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ASCO reports progress, challenges in cancer care
The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).
ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.
However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.
The report was published in the Journal of Oncology Practice.
Challenges
The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.
It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.
Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.
And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.
The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.
Progress
Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.
For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.
In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.
“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.
“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”
The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal. 
The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).
ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.
However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.
The report was published in the Journal of Oncology Practice.
Challenges
The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.
It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.
Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.
And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.
The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.
Progress
Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.
For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.
In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.
“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.
“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”
The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.
The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).
ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.
However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.
The report was published in the Journal of Oncology Practice.
Challenges
The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.
It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.
Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.
And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.
The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.
Progress
Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.
For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.
In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.
“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.
“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”
The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.
New resource designed to help prevent CINV
The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.
The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.
The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.
The entire toolkit is available for free download at TimeToTalkCINV.com.
The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).
The campaign began in response to results from a survey of cancer patients.
“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.
“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”
The Time to Talk CINV toolkit includes the following resources:
- A list of myths and truths about CINV intended to eliminate common misperceptions
- A checklist of questions patients can ask healthcare providers to better understand CINV
- A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
- A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.
Each tool can be printed or filled out digitally.
Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.
The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.
The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.
The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.
The entire toolkit is available for free download at TimeToTalkCINV.com.
The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).
The campaign began in response to results from a survey of cancer patients.
“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.
“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”
The Time to Talk CINV toolkit includes the following resources:
- A list of myths and truths about CINV intended to eliminate common misperceptions
- A checklist of questions patients can ask healthcare providers to better understand CINV
- A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
- A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.
Each tool can be printed or filled out digitally.
Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.
The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.
The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.
The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.
The entire toolkit is available for free download at TimeToTalkCINV.com.
The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).
The campaign began in response to results from a survey of cancer patients.
“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.
“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”
The Time to Talk CINV toolkit includes the following resources:
- A list of myths and truths about CINV intended to eliminate common misperceptions
- A checklist of questions patients can ask healthcare providers to better understand CINV
- A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
- A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.
Each tool can be printed or filled out digitally.
Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.
New approach for monitoring minimum residual disease in multiple myeloma
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.
Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.
“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).
Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.
After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).
“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.
Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
Key clinical point: Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma.
Major finding: Of patients who at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001).
Data source: A pilot study of 27 patients with multiple myeloma.
Disclosures: Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.
ADCs could treat myeloma, other malignancies
A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.
The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).
The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.
“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.
“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”
He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”
For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.
The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.
Both types of ADCs demonstrated efficacy in mouse models as well.
One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.
One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.
CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.
Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”
A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.
The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).
The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.
“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.
“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”
He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”
For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.
The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.
Both types of ADCs demonstrated efficacy in mouse models as well.
One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.
One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.
CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.
Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”
A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.
The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).
The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.
“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.
“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”
He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”
For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.
The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.
Both types of ADCs demonstrated efficacy in mouse models as well.
One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.
One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.
CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.
Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”
Auto-HCT patients run high risks for myeloid neoplasms
ORLANDO – For post–autologous hematopoietic cell transplant (auto-HCT) patients, the 10-year risk of developing a myeloid neoplasm was as high as 6%, based on a recent review of two large cancer databases.
Older age at transplant, receiving total body irradiation, and receiving multiple lines of chemotherapy before transplant all upped the risk of later cancers, according to a study presented by Shahrukh Hashmi, MD, and his collaborators at the combined annual meetings of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the American Society for Blood and Marrow Transplantation.
“The guidelines for autologous stem cell transplantation for surveillance for AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome] need to be clearly formulated. We are doing 30,000 autologous transplants a year globally and these patients are at risk for the most feared cancer, which is leukemia and MDS, for which outcomes are very poor,” said Dr. Hashmi of the Mayo Clinic in Rochester, Minn.
The researchers examined data from auto-HCT patients with diagnoses of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and multiple myeloma to determine the relative risks of developing AML and MDS. The study also explored which patient characteristics and aspects of the conditioning regimen might affect risk for later myeloid neoplasms.
In the dataset of 9,108 patients that Dr. Hashmi and his colleagues obtained from CIBMTR, 3,540 patients had NHL.
“As age progresses, the risk of acquiring myeloid neoplasms increases significantly,” he said, noting that the relative risk (RR) rose to 4.52 for patients aged 55 years and older at the time of transplant (95% confidence interval [CI], 2.63-7.77; P less than .0001).
Patients with NHL who received more than two lines of chemotherapy had approximately double the rate of myeloid cancers (RR, 1.93; 95% CI, 1.34-2.78; P = .0004).
The type of conditioning regimen made a difference for NHL patients as well. With total-body irradiation set as the reference at RR = 1, carmustine-etoposide-cytarabine-melphalan (BEAM) or similar therapies were relatively protective, with an RR of 0.59 (95% CI, 0.40-0.87; P = .0083). Also protective were cyclophosphamide-carmustine-etoposide (CBV) and similar therapies (RR, 0.57; 95% CI, 0.33-0.99; P = .0463).
Age at transplant was a factor among the 4,653 patients with multiple myeloma, with an RR of 2.47 for those transplanted at age 55 years or older (95% CI, 1.55-3.93; P = .0001). Multiple lines of chemotherapy also increased risk, with patients who received more than two lines having an RR of 1.77 for neoplasm (95% CI, 0.04-2.06; P = .0302). Women had less than half the risk of recurrence as men (RR, 0.44; 95% CI, 0.28-0.69; P = .0003).
Among the 915 study patients with Hodgkin lymphoma, patients aged 45 years and older at the time of transplant carried an RR of 5.59 for new myeloid neoplasms (95% CI, 2.98-11.70; P less than .0001).
Total-body irradiation was received by 14% of patients with non-Hodgkin lymphoma and by 5% of patients with multiple myeloma and Hodgkin lymphoma. Total-body irradiation was associated with a fourfold increase in neoplasm risk (RR, 4.02; 95% CI, 1.40-11.55; P = .0096).
Dr. Hashmi and his colleagues then examined the incidence rates for myelodysplastic syndrome and acute myelogenous leukemia in the Surveillance, Epidemiology, and End Results (SEER) database , finding that, even at baseline, the rates of myeloid neoplasms were higher for patients with NHL, Hodgkin lymphoma, or MM patients than for the general population of cancer survivors. “Post NHL, Hodgkin lymphoma, and myeloma, the risks are significantly higher to begin with. … We saw a high risk of AML and MDS compared to the SEER controls – risks as high as 100 times greater for auto-transplant patients,” said Dr. Hashmi. “A risk of one hundred times more for MDS was astounding, surprising, unexpected,” he said. The risk of AML, he said, was elevated about 10-50 times in the CIBMTR data.
The cumulative incidence of MDS or AML for NHL was 6% at 10 years post transplant, 4% for Hodgkin lymphoma, and 3% for multiple myeloma.
A limitation of the study, said Dr. Hashmi, was that the investigators did not assess for post-transplant maintenance chemotherapy.
“We have to prospectively assess our transplant patients in a fashion to detect changes early. Or maybe they were present at the time of transplant and we never did sophisticated methods [like] next-generation sequencing” to detect them, he said.
Dr. Hashmi reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – For post–autologous hematopoietic cell transplant (auto-HCT) patients, the 10-year risk of developing a myeloid neoplasm was as high as 6%, based on a recent review of two large cancer databases.
Older age at transplant, receiving total body irradiation, and receiving multiple lines of chemotherapy before transplant all upped the risk of later cancers, according to a study presented by Shahrukh Hashmi, MD, and his collaborators at the combined annual meetings of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the American Society for Blood and Marrow Transplantation.
“The guidelines for autologous stem cell transplantation for surveillance for AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome] need to be clearly formulated. We are doing 30,000 autologous transplants a year globally and these patients are at risk for the most feared cancer, which is leukemia and MDS, for which outcomes are very poor,” said Dr. Hashmi of the Mayo Clinic in Rochester, Minn.
The researchers examined data from auto-HCT patients with diagnoses of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and multiple myeloma to determine the relative risks of developing AML and MDS. The study also explored which patient characteristics and aspects of the conditioning regimen might affect risk for later myeloid neoplasms.
In the dataset of 9,108 patients that Dr. Hashmi and his colleagues obtained from CIBMTR, 3,540 patients had NHL.
“As age progresses, the risk of acquiring myeloid neoplasms increases significantly,” he said, noting that the relative risk (RR) rose to 4.52 for patients aged 55 years and older at the time of transplant (95% confidence interval [CI], 2.63-7.77; P less than .0001).
Patients with NHL who received more than two lines of chemotherapy had approximately double the rate of myeloid cancers (RR, 1.93; 95% CI, 1.34-2.78; P = .0004).
The type of conditioning regimen made a difference for NHL patients as well. With total-body irradiation set as the reference at RR = 1, carmustine-etoposide-cytarabine-melphalan (BEAM) or similar therapies were relatively protective, with an RR of 0.59 (95% CI, 0.40-0.87; P = .0083). Also protective were cyclophosphamide-carmustine-etoposide (CBV) and similar therapies (RR, 0.57; 95% CI, 0.33-0.99; P = .0463).
Age at transplant was a factor among the 4,653 patients with multiple myeloma, with an RR of 2.47 for those transplanted at age 55 years or older (95% CI, 1.55-3.93; P = .0001). Multiple lines of chemotherapy also increased risk, with patients who received more than two lines having an RR of 1.77 for neoplasm (95% CI, 0.04-2.06; P = .0302). Women had less than half the risk of recurrence as men (RR, 0.44; 95% CI, 0.28-0.69; P = .0003).
Among the 915 study patients with Hodgkin lymphoma, patients aged 45 years and older at the time of transplant carried an RR of 5.59 for new myeloid neoplasms (95% CI, 2.98-11.70; P less than .0001).
Total-body irradiation was received by 14% of patients with non-Hodgkin lymphoma and by 5% of patients with multiple myeloma and Hodgkin lymphoma. Total-body irradiation was associated with a fourfold increase in neoplasm risk (RR, 4.02; 95% CI, 1.40-11.55; P = .0096).
Dr. Hashmi and his colleagues then examined the incidence rates for myelodysplastic syndrome and acute myelogenous leukemia in the Surveillance, Epidemiology, and End Results (SEER) database , finding that, even at baseline, the rates of myeloid neoplasms were higher for patients with NHL, Hodgkin lymphoma, or MM patients than for the general population of cancer survivors. “Post NHL, Hodgkin lymphoma, and myeloma, the risks are significantly higher to begin with. … We saw a high risk of AML and MDS compared to the SEER controls – risks as high as 100 times greater for auto-transplant patients,” said Dr. Hashmi. “A risk of one hundred times more for MDS was astounding, surprising, unexpected,” he said. The risk of AML, he said, was elevated about 10-50 times in the CIBMTR data.
The cumulative incidence of MDS or AML for NHL was 6% at 10 years post transplant, 4% for Hodgkin lymphoma, and 3% for multiple myeloma.
A limitation of the study, said Dr. Hashmi, was that the investigators did not assess for post-transplant maintenance chemotherapy.
“We have to prospectively assess our transplant patients in a fashion to detect changes early. Or maybe they were present at the time of transplant and we never did sophisticated methods [like] next-generation sequencing” to detect them, he said.
Dr. Hashmi reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – For post–autologous hematopoietic cell transplant (auto-HCT) patients, the 10-year risk of developing a myeloid neoplasm was as high as 6%, based on a recent review of two large cancer databases.
Older age at transplant, receiving total body irradiation, and receiving multiple lines of chemotherapy before transplant all upped the risk of later cancers, according to a study presented by Shahrukh Hashmi, MD, and his collaborators at the combined annual meetings of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the American Society for Blood and Marrow Transplantation.
“The guidelines for autologous stem cell transplantation for surveillance for AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome] need to be clearly formulated. We are doing 30,000 autologous transplants a year globally and these patients are at risk for the most feared cancer, which is leukemia and MDS, for which outcomes are very poor,” said Dr. Hashmi of the Mayo Clinic in Rochester, Minn.
The researchers examined data from auto-HCT patients with diagnoses of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and multiple myeloma to determine the relative risks of developing AML and MDS. The study also explored which patient characteristics and aspects of the conditioning regimen might affect risk for later myeloid neoplasms.
In the dataset of 9,108 patients that Dr. Hashmi and his colleagues obtained from CIBMTR, 3,540 patients had NHL.
“As age progresses, the risk of acquiring myeloid neoplasms increases significantly,” he said, noting that the relative risk (RR) rose to 4.52 for patients aged 55 years and older at the time of transplant (95% confidence interval [CI], 2.63-7.77; P less than .0001).
Patients with NHL who received more than two lines of chemotherapy had approximately double the rate of myeloid cancers (RR, 1.93; 95% CI, 1.34-2.78; P = .0004).
The type of conditioning regimen made a difference for NHL patients as well. With total-body irradiation set as the reference at RR = 1, carmustine-etoposide-cytarabine-melphalan (BEAM) or similar therapies were relatively protective, with an RR of 0.59 (95% CI, 0.40-0.87; P = .0083). Also protective were cyclophosphamide-carmustine-etoposide (CBV) and similar therapies (RR, 0.57; 95% CI, 0.33-0.99; P = .0463).
Age at transplant was a factor among the 4,653 patients with multiple myeloma, with an RR of 2.47 for those transplanted at age 55 years or older (95% CI, 1.55-3.93; P = .0001). Multiple lines of chemotherapy also increased risk, with patients who received more than two lines having an RR of 1.77 for neoplasm (95% CI, 0.04-2.06; P = .0302). Women had less than half the risk of recurrence as men (RR, 0.44; 95% CI, 0.28-0.69; P = .0003).
Among the 915 study patients with Hodgkin lymphoma, patients aged 45 years and older at the time of transplant carried an RR of 5.59 for new myeloid neoplasms (95% CI, 2.98-11.70; P less than .0001).
Total-body irradiation was received by 14% of patients with non-Hodgkin lymphoma and by 5% of patients with multiple myeloma and Hodgkin lymphoma. Total-body irradiation was associated with a fourfold increase in neoplasm risk (RR, 4.02; 95% CI, 1.40-11.55; P = .0096).
Dr. Hashmi and his colleagues then examined the incidence rates for myelodysplastic syndrome and acute myelogenous leukemia in the Surveillance, Epidemiology, and End Results (SEER) database , finding that, even at baseline, the rates of myeloid neoplasms were higher for patients with NHL, Hodgkin lymphoma, or MM patients than for the general population of cancer survivors. “Post NHL, Hodgkin lymphoma, and myeloma, the risks are significantly higher to begin with. … We saw a high risk of AML and MDS compared to the SEER controls – risks as high as 100 times greater for auto-transplant patients,” said Dr. Hashmi. “A risk of one hundred times more for MDS was astounding, surprising, unexpected,” he said. The risk of AML, he said, was elevated about 10-50 times in the CIBMTR data.
The cumulative incidence of MDS or AML for NHL was 6% at 10 years post transplant, 4% for Hodgkin lymphoma, and 3% for multiple myeloma.
A limitation of the study, said Dr. Hashmi, was that the investigators did not assess for post-transplant maintenance chemotherapy.
“We have to prospectively assess our transplant patients in a fashion to detect changes early. Or maybe they were present at the time of transplant and we never did sophisticated methods [like] next-generation sequencing” to detect them, he said.
Dr. Hashmi reported no conflicts of interest.
[email protected]
On Twitter @karioakes
AT THE BMT TANDEM MEETINGS
Key clinical point:
Major finding: The 10-year cumulative risk for auto-HCT patients with Hodgkin or non-Hodgkin lymphoma or multiple myeloma was as high at 6%.
Data source: Review of 9,108 patients from an international transplant database.
Disclosures: Dr. Hashmi reported no conflicts of interest.
Selinexor trials placed on partial hold
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
Drug exhibits anti-myeloma activity in mice, humans
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial. 
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.
An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.
Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.
Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.
The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.
“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.
“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”
Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.
And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.
Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.
Results in mice
The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.
The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.
The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.
The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.
Results in patients
Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.
The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.
Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.
None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.
There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.
Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).
Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).
Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.
The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.
Combo prolongs OS in relapsed/refractory MM
NEW DEHLI—A 2-drug combination previously shown to prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM) can prolong overall survival (OS) as well, according to researchers.
Updated results of the phase 3 ENDEAVOR trial showed that patients who received treatment with carfilzomib and dexamethasone had a 7.6-month benefit in median OS when compared to patients who received bortezomib and dexamethasone.
Previous results from this trial showed a 9.3-month benefit in median PFS with carfilzomib and dexamethasone.
“Based on these data, we now know that [carfilzomib] not only significantly extended progression-free survival compared to [bortezomib] but also overall survival, making it a clinically meaningful advance in the treatment of relapsed or refractory multiple myeloma,” said Meletios A. Dimopoulos, MD, of the University of Athens in Greece.
Dr Dimopoulos presented OS results from ENDEAVOR at the 16th International Myeloma Workshop. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.
ENDEAVOR included 929 MM patients who had received 1 to 3 prior treatment regimens. The patients were randomized to receive carfilzomib and low-dose dexamethasone (n=464) or bortezomib and low-dose dexamethasone (n=465) until disease progression.
Baseline characteristics were similar between the treatment arms.
Detailed patient and treatment characteristics, as well as response and PFS data, have been previously reported.
OS and safety
The median OS was 47.6 months in the carfilzomib arm and 40.0 months in the bortezomib arm. All-cause mortality was significantly lower with the carfilzomib combination than the bortezomib combination (hazard ratio [HR]=0.791, 1-sided P=0.0100).
Researchers said there was an OS benefit with the carfilzomib combination whether or not patients received prior treatment with bortezomib and regardless of patients’ age, ECOG performance status at baseline, cytogenetic risk group, or the number of previous therapies they received.
The HR was 0.75 (carfilzomib vs bortezomib) for patients with no prior bortezomib and 0.84 for patients who received prior bortezomib. The HR was 0.85 for patients younger than 65, 0.71 for those ages 65 to 74, and 0.84 for patients age 75 and older.
The HR was 0.81 for patients with an ECOG status of 0, 0.80 for those with a status of 1, and 0.50 for those with a status of 2. The HR was 0.83 for patients with high-risk cytogenetics and 0.85 for those with standard-risk cytogenetics.
The HR was 0.83 for patients with 1 prior line of therapy and 0.76 for those with 2 to 3 prior lines of therapy.
The researchers said safety results in this analysis were comparable with previously reported results. The incidence of grade 3 or higher adverse events was 81.4% in the carfilzomib arm and 71.1% in the bortezomib arm.
The most common adverse events of any grade (in the carfilzomib and bortezomib arms, respectively) were anemia (42.5% and 28.3%), diarrhea (36.3% and 40.6%), pyrexia (32.4% and 15.4%), dyspnea (32.2% and 13.6%), fatigue (32.2% and 30.7%), and hypertension (32.2% and 9.9%).
NEW DEHLI—A 2-drug combination previously shown to prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM) can prolong overall survival (OS) as well, according to researchers.
Updated results of the phase 3 ENDEAVOR trial showed that patients who received treatment with carfilzomib and dexamethasone had a 7.6-month benefit in median OS when compared to patients who received bortezomib and dexamethasone.
Previous results from this trial showed a 9.3-month benefit in median PFS with carfilzomib and dexamethasone.
“Based on these data, we now know that [carfilzomib] not only significantly extended progression-free survival compared to [bortezomib] but also overall survival, making it a clinically meaningful advance in the treatment of relapsed or refractory multiple myeloma,” said Meletios A. Dimopoulos, MD, of the University of Athens in Greece.
Dr Dimopoulos presented OS results from ENDEAVOR at the 16th International Myeloma Workshop. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.
ENDEAVOR included 929 MM patients who had received 1 to 3 prior treatment regimens. The patients were randomized to receive carfilzomib and low-dose dexamethasone (n=464) or bortezomib and low-dose dexamethasone (n=465) until disease progression.
Baseline characteristics were similar between the treatment arms.
Detailed patient and treatment characteristics, as well as response and PFS data, have been previously reported.
OS and safety
The median OS was 47.6 months in the carfilzomib arm and 40.0 months in the bortezomib arm. All-cause mortality was significantly lower with the carfilzomib combination than the bortezomib combination (hazard ratio [HR]=0.791, 1-sided P=0.0100).
Researchers said there was an OS benefit with the carfilzomib combination whether or not patients received prior treatment with bortezomib and regardless of patients’ age, ECOG performance status at baseline, cytogenetic risk group, or the number of previous therapies they received.
The HR was 0.75 (carfilzomib vs bortezomib) for patients with no prior bortezomib and 0.84 for patients who received prior bortezomib. The HR was 0.85 for patients younger than 65, 0.71 for those ages 65 to 74, and 0.84 for patients age 75 and older.
The HR was 0.81 for patients with an ECOG status of 0, 0.80 for those with a status of 1, and 0.50 for those with a status of 2. The HR was 0.83 for patients with high-risk cytogenetics and 0.85 for those with standard-risk cytogenetics.
The HR was 0.83 for patients with 1 prior line of therapy and 0.76 for those with 2 to 3 prior lines of therapy.
The researchers said safety results in this analysis were comparable with previously reported results. The incidence of grade 3 or higher adverse events was 81.4% in the carfilzomib arm and 71.1% in the bortezomib arm.
The most common adverse events of any grade (in the carfilzomib and bortezomib arms, respectively) were anemia (42.5% and 28.3%), diarrhea (36.3% and 40.6%), pyrexia (32.4% and 15.4%), dyspnea (32.2% and 13.6%), fatigue (32.2% and 30.7%), and hypertension (32.2% and 9.9%).
NEW DEHLI—A 2-drug combination previously shown to prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM) can prolong overall survival (OS) as well, according to researchers.
Updated results of the phase 3 ENDEAVOR trial showed that patients who received treatment with carfilzomib and dexamethasone had a 7.6-month benefit in median OS when compared to patients who received bortezomib and dexamethasone.
Previous results from this trial showed a 9.3-month benefit in median PFS with carfilzomib and dexamethasone.
“Based on these data, we now know that [carfilzomib] not only significantly extended progression-free survival compared to [bortezomib] but also overall survival, making it a clinically meaningful advance in the treatment of relapsed or refractory multiple myeloma,” said Meletios A. Dimopoulos, MD, of the University of Athens in Greece.
Dr Dimopoulos presented OS results from ENDEAVOR at the 16th International Myeloma Workshop. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.
ENDEAVOR included 929 MM patients who had received 1 to 3 prior treatment regimens. The patients were randomized to receive carfilzomib and low-dose dexamethasone (n=464) or bortezomib and low-dose dexamethasone (n=465) until disease progression.
Baseline characteristics were similar between the treatment arms.
Detailed patient and treatment characteristics, as well as response and PFS data, have been previously reported.
OS and safety
The median OS was 47.6 months in the carfilzomib arm and 40.0 months in the bortezomib arm. All-cause mortality was significantly lower with the carfilzomib combination than the bortezomib combination (hazard ratio [HR]=0.791, 1-sided P=0.0100).
Researchers said there was an OS benefit with the carfilzomib combination whether or not patients received prior treatment with bortezomib and regardless of patients’ age, ECOG performance status at baseline, cytogenetic risk group, or the number of previous therapies they received.
The HR was 0.75 (carfilzomib vs bortezomib) for patients with no prior bortezomib and 0.84 for patients who received prior bortezomib. The HR was 0.85 for patients younger than 65, 0.71 for those ages 65 to 74, and 0.84 for patients age 75 and older.
The HR was 0.81 for patients with an ECOG status of 0, 0.80 for those with a status of 1, and 0.50 for those with a status of 2. The HR was 0.83 for patients with high-risk cytogenetics and 0.85 for those with standard-risk cytogenetics.
The HR was 0.83 for patients with 1 prior line of therapy and 0.76 for those with 2 to 3 prior lines of therapy.
The researchers said safety results in this analysis were comparable with previously reported results. The incidence of grade 3 or higher adverse events was 81.4% in the carfilzomib arm and 71.1% in the bortezomib arm.
The most common adverse events of any grade (in the carfilzomib and bortezomib arms, respectively) were anemia (42.5% and 28.3%), diarrhea (36.3% and 40.6%), pyrexia (32.4% and 15.4%), dyspnea (32.2% and 13.6%), fatigue (32.2% and 30.7%), and hypertension (32.2% and 9.9%).
Treating Patients With Multiple Myeloma in the VA
The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.
Biology of Multiple Myeloma
Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.
One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.
Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.
The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.
What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.
Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?
Tissue Banking
Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.
Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.
Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.
Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.
Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?
Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.
How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.
Relapse
Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.
Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.
Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.
Immune System
Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?
Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.
The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.
The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.
Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”
Standard of Therapy
Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?
Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.
An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.
The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.
The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.
Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.
Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.
Dr. Mehta. Yes, to reduce the neurotoxicity.
Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.
Dr. Mehta. They have all the comorbidities.
Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.
For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.
Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?
Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.
This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.
Pricing
Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.
Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.
Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.
Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.
Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.
Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.
Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.
While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.
We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.
We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.
Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.
Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.
Managing Adverse Effects
Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.
So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.
Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.
Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.
Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.
The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.
Thrombosis
Dr. Mehta. It’s also prothrombotic.
Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.
Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.
Dr. Chauncey. They are. And as soon as they stop, often there is a depression.
Dr. Mehta. It is very, very difficult. And some actually develop psychosis.
Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?
Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.
There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.
Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.
Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.
Click to read the digital edition.
The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.
Biology of Multiple Myeloma
Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.
One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.
Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.
The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.
What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.
Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?
Tissue Banking
Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.
Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.
Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.
Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.
Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?
Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.
How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.
Relapse
Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.
Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.
Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.
Immune System
Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?
Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.
The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.
The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.
Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”
Standard of Therapy
Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?
Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.
An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.
The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.
The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.
Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.
Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.
Dr. Mehta. Yes, to reduce the neurotoxicity.
Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.
Dr. Mehta. They have all the comorbidities.
Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.
For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.
Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?
Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.
This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.
Pricing
Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.
Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.
Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.
Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.
Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.
Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.
Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.
While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.
We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.
We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.
Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.
Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.
Managing Adverse Effects
Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.
So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.
Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.
Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.
Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.
The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.
Thrombosis
Dr. Mehta. It’s also prothrombotic.
Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.
Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.
Dr. Chauncey. They are. And as soon as they stop, often there is a depression.
Dr. Mehta. It is very, very difficult. And some actually develop psychosis.
Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?
Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.
There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.
Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.
Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.
Click to read the digital edition.
The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.
Biology of Multiple Myeloma
Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.
One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.
Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.
The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.
What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.
Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?
Tissue Banking
Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.
Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.
Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.
Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.
Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?
Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.
How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.
Relapse
Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.
Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.
Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.
Immune System
Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?
Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.
The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.
The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.
Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”
Standard of Therapy
Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?
Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.
An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.
The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.
The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.
Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.
Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.
Dr. Mehta. Yes, to reduce the neurotoxicity.
Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.
Dr. Mehta. They have all the comorbidities.
Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.
For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.
Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?
Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.
This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.
Pricing
Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.
Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.
Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.
Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.
Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.
Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.
Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.
While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.
We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.
We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.
Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.
Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.
Managing Adverse Effects
Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.
So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.
Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.
Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.
Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.
The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.
Thrombosis
Dr. Mehta. It’s also prothrombotic.
Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.
Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.
Dr. Chauncey. They are. And as soon as they stop, often there is a depression.
Dr. Mehta. It is very, very difficult. And some actually develop psychosis.
Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?
Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.
There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.
Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.
Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.
Click to read the digital edition.
Consensus Statement Supporting the Recommendation for Single-Fraction Palliative Radiotherapy for Uncomplicated, Painful Bone Metastases
The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.
Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.
Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.1 Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.4 For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.
Veterans, Cancer, and Metastases
Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.1 Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.8
Single-Fraction Palliatiev Radiation Therapy
Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.13-15
For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.
Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.16,17
For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
1. Zullig LL, Jackson GL, Dorn RA, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Mil Med. 2012;177(6):693-701.
2. Moghanaki D, Cheuk AV, Fosmire H, et al; U.S. Veterans Healthcare Administration National Palliative Radiotherapy Taskforce. Availability of single fraction palliative radiotherapy for cancer patients receiving end-of-life care within the Veterans Healthcare Administration. J Palliat Med. 2014;17(11):1221-1225.
3. Dawson GA, Glushko I, Hagan MP. A cross-sectional view of radiation dose fractionation schemes used for painful bone metastases cases within Veterans Health Administration Radiation Oncology Centers. J Clin Oncol. 2015;33(29 suppl):abstract 177.
4. Bekelman JE, Epstein AJ, Emanuel EJ. Single- vs multiple-fraction radiotherapy for bone metastases from prostate cancer. JAMA. 2013;310(14):1501-1502.
5. Galasko CSB. The anatomy and pathways of skeletal metastases. In: Weiss L, Gilbert AH, eds. Bone Metastasis. Boston, MA: GK Hall; 1981:49-63.
6. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns in prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583.
7. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20, pt 2):6243s-6249s.
8. Geriatrics and Extended Care Strategic Healthcare Group, National Pain Management Coordinating Committee, Veterans Health Administration. Pain as the 5th Vital Sign Toolkit. Rev. ed. Washington, DC: National Pain Management Coordinating Committee; 2000.
9. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798-804.
10. Chow E, Hoskins PJ, Wu J, et al. A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCTC CTG) SC 20. Clin Oncol (R Coll Radiol). 2006;18(2):125-128.
11. Fairchild A, Barnes E, Ghosh S, et al. International patterns of practice in palliative radiotherapy for painful bone metastases: evidence-based practice? Int J Radiat Oncol Biol Phys. 2009;75(5):1501-1510.
12. Chow E, van der Linden YM, Roos D, et al. Single fraction versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol. 2014;15(2):164-171.
13. Lutz ST, Berk L, Chang E, et al; American Society for Radiation Oncology (ASTRO). Palliative radiotherapy for bone metastases: an ASTRO evidencebased guideline. Int J Radiat Oncol, Biol, Phys. 2011;79(4):965-976.
14. Expert Panel on Radiation Oncology-Bone Metastases, Lo SS, Lutz ST, Chang EL, et al. ACR Appropriateness Criteria® spinal bone metastases. J Palliat Med. 2013;16(1):9-19.
15. Expert Panel on Radiation Oncology-Bone Metastases, Lutz ST, Lo SS, Chang EL, et al. ACR Appropriateness Criteria® non-spinal bone metastases. J Palliative Med. 2012;15(5):521-526.
16. Guadagnolo BA, Liao KP, Elting L, Giordano S, Buchholz TA, Shih YC. Use of radiation therapy in the last 30 days of life among a large population-based cohort of elderly patients in the United States. J Clin Oncol. 2013;31(1):80-87.
17. Schuster J, Han T, Anscher M, Moghanaki D. Hospice providers awareness of the benefits and availability of single-fraction palliative radiotherapy. J Hospice Palliat Care Nurs. 2014;16(2):67-72.
18. Cheon PM, Wong E, Thavarajah N, et al. A definition of “uncomplicated bone metastases” based on previous bone metastases trials comparing single-fraction and multi-fraction radiation therapy. J Bone Oncol. 2015;4(1):13-17.
The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.
Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.
Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.1 Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.4 For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.
Veterans, Cancer, and Metastases
Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.1 Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.8
Single-Fraction Palliatiev Radiation Therapy
Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.13-15
For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.
Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.16,17
For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
The authors would like to acknowledge Tony Quang, MD, JD, for the advice given on this project.
Palliative radiotherapy for bone metastases is typically delivered either as a short course of 1 to 5 fractions or protracted over longer courses of up to 20 treatments. These longer courses can be burdensome and discourage its utilization, despite a 50% to 80% likelihood of meaningful pain relief from only a single fraction of radiation therapy. Meanwhile, there are multiple randomized studies that have demonstrated that shorter course(s) are equivalent for pain control.
Although the VHA currently has 143 medical facilities that have cancer diagnostic and treatment capabilities, only 40 have radiation oncology services on-site.1 Thus, access to palliative radiotherapy may be limited for veterans who do not live close by, and many may seek care outside the VHA. At VHA radiation oncology centers, single-fraction radiation therapy (SFRT) is routinely offered by the majority of radiation oncologists.2,3 However, the longer course is commonly preferred outside the VA, and a recent SEER-Medicare analysis of more than 3,000 patients demonstrated that the majority of patients treated outside the VA actually receive more than 10 treatments.4 For this reason, the VA National Palliative Radiotherapy Task Force prepared this document to provide guidance for clinicians within and outside the VA to increase awareness of the appropriateness, effectiveness, and convenience of SFRT as opposed to longer courses of treatment that increase the burden of care at the end of life and often are unnecessary.
Veterans, Cancer, and Metastases
Within the VA, an estimated 40,000 new cancer cases are diagnosed each year, and 175,000 veterans undergo cancer care within the VHA annually.1 Unfortunately, the majority will develop bone metastases with postmortem examinations, suggesting that the rate can be as high as 90% at the end of life.5-7 For many, including veterans with cancer, pain control can be difficult, and access to palliative radiotherapy is critical.8
Single-Fraction Palliatiev Radiation Therapy
Historically, patients with painful bone metastases have been treated with courses of palliative radiotherapy ranging between 2 and 4 weeks of daily treatments. However, several large randomized clinical trials comparing a single treatment with multiple treatments have established that SFRT provides equivalent rates of pain relief even when it may be required for a second time.9-12 Recommendations based on these trials have been incorporated into various treatment guidelines that widely acknowledge the efficacy of SFRT.13-15
For this reason, SFRT is often preferred at many centers because it is substantially more convenient for patients with cancer. It reduces travel time for daily radiation clinic visits, which allows for more time with loved ones outside the medical establishment. Furthermore, SFRT improves patient access to radiotherapy and reduces costs. The benefits can be direct as well as indirect to those who have to take time for numerous visits.
Longer courses of palliative radiotherapy can be burdensome for patients and primary care providers. Unnecessarily protracted courses of palliative radiotherapy also delay the receipt of systemic therapies because they are typically considered unsafe to administer concurrently. Moreover, when SFRT is unavailable, the burden of long-course palliation is known to discourage health care providers from referring patients since opioid therapy is more convenient, even though it exchanges lucidity for analgesia.16,17
For this reason, the authors believe that it is in the best interest for veterans with terminal cancers and their providers to be aware of the shorter SFRT for effective, convenient pain relief. This treatment option is particularly relevant for patients with a poor performance status, patients already in hospice care, or patient who travel long distances.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
1. Zullig LL, Jackson GL, Dorn RA, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Mil Med. 2012;177(6):693-701.
2. Moghanaki D, Cheuk AV, Fosmire H, et al; U.S. Veterans Healthcare Administration National Palliative Radiotherapy Taskforce. Availability of single fraction palliative radiotherapy for cancer patients receiving end-of-life care within the Veterans Healthcare Administration. J Palliat Med. 2014;17(11):1221-1225.
3. Dawson GA, Glushko I, Hagan MP. A cross-sectional view of radiation dose fractionation schemes used for painful bone metastases cases within Veterans Health Administration Radiation Oncology Centers. J Clin Oncol. 2015;33(29 suppl):abstract 177.
4. Bekelman JE, Epstein AJ, Emanuel EJ. Single- vs multiple-fraction radiotherapy for bone metastases from prostate cancer. JAMA. 2013;310(14):1501-1502.
5. Galasko CSB. The anatomy and pathways of skeletal metastases. In: Weiss L, Gilbert AH, eds. Bone Metastasis. Boston, MA: GK Hall; 1981:49-63.
6. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns in prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583.
7. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20, pt 2):6243s-6249s.
8. Geriatrics and Extended Care Strategic Healthcare Group, National Pain Management Coordinating Committee, Veterans Health Administration. Pain as the 5th Vital Sign Toolkit. Rev. ed. Washington, DC: National Pain Management Coordinating Committee; 2000.
9. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798-804.
10. Chow E, Hoskins PJ, Wu J, et al. A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCTC CTG) SC 20. Clin Oncol (R Coll Radiol). 2006;18(2):125-128.
11. Fairchild A, Barnes E, Ghosh S, et al. International patterns of practice in palliative radiotherapy for painful bone metastases: evidence-based practice? Int J Radiat Oncol Biol Phys. 2009;75(5):1501-1510.
12. Chow E, van der Linden YM, Roos D, et al. Single fraction versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol. 2014;15(2):164-171.
13. Lutz ST, Berk L, Chang E, et al; American Society for Radiation Oncology (ASTRO). Palliative radiotherapy for bone metastases: an ASTRO evidencebased guideline. Int J Radiat Oncol, Biol, Phys. 2011;79(4):965-976.
14. Expert Panel on Radiation Oncology-Bone Metastases, Lo SS, Lutz ST, Chang EL, et al. ACR Appropriateness Criteria® spinal bone metastases. J Palliat Med. 2013;16(1):9-19.
15. Expert Panel on Radiation Oncology-Bone Metastases, Lutz ST, Lo SS, Chang EL, et al. ACR Appropriateness Criteria® non-spinal bone metastases. J Palliative Med. 2012;15(5):521-526.
16. Guadagnolo BA, Liao KP, Elting L, Giordano S, Buchholz TA, Shih YC. Use of radiation therapy in the last 30 days of life among a large population-based cohort of elderly patients in the United States. J Clin Oncol. 2013;31(1):80-87.
17. Schuster J, Han T, Anscher M, Moghanaki D. Hospice providers awareness of the benefits and availability of single-fraction palliative radiotherapy. J Hospice Palliat Care Nurs. 2014;16(2):67-72.
18. Cheon PM, Wong E, Thavarajah N, et al. A definition of “uncomplicated bone metastases” based on previous bone metastases trials comparing single-fraction and multi-fraction radiation therapy. J Bone Oncol. 2015;4(1):13-17.
1. Zullig LL, Jackson GL, Dorn RA, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Mil Med. 2012;177(6):693-701.
2. Moghanaki D, Cheuk AV, Fosmire H, et al; U.S. Veterans Healthcare Administration National Palliative Radiotherapy Taskforce. Availability of single fraction palliative radiotherapy for cancer patients receiving end-of-life care within the Veterans Healthcare Administration. J Palliat Med. 2014;17(11):1221-1225.
3. Dawson GA, Glushko I, Hagan MP. A cross-sectional view of radiation dose fractionation schemes used for painful bone metastases cases within Veterans Health Administration Radiation Oncology Centers. J Clin Oncol. 2015;33(29 suppl):abstract 177.
4. Bekelman JE, Epstein AJ, Emanuel EJ. Single- vs multiple-fraction radiotherapy for bone metastases from prostate cancer. JAMA. 2013;310(14):1501-1502.
5. Galasko CSB. The anatomy and pathways of skeletal metastases. In: Weiss L, Gilbert AH, eds. Bone Metastasis. Boston, MA: GK Hall; 1981:49-63.
6. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns in prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583.
7. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20, pt 2):6243s-6249s.
8. Geriatrics and Extended Care Strategic Healthcare Group, National Pain Management Coordinating Committee, Veterans Health Administration. Pain as the 5th Vital Sign Toolkit. Rev. ed. Washington, DC: National Pain Management Coordinating Committee; 2000.
9. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798-804.
10. Chow E, Hoskins PJ, Wu J, et al. A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCTC CTG) SC 20. Clin Oncol (R Coll Radiol). 2006;18(2):125-128.
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