Multiple Myeloma

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Bisphosphonates should be prescribed for any patient receiving treatment for active multiple myeloma, regardless of whether or not there is evidence of lytic bone destruction or spinal compression fracture, according to updated guidelines from the American Society of Clinical Oncology.

Previous guidelines from the society, last updated in 2007, recommended the use of intravenous bisphosphonates for patients with myeloma with evidence of bone disease, according to the expert panel that drafted the update.

[email protected]

SOURCE: Anderson K et al. J Clin Oncol. 2018 Jan 17:JCO2017766402. doi: 10.1200/JCO.2017.76.6402.

Bisphosphonates should be prescribed for any patient receiving treatment for active multiple myeloma, regardless of whether or not there is evidence of lytic bone destruction or spinal compression fracture, according to updated guidelines from the American Society of Clinical Oncology.

Previous guidelines from the society, last updated in 2007, recommended the use of intravenous bisphosphonates for patients with myeloma with evidence of bone disease, according to the expert panel that drafted the update.

[email protected]

SOURCE: Anderson K et al. J Clin Oncol. 2018 Jan 17:JCO2017766402. doi: 10.1200/JCO.2017.76.6402.

Bisphosphonates should be prescribed for any patient receiving treatment for active multiple myeloma, regardless of whether or not there is evidence of lytic bone destruction or spinal compression fracture, according to updated guidelines from the American Society of Clinical Oncology.

Previous guidelines from the society, last updated in 2007, recommended the use of intravenous bisphosphonates for patients with myeloma with evidence of bone disease, according to the expert panel that drafted the update.

[email protected]

SOURCE: Anderson K et al. J Clin Oncol. 2018 Jan 17:JCO2017766402. doi: 10.1200/JCO.2017.76.6402.

Longer duration of second-line therapy is strongly linked to improved 1-year overall survival in patients with relapsed and refractory multiple myeloma, according to findings from a real-world analysis.

The retrospective, observational study evaluated outcomes in 628 patients with multiple myeloma who relapsed after initial treatment. Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee and his colleagues sought to test the growing consensus that prolonged therapy is the best approach in a cohort of patients who received care in a routine setting and were older and had more comorbidities than patients in clinical trials.

Nephron/Wikimedia Commons

“Despite substantial heterogeneity in patient and disease characteristics and treatment patterns, the clinical benefit of continued longer-term therapy at relapse appears to be generalizable to patients receiving care in the routine care settings,” the researchers wrote.

Takeda funded the study and four of the authors are Takeda employees. Dr. Hari reported fees from Takeda and several other pharmaceutical companies.

[email protected]

SOURCE: Hari P et al. Clin Lymphoma Myeloma Leuk. 2018 Jan 5. doi: 10.1016/j.clml.2017.12.012.

Longer duration of second-line therapy is strongly linked to improved 1-year overall survival in patients with relapsed and refractory multiple myeloma, according to findings from a real-world analysis.

The retrospective, observational study evaluated outcomes in 628 patients with multiple myeloma who relapsed after initial treatment. Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee and his colleagues sought to test the growing consensus that prolonged therapy is the best approach in a cohort of patients who received care in a routine setting and were older and had more comorbidities than patients in clinical trials.

Nephron/Wikimedia Commons

“Despite substantial heterogeneity in patient and disease characteristics and treatment patterns, the clinical benefit of continued longer-term therapy at relapse appears to be generalizable to patients receiving care in the routine care settings,” the researchers wrote.

Takeda funded the study and four of the authors are Takeda employees. Dr. Hari reported fees from Takeda and several other pharmaceutical companies.

[email protected]

SOURCE: Hari P et al. Clin Lymphoma Myeloma Leuk. 2018 Jan 5. doi: 10.1016/j.clml.2017.12.012.

Longer duration of second-line therapy is strongly linked to improved 1-year overall survival in patients with relapsed and refractory multiple myeloma, according to findings from a real-world analysis.

The retrospective, observational study evaluated outcomes in 628 patients with multiple myeloma who relapsed after initial treatment. Parameswaran Hari, MD, of the Medical College of Wisconsin in Milwaukee and his colleagues sought to test the growing consensus that prolonged therapy is the best approach in a cohort of patients who received care in a routine setting and were older and had more comorbidities than patients in clinical trials.

Nephron/Wikimedia Commons

“Despite substantial heterogeneity in patient and disease characteristics and treatment patterns, the clinical benefit of continued longer-term therapy at relapse appears to be generalizable to patients receiving care in the routine care settings,” the researchers wrote.

Takeda funded the study and four of the authors are Takeda employees. Dr. Hari reported fees from Takeda and several other pharmaceutical companies.

[email protected]

SOURCE: Hari P et al. Clin Lymphoma Myeloma Leuk. 2018 Jan 5. doi: 10.1016/j.clml.2017.12.012.

Washington University

Preclinical research suggests that light-triggered, chemotherapy-loaded nanoparticles could treat multiple myeloma (MM) and other malignancies.

Researchers showed that light emitted as part of traditional cancer-imaging techniques could also trigger a light-sensitive chemotherapy drug.

When this drug was packaged into nanoparticles that target lit-up cancer cells, the drug produced toxic free radicals that killed the cancer cells.

Researchers found this technique to be effective in mice with MM and aggressive, metastatic breast cancer.

“Our study shows that this phototherapeutic technology is particularly suited to attacking small tumors that spread to different parts of the body, including deep in the bone marrow,” said Samuel Achilefu, PhD, of Washington University in St. Louis, Missouri.

Dr Achilefu and his colleagues described the technology in Nature Communications.

The technology harnesses the chemotherapy drug titanocene. When used alone, titanocene did not work well in clinical trials, even at relatively high doses. However, when it is exposed to the radiation emitted by visible light, titanocene produces reactive particles that are toxic to cells, even at low doses.

Dr Achilefu and his colleagues packaged low doses of titanocene inside nanoparticles targeted to proteins on the surface of cancer cells. Specifically, the team used nanomicelles targeting VLA-4, “an attractive target for precision imaging and therapy” in MM, according to the researchers.

When these nanomicelles made contact with MM cells, their membranes fused together, releasing titanocene into the cells.

The researchers then delivered the imaging agent fluorodeoxyglucose (FDG). MM cells took up the FDG at high rates, causing the cells to glow in a positron emission tomography scan. This glow also triggered the titanocene, releasing free radicals and killing the MM cells.

This treatment strategy was used on mice with MM once a week for 4 weeks. In the weeks following, the treated mice had significantly smaller tumors and survived longer than control mice. Fifty percent of treated mice survived at least 90 days, and 50% of control mice survived 62 days.

This strategy also produced an anti-tumor effect in mice with breast cancer, although, in these experiments, the researchers used human serum albumin nanoparticles.

The effect in breast cancer was less pronounced than in MM. The researchers said this was likely due to the extreme aggressiveness of the breast cancer cell line used.

The team also found that certain MM cells were resistant to this treatment technique.

“This is an opportunity to learn because it’s similar to what is seen in patients—some of the cells become dormant but don’t die after treatment,” Dr Achilefu said. “When we looked closer at the cells that were resistant to our phototherapy, we saw that the surface protein we are targeting was not there.”

Specifically, the resistant cells had downregulated expression of CD49d, and the researchers believe this may have impaired the binding of nanomicelles to the MM cells.

“So next, we want to find out if we can pinpoint another surface protein to target and kill these resistant cells along with the myeloma cells that did respond to the original therapy, which could lead to complete remission,” Dr Achilefu said.

Furthermore, Dr Achilefu envisions that, one day, doctors might be able to use this technology to prevent cancer from recurring.

“We are interested in exploring whether this is something a patient in remission could take once a year for prevention,” Dr Achilefu said. “The toxicity appears to be low, so we imagine an outpatient procedure that could involve zapping any cancerous cells, making cancer a chronic condition that could be controlled long-term.”

Dr Achilefu and his colleagues believe this phototherapeutic technology is less toxic than standard radiation and chemotherapy because the titanocene and FDG are targeted to the same place at the same time only in cancer cells.

The body rids itself of titanocene through the liver, while FDG is cleared through the kidneys. The fact that these components are disposed of separately minimizes damage to other organs. When separated, the components are not toxic, according to the researchers.

Washington University

Preclinical research suggests that light-triggered, chemotherapy-loaded nanoparticles could treat multiple myeloma (MM) and other malignancies.

Researchers showed that light emitted as part of traditional cancer-imaging techniques could also trigger a light-sensitive chemotherapy drug.

When this drug was packaged into nanoparticles that target lit-up cancer cells, the drug produced toxic free radicals that killed the cancer cells.

Researchers found this technique to be effective in mice with MM and aggressive, metastatic breast cancer.

“Our study shows that this phototherapeutic technology is particularly suited to attacking small tumors that spread to different parts of the body, including deep in the bone marrow,” said Samuel Achilefu, PhD, of Washington University in St. Louis, Missouri.

Dr Achilefu and his colleagues described the technology in Nature Communications.

The technology harnesses the chemotherapy drug titanocene. When used alone, titanocene did not work well in clinical trials, even at relatively high doses. However, when it is exposed to the radiation emitted by visible light, titanocene produces reactive particles that are toxic to cells, even at low doses.

Dr Achilefu and his colleagues packaged low doses of titanocene inside nanoparticles targeted to proteins on the surface of cancer cells. Specifically, the team used nanomicelles targeting VLA-4, “an attractive target for precision imaging and therapy” in MM, according to the researchers.

When these nanomicelles made contact with MM cells, their membranes fused together, releasing titanocene into the cells.

The researchers then delivered the imaging agent fluorodeoxyglucose (FDG). MM cells took up the FDG at high rates, causing the cells to glow in a positron emission tomography scan. This glow also triggered the titanocene, releasing free radicals and killing the MM cells.

This treatment strategy was used on mice with MM once a week for 4 weeks. In the weeks following, the treated mice had significantly smaller tumors and survived longer than control mice. Fifty percent of treated mice survived at least 90 days, and 50% of control mice survived 62 days.

This strategy also produced an anti-tumor effect in mice with breast cancer, although, in these experiments, the researchers used human serum albumin nanoparticles.

The effect in breast cancer was less pronounced than in MM. The researchers said this was likely due to the extreme aggressiveness of the breast cancer cell line used.

The team also found that certain MM cells were resistant to this treatment technique.

“This is an opportunity to learn because it’s similar to what is seen in patients—some of the cells become dormant but don’t die after treatment,” Dr Achilefu said. “When we looked closer at the cells that were resistant to our phototherapy, we saw that the surface protein we are targeting was not there.”

Specifically, the resistant cells had downregulated expression of CD49d, and the researchers believe this may have impaired the binding of nanomicelles to the MM cells.

“So next, we want to find out if we can pinpoint another surface protein to target and kill these resistant cells along with the myeloma cells that did respond to the original therapy, which could lead to complete remission,” Dr Achilefu said.

Furthermore, Dr Achilefu envisions that, one day, doctors might be able to use this technology to prevent cancer from recurring.

“We are interested in exploring whether this is something a patient in remission could take once a year for prevention,” Dr Achilefu said. “The toxicity appears to be low, so we imagine an outpatient procedure that could involve zapping any cancerous cells, making cancer a chronic condition that could be controlled long-term.”

Dr Achilefu and his colleagues believe this phototherapeutic technology is less toxic than standard radiation and chemotherapy because the titanocene and FDG are targeted to the same place at the same time only in cancer cells.

The body rids itself of titanocene through the liver, while FDG is cleared through the kidneys. The fact that these components are disposed of separately minimizes damage to other organs. When separated, the components are not toxic, according to the researchers.

Washington University

Preclinical research suggests that light-triggered, chemotherapy-loaded nanoparticles could treat multiple myeloma (MM) and other malignancies.

Researchers showed that light emitted as part of traditional cancer-imaging techniques could also trigger a light-sensitive chemotherapy drug.

When this drug was packaged into nanoparticles that target lit-up cancer cells, the drug produced toxic free radicals that killed the cancer cells.

Researchers found this technique to be effective in mice with MM and aggressive, metastatic breast cancer.

“Our study shows that this phototherapeutic technology is particularly suited to attacking small tumors that spread to different parts of the body, including deep in the bone marrow,” said Samuel Achilefu, PhD, of Washington University in St. Louis, Missouri.

Dr Achilefu and his colleagues described the technology in Nature Communications.

The technology harnesses the chemotherapy drug titanocene. When used alone, titanocene did not work well in clinical trials, even at relatively high doses. However, when it is exposed to the radiation emitted by visible light, titanocene produces reactive particles that are toxic to cells, even at low doses.

Dr Achilefu and his colleagues packaged low doses of titanocene inside nanoparticles targeted to proteins on the surface of cancer cells. Specifically, the team used nanomicelles targeting VLA-4, “an attractive target for precision imaging and therapy” in MM, according to the researchers.

When these nanomicelles made contact with MM cells, their membranes fused together, releasing titanocene into the cells.

The researchers then delivered the imaging agent fluorodeoxyglucose (FDG). MM cells took up the FDG at high rates, causing the cells to glow in a positron emission tomography scan. This glow also triggered the titanocene, releasing free radicals and killing the MM cells.

This treatment strategy was used on mice with MM once a week for 4 weeks. In the weeks following, the treated mice had significantly smaller tumors and survived longer than control mice. Fifty percent of treated mice survived at least 90 days, and 50% of control mice survived 62 days.

This strategy also produced an anti-tumor effect in mice with breast cancer, although, in these experiments, the researchers used human serum albumin nanoparticles.

The effect in breast cancer was less pronounced than in MM. The researchers said this was likely due to the extreme aggressiveness of the breast cancer cell line used.

The team also found that certain MM cells were resistant to this treatment technique.

“This is an opportunity to learn because it’s similar to what is seen in patients—some of the cells become dormant but don’t die after treatment,” Dr Achilefu said. “When we looked closer at the cells that were resistant to our phototherapy, we saw that the surface protein we are targeting was not there.”

Specifically, the resistant cells had downregulated expression of CD49d, and the researchers believe this may have impaired the binding of nanomicelles to the MM cells.

“So next, we want to find out if we can pinpoint another surface protein to target and kill these resistant cells along with the myeloma cells that did respond to the original therapy, which could lead to complete remission,” Dr Achilefu said.

Furthermore, Dr Achilefu envisions that, one day, doctors might be able to use this technology to prevent cancer from recurring.

“We are interested in exploring whether this is something a patient in remission could take once a year for prevention,” Dr Achilefu said. “The toxicity appears to be low, so we imagine an outpatient procedure that could involve zapping any cancerous cells, making cancer a chronic condition that could be controlled long-term.”

Dr Achilefu and his colleagues believe this phototherapeutic technology is less toxic than standard radiation and chemotherapy because the titanocene and FDG are targeted to the same place at the same time only in cancer cells.

The body rids itself of titanocene through the liver, while FDG is cleared through the kidneys. The fact that these components are disposed of separately minimizes damage to other organs. When separated, the components are not toxic, according to the researchers.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.

This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).

Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.

The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.

The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.

The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.

The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.

This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).

Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.

The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.

The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.

The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.

The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.

This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).

Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.

The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.

The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.

The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.

The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

Photo by Rhoda Baer

Treatment costs are the greatest threat to the growth of cancer programs, according to a survey of nearly 300 cancer program administrators and providers.

Sixty-eight percent of survey respondents said treatment costs were among the biggest threats to future cancer program growth at their organization.

Other top threats to growth included physician alignment around services and program goals—cited by 47% of respondents—and changes in healthcare coverage—cited by 46%.

This survey—the “2017 Trending Now in Cancer Care Survey”—was conducted by the Association of Community Cancer Centers (ACCC) and Advisory Board’s Oncology Roundtable. It was supported by Pfizer Oncology.

The survey was distributed via email on July 24, 2017. Respondents included 293 cancer program administrators and providers from 209 institutions. They submitted responses over 6 weeks.

Respondents identified the following “biggest threats” to cancer program growth:

• Cost of drugs and/or new treatment modalities—68%
• Physician alignment around services and program goals—47%
• Changes in healthcare coverage—46%
• Cuts to fee-for-service reimbursement—44%
• Shifting reimbursement to value-based care—43%
• Marketplace competition—35%
• Workforce planning (eg, managing staff shortages)—34%
• Network strategy and integration—33%
• Site of care policies issued by private payers—27%
• Access to capital—26%
• Quality reporting requirements—22%
• Health information technology—21%
• Other—6%.

When asked to identify their greatest opportunities for cost savings, respondents overwhelmingly pointed toward clinical standardization (63%) and drugs (62%).

Other opportunities included:

• Supplies—28%
• Capital expenses (eg, imaging technology)—24%
• Non-clinical staff (eg, billing and coding specialists)—22%
• Technology maintenance—20%
• Clinical staff—16%
• Retail pharmacy—14%
• Clinical research—10%
• Support services (eg, acupuncture)—9%
• Other—4%.

Respondents also said the investments most likely to yield a return for their cancer program were:

• Increasing the number of sub-specialists (eg, breast surgeons)—59%
• Marketing—41%
• Specialty pharmacy—36%
• Increasing the number of general oncology physicians—34%
• Screening services (eg, mobile screening unit)—29%
• Capital investments—24%
• Clinical research—16%
• Support services—15%
• Retail pharmacy—14%
• Building upgrades—14%.

More details on the “2017 Trending Now in Cancer Care Survey” can be found on the ACCC website.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

After decades of hype, dashed hopes, and setbacks, gene therapy has finally arrived and is poised to transform the treatment paradigm for many diseases, according to Cynthia E. Dunbar, MD, senior investigator at the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Hematologists can expect more developments that build on current successes with chimeric antigen receptor (CAR) T-cell therapy and gene therapy advances for hemophilia, as well as emerging advances in gene editing techniques including the CRISPR/Cas9 approach, Dr. Dunbar said in an interview.

Courtesy National Heart, Lung, and Blood Institute

Milestones

A new approach to cancer treatment was ushered in on Aug. 30, 2017, with the Food and Drug Administration approval of tisagenlecleucel, the first-ever gene therapy available in the United States. The CD19-directed CAR T-cell therapy is indicated for treatment of certain pediatric or young adult patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Soon afterward, FDA approved another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, for adult patients with large B-cell lymphoma after two or more lines of systemic therapy.

“It’s a very interesting time for immunotherapies in general,” Dr. Dunbar said. “There’s a huge number of options in terms of PD-1 inhibitors and other pharmacologics or antibodies that allow the patient’s own immune system to attack tumors. CAR T-cell therapy is an obvious step beyond that, in terms of arming your own T cells to very specifically target tumor cells.”

But randomized trials or meta-analyses may be necessary to determine the place of CAR T-cell therapy in the treatment armamentarium for acute lymphoblastic leukemia and large B-cell lymphoma given their cost and the availability of other therapeutic options, Dr. Dunbar suggested.

“Gene therapies have a large upfront cost, but if they’re truly curative and a one-time treatment, then they may in the long run be much cheaper than doing failed multiple transplants or needing monoclonal antibody infusion every 2 weeks for the rest of your life,” she said.

Another major success story still in the works, according to Dr. Dunbar, is the treatment of hemophilia A and B with gene therapy approaches. The positive data include a recent report showing that transgene-derived factor IX coagulant activity allowed for the termination of baseline prophylaxis, and the near elimination of bleeding and factor use, in patients with hemophilia B (N Engl J Med. 2017 Dec 7;377[23]:2215-27).

While gene therapy for hemophilia A has been more challenging, another recent report nevertheless demonstrated sustained normalization of factor VIII activity level with a single intravenous infusion of adeno-associated virus serotype 5 vector encoding a B-domain–deleted human factor VIII (N Engl J Med. 2017 Dec 28;377[26]:2519-30).

“The proof-of-principle was already there in hemophilia B,” Dr. Dunbar said. “It really was just a question of figuring out a way to package and deliver a Factor VIII that would work in the constraints of an AAV [adeno-associated virus] vector.”

Meanwhile, myeloma trials of CAR T-cell therapy seem very promising so far, but the challenge in that disease could be finding a place for gene therapy in a “much more diverse treatment landscape” that includes multiple effective regimens, according to Dr. Dunbar.
 

Future trends, challenges

Looking forward, gene editing with methods including the CRISPR/Cas9 approach have the potential to revolutionize treatment in HIV, b-thalassemia, and sickle cell disease, she said.

Notably, genome editing approaches to treat sickle cell anemia are likely to move forward in the near future, according to Dr. Dunbar, following reports validating an erythroid enhancer of human BCL11A as a target for reinduction of fetal hemoglobin (Nature. 2015 Nov 12;527[7577]:192-7).

But all of this gene therapy development creates an educational challenge for frontline clinicians, even if the administration of CAR T-cell therapy and other advanced treatments is limited to highly specialized centers.

“There’s a lot of training that needs to go on with hematologists, oncologists, and other doctors about how to care for these patients after these treatments, in terms of what to look for and how to intervene early to prevent, for instance, severe toxicity from cytokine release syndrome,” Dr. Dunbar said.

Dr. Dunbar reported having no relevant financial disclosures.

The Food and Drug Administration has granted priority review for daratumumab, a monoclonal antibody treatment for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplant.

The current application is based on the randomized, multicenter, phase 3 ALCYONE study of daratumumab in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) in de novo multiple myeloma patients.

Daratumumab is being developed by Janssen Biotech, in partnership with Genmab.

[email protected]

The Food and Drug Administration has granted priority review for daratumumab, a monoclonal antibody treatment for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplant.

The current application is based on the randomized, multicenter, phase 3 ALCYONE study of daratumumab in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) in de novo multiple myeloma patients.

Daratumumab is being developed by Janssen Biotech, in partnership with Genmab.

[email protected]

The Food and Drug Administration has granted priority review for daratumumab, a monoclonal antibody treatment for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplant.

The current application is based on the randomized, multicenter, phase 3 ALCYONE study of daratumumab in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) in de novo multiple myeloma patients.

Daratumumab is being developed by Janssen Biotech, in partnership with Genmab.

[email protected]

The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.

The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.

Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.

The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.

The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.

Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.

“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.

They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”

During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).

The overall risk of progression to a plasma cell–related disorder was 10% at 10 years; 18% at 20 years; 28% at 30 years; 36% at 35 years, and 36% at 40 years.

Among patients with IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.

Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.

Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).

“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.

The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”

The study was funded in part by the National Cancer Institute.

Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.

[email protected]

SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
  

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
  

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for daratumumab (Darzalex®).

This sBLA is for daratumumab (D) to be used in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The FDA expects to make a decision on the sBLA by May 21, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on data from the phase 3 ALCYONE study, which were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this study, researchers compared VMP to D-VMP in 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.

D-VMP produced deeper responses than VMP. The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The rate of complete response was 24% and 43%, respectively (P<0.0001).

D-VMP also prolonged progression-free survival (PFS) compared to VMP.

The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.

The median overall survival was not reached in either treatment arm.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.

There were 6 deaths due to treatment-emergent adverse events in the D-VMP arm and 5 in the VMP arm.

About daratumumab

Daratumumab is a CD38-directed cytolytic antibody that is FDA approved for the following indications:

• In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of MM patients who have received at least 1 prior therapy
• In combination with pomalidomide and dexamethasone for the treatment of MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI)
• As monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.