexamethasone to treat adult myeloma patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from ELOQUENT-3. This phase 2 trial enrolled multiple myeloma patients who had refractory or relapsed disease and had received both lenalidomide and a proteasome inhibitor.

In the trial, patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n = 60) or pomalidomide and dexamethasone (Pd, n = 57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P = .0029); the rate of complete response or stringent complete response was 8.3% and 1.8%, respectively.


Median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (P = .0078).

Serious adverse events occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious adverse events were pneumonia and respiratory tract infection.

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available on the Empliciti website.

Bristol-Myers Squibb and AbbVie are codeveloping elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

[email protected]

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

In multiple myeloma patients who have no matched donor, haploidentical allogeneic transplantation is feasible and has an acceptable rate of non-relapse mortality in comparison to donor-based transplants, investigators have reported.

The rate of non-relapse mortality at one year was 21% in the retrospective analysis of 96 patients, recently reported in the journal Biology of Blood and Marrow Transplantation.

Haploidentical allogeneic hematopoietic stem cell transplant (allo-HCT) is currently limited in use due to a high rate of relapse, but may hold potential promise for future applications, according to Firoozeh Sahebi, MD, a hematologist with the City of Hope Medical Center, Duarte, Calif., and colleagues. “Our results demonstrate that haploidentical allo-HCT can be safely performed in appropriate patients with MM who lack on HLA-matched sibling or unrelated donor.”

“The allo-HCT platform can be used in the context of other post-transplantation immune-based strategies, such as donor-derived chimeric antigen receptor T cells and natural killer cell infusions, newer immunomodulatory drugs or proteasome inhibitors, bispecific T cell engagers, and bispecific killer cell engagers, to further enhance antitumor effects and ultimately improve survival in an appropriate patient population,” Dr. Sahebi and colleagues said in their report.

The investigators reported results of a retrospective analysis including 96 patients with relapsed multiple myeloma who had failed at least one previous autologous HCT. They underwent haploidentical allo-HCT at European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers between 2008 and 2016.

Median follow-up in the analysis was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, while 75% had recovery of platelets by day 60, Dr. Sahebi and co-investigators reported.

The 1-year nonrelapse mortality rate was 21%, but the cumulative risk of relapse and progression at 2 years was 56%, according to the study results. Two-year progression-free survival was reported to be 17%, while overall survival was 48%.

Acute graft-versus-host-disease (GVHD) of grades II-IV occurred in 39% by 100 days, while chronic GVHD was seen in 46% at 2 years, the report shows.

Factors linked to improved overall survival at 2 years included use of bone marrow as the source of stem cells, and the use of cyclophosphamide after transplantation, according to Dr. Sahebi and co-authors.

By contrast, factors that had no impact on overall survival, progression-free survival, or non-relapse mortality included disease status (ie, degree of response), gender, conditioning regimen intensity, presence of cytomegalovirus in the blood, or donor-recipient sex mismatch.

This analysis was conducted in part due to the limited availability of matched donors, along with the promising results of allo-HCT in other malignancies, according to investigators.

There were no conflicts of interest to report related to this research, Dr. Sahebi and colleagues reported in the journal.
 

SOURCE: Sahebi F, et al. Biol Blood Marrow Transplant. 2018 Sep 20. pii: S1083-8791(18)30575-5.

In multiple myeloma patients who have no matched donor, haploidentical allogeneic transplantation is feasible and has an acceptable rate of non-relapse mortality in comparison to donor-based transplants, investigators have reported.

The rate of non-relapse mortality at one year was 21% in the retrospective analysis of 96 patients, recently reported in the journal Biology of Blood and Marrow Transplantation.

Haploidentical allogeneic hematopoietic stem cell transplant (allo-HCT) is currently limited in use due to a high rate of relapse, but may hold potential promise for future applications, according to Firoozeh Sahebi, MD, a hematologist with the City of Hope Medical Center, Duarte, Calif., and colleagues. “Our results demonstrate that haploidentical allo-HCT can be safely performed in appropriate patients with MM who lack on HLA-matched sibling or unrelated donor.”

“The allo-HCT platform can be used in the context of other post-transplantation immune-based strategies, such as donor-derived chimeric antigen receptor T cells and natural killer cell infusions, newer immunomodulatory drugs or proteasome inhibitors, bispecific T cell engagers, and bispecific killer cell engagers, to further enhance antitumor effects and ultimately improve survival in an appropriate patient population,” Dr. Sahebi and colleagues said in their report.

The investigators reported results of a retrospective analysis including 96 patients with relapsed multiple myeloma who had failed at least one previous autologous HCT. They underwent haploidentical allo-HCT at European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers between 2008 and 2016.

Median follow-up in the analysis was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, while 75% had recovery of platelets by day 60, Dr. Sahebi and co-investigators reported.

The 1-year nonrelapse mortality rate was 21%, but the cumulative risk of relapse and progression at 2 years was 56%, according to the study results. Two-year progression-free survival was reported to be 17%, while overall survival was 48%.

Acute graft-versus-host-disease (GVHD) of grades II-IV occurred in 39% by 100 days, while chronic GVHD was seen in 46% at 2 years, the report shows.

Factors linked to improved overall survival at 2 years included use of bone marrow as the source of stem cells, and the use of cyclophosphamide after transplantation, according to Dr. Sahebi and co-authors.

By contrast, factors that had no impact on overall survival, progression-free survival, or non-relapse mortality included disease status (ie, degree of response), gender, conditioning regimen intensity, presence of cytomegalovirus in the blood, or donor-recipient sex mismatch.

This analysis was conducted in part due to the limited availability of matched donors, along with the promising results of allo-HCT in other malignancies, according to investigators.

There were no conflicts of interest to report related to this research, Dr. Sahebi and colleagues reported in the journal.
 

SOURCE: Sahebi F, et al. Biol Blood Marrow Transplant. 2018 Sep 20. pii: S1083-8791(18)30575-5.

In multiple myeloma patients who have no matched donor, haploidentical allogeneic transplantation is feasible and has an acceptable rate of non-relapse mortality in comparison to donor-based transplants, investigators have reported.

The rate of non-relapse mortality at one year was 21% in the retrospective analysis of 96 patients, recently reported in the journal Biology of Blood and Marrow Transplantation.

Haploidentical allogeneic hematopoietic stem cell transplant (allo-HCT) is currently limited in use due to a high rate of relapse, but may hold potential promise for future applications, according to Firoozeh Sahebi, MD, a hematologist with the City of Hope Medical Center, Duarte, Calif., and colleagues. “Our results demonstrate that haploidentical allo-HCT can be safely performed in appropriate patients with MM who lack on HLA-matched sibling or unrelated donor.”

“The allo-HCT platform can be used in the context of other post-transplantation immune-based strategies, such as donor-derived chimeric antigen receptor T cells and natural killer cell infusions, newer immunomodulatory drugs or proteasome inhibitors, bispecific T cell engagers, and bispecific killer cell engagers, to further enhance antitumor effects and ultimately improve survival in an appropriate patient population,” Dr. Sahebi and colleagues said in their report.

The investigators reported results of a retrospective analysis including 96 patients with relapsed multiple myeloma who had failed at least one previous autologous HCT. They underwent haploidentical allo-HCT at European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers between 2008 and 2016.

Median follow-up in the analysis was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, while 75% had recovery of platelets by day 60, Dr. Sahebi and co-investigators reported.

The 1-year nonrelapse mortality rate was 21%, but the cumulative risk of relapse and progression at 2 years was 56%, according to the study results. Two-year progression-free survival was reported to be 17%, while overall survival was 48%.

Acute graft-versus-host-disease (GVHD) of grades II-IV occurred in 39% by 100 days, while chronic GVHD was seen in 46% at 2 years, the report shows.

Factors linked to improved overall survival at 2 years included use of bone marrow as the source of stem cells, and the use of cyclophosphamide after transplantation, according to Dr. Sahebi and co-authors.

By contrast, factors that had no impact on overall survival, progression-free survival, or non-relapse mortality included disease status (ie, degree of response), gender, conditioning regimen intensity, presence of cytomegalovirus in the blood, or donor-recipient sex mismatch.

This analysis was conducted in part due to the limited availability of matched donors, along with the promising results of allo-HCT in other malignancies, according to investigators.

There were no conflicts of interest to report related to this research, Dr. Sahebi and colleagues reported in the journal.
 

SOURCE: Sahebi F, et al. Biol Blood Marrow Transplant. 2018 Sep 20. pii: S1083-8791(18)30575-5.

Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.

They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.

And these subtypes are driving the disparity in MM diagnoses between the populations.

Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.

“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.

All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.

Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.

Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.

Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.

Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).

The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.

Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.

The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.

The team observed no significant differences when the cutoff for African ancestry was greater than 50%.

The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.

SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.

Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.

They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.

And these subtypes are driving the disparity in MM diagnoses between the populations.

Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.

“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.

All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.

Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.

Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.

Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.

Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).

The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.

Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.

The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.

The team observed no significant differences when the cutoff for African ancestry was greater than 50%.

The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.

SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.

Researchers say they may have determined why African Americans have a two- to threefold increased risk of multiple myeloma (MM), compared with European Americans.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The team genotyped 881 MM samples from various racial groups and identified three gene subtypes – t(11;14), t(14;16), and t(14;20) – that explain the racial disparity.

They found that patients with African ancestry of 80% or more had a significantly higher occurrence of these subtypes, compared with individuals with African ancestry of less than 0.1%.

And these subtypes are driving the disparity in MM diagnoses between the populations.

Previous attempts to explain the disparity relied on self-reported race rather than quantitatively measured genetic ancestry, which could result in bias, Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., and his colleagues reported in Blood Cancer Journal.

“A major new aspect of this study is that we identified the ancestry of each patient through DNA sequencing, which allowed us to determine ancestry more accurately,” Dr. Rajkumar said in a statement.

All 881 samples had abnormal plasma cell FISH, 851 had a normal chromosome study, and 30 had an abnormal study.

Median age for the entire group was 64 years. More samples were from men (54.3%) than women (45.7%). Researchers observed no significant difference between men and women in the proportion of primary cytogenetic abnormalities.

Of the 881 samples, the median African ancestry was 2.3%, the median European ancestry was 64.7%, and Northern European ancestry was 26.6%.

Thirty percent of the entire cohort had less than 0.1% African ancestry, and 13.6% had 80% or greater African ancestry.

Using a logistic regression model, the researchers determined that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting t(11;14), t(14;16), or t(14;20) odds ratio, 1.06; 95% confidence interval, 1.02-1.11; P = .05).

The researchers plotted the probability of observing these cytogenetic abnormalities with the percentage of African ancestry and found the differences were most striking in the extreme populations – individuals with 80% or greater African ancestry and individuals with less than 0.1% African ancestry.

Upon further analysis, the team found a significantly higher prevalence of t(11;14), t(14;16), and t(14;20) in the group of patients with the greatest proportion of African ancestry (P = .008), compared with the European cohort.

The differences emerged in only the highest and lowest cohorts, they noted. Most patients (60%) were not included in these extreme populations because they had mixed ancestry.

The team observed no significant differences when the cutoff for African ancestry was greater than 50%.

The research was supported by the National Cancer Institute and the Mayo Clinic. One study author reported relationships with Celgene, Takeda, Prothena, Janssen, Pfizer, Alnylam, and GSK. Two authors reported relationships with the DNA Diagnostics Center.

SOURCE: Baughn LB et al. Blood Cancer J. 2018 Oct 10;8(10):96.