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Making sense of the expanded myeloma treatment landscape
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
ORLANDO – The moment the Food and Drug Administration approved daratumumab, ixazomib, and elotuzumab in rapid-fire succession over 15 days in November 2015, Dr. S. Vincent Rajkumar’s phone started ringing.
As with other multiple myeloma experts, three common questions kept cropping up:
• For previously untreated patients, should we add bortezomib to lenalidomide plus dexamethasone (Rd) based on the S0777 results?
• For previously treated patients, should we add ixazomib or elotuzumab to Rd?
• Should we add daratumumab to frontline therapy right out of the box?
Daratumumab (Darzalex), ixazomib (Ninlaro), and elotuzumab (Empliciti) are welcome additions to the armamentarium, but the problem with this plethora of riches is that numerous treatments already exist for frontline multiple myeloma, observed Dr. Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minn.
In fact, the National Comprehensive Cancer Network guidelines list 22 possible newly diagnosed myeloma regimens that can be potentially recommended for patients.
“This definitely leads to confusion in the community. And this was the result of the fact that we didn’t have a single, good randomized trial with a survival benefit of a modern therapy against another modern therapy,” Dr. Rajkumar said at the annual meeting of the American Society of Hematology during a joint FDA/ASH symposium on the three newly approved agents.
This quandary was solved at ASH with phase III randomized data from the Southwest Oncology Group S0777 study showing a significant overall survival advantage with a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) followed by continuous Rd maintenance compared with Rd alone and ongoing maintenance in untreated patients who did not intend to receive stem cell transplant, he said.
Median overall survival was 75 months for the triplet vs. 64 months for the Rd doublet (hazard ratio, 0.709; two-sided log-rank P = .0250), and median PFS 43 months vs. 30 months (HR, 0.712; one-sided P = .0018), study author Dr. Brian Durie, of Cedars-Sinai Comprehensive Cancer Center in Los Angeles, reported (Abstract 25).
The VRd triplet is already in use in the United States, but based on the S0777 results, many groups, including the Mayo Clinic, have changed treatment guidelines and now “prefer bortezomib, len-dex for frontline therapy, not just in transplant candidates, but also in non-transplant candidates,” Dr. Rajkumar said.
In countries where VRd is not possible, bortezomib, thalidomide, and dexamethasone (VTd) is a second option.
Rd is an appropriate therapy for non-transplant candidates who are frail or aged 75 years or older, he said, adding that there is no need to add bortezomib for patients already on Rd and doing well.
“If your patient is doing well on a doublet, leave them alone,” Dr. Rajkumar advised.
Similarly, for patients with relapsed myeloma who are doing well on Rd, there isn’t “an urgent need” to add ixazomib or elotuzumab, but rather, he said, “We can reserve those for when the patient progresses.”
Ixazomib is approved in combination with Rd after at least one prior therapy, but the oral proteasome inhibitor may have a role in the frontline treatment of standard-risk patients. It is a very simple regimen, just three pills a month, and “the side effect profile is outstanding; virtually difficult to tell who’s taking placebo and who’s taking drug,” Dr. Rajkumar observed.
In addition, some patients may not have access to bortezomib because of insurance reasons or can’t drive to the clinic once a week to get the shot, while others may be too frail to get an intravenous or subcutaneous shot or may have neuropathy.
“For whatever reason, I think it is reasonable to keep in mind that we may have a situation where we can use ixazomib/len-dex in clinical practice if the patient’s best interests so dictate,” he said.
For high-risk patients (deletion 17p or translocations t(4;14), t(14;16), t(14;20), VRd or VTd are obvious upfront choices. Based on four phase II trials and the ASPIRE results in the relapsed and refractory setting, however, the Mayo Clinic has already decided that the recently approved second-generation proteasome inhibitor carfilzomib (Kyprolis) plus Rd is also worth considering.
Adding a monoclonal antibody such as elotuzumab or daratumumab to a VRd triplet or ixazomib, lenalidomide, and dexamethasone (IRd) triplet may be another way to improve outcomes in high-risk patients, who still die with a median overall survival of 3 years, Dr. Rajkumar said. This strategy is already being used in the ongoing SWOG S1211 study.
For maintenance therapy after VRd or VTd and autologous stem cell transplant, he recommended lenalidomide for standard-risk patients and bortezomib-based maintenance for high-risk patients, but said ixazomib-based maintenance with the addition of monoclonal antibodies may also have a role in high-risk patients.
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
EXPERT ANALYSIS FROM ASH 2015
Cancer prevention field riding high into the new year
The new year has us all looking forward and the cancer prevention community is no exception.
In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.
“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).
The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.
Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.
Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.
In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.
A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.
In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.
The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.
The new year has us all looking forward and the cancer prevention community is no exception.
In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.
“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).
The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.
Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.
Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.
In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.
A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.
In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.
The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.
The new year has us all looking forward and the cancer prevention community is no exception.
In a special report entitled “Transforming Cancer Prevention through Precision Medicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, including a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism.
“Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characterizing the molecular and cellular events that drive premalignant progression (e.g. PCGA),” Dr. Scott M. Lippman, director of the University of California San Diego Moores Cancer Center, and his coauthors wrote (Cancer Prev Res. 2016;9:2-10).
The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal hematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the U.S. Preventive Services Task Force recommending low-dose aspirin for colorectal cancer prevention based on age and risk.
Randomized trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumor biology studies established new chemoprevention for familial adenomatous polyposis syndrome and universal tumor screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome.
Further, remarkable advances have been made in liquid biopsy technology, high-throughput functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted.
In an American Association for Cancer Research blog post, Dr. Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention.
A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable.
In February, an AACR Cancer Prevention Summit will bring together various stakeholders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted.
The authors acknowledged grant support from the National Institutes of Health/National Cancer Institute.
FROM CANCER PREVENTION RESEARCH
Heavily pretreated myeloma responds to pembrolizumab combo
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.
This included four very good partial responses (24%) and nine partial responses (53%).
In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).
The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.
He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.
The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.
The median duration of response among the 17 evaluable patients was 9.7 months.
The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.
The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.
“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.
Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.
The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.
In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.
After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.
The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.
Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).
The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.
Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.
In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.
AT ASH 2015
Key clinical point: Initial results show promising activity for pembrolizumab in combination with lenalidomide and low-dose dexamethasone in heavily pretreated relapsed or refractory multiple myeloma.
Major finding: The overall response rate was 76% (13/17 patients).
Data source: Phase I study in 50 patients with relapsed or refractory multiple myeloma.
Disclosures: The study was supported by Merck. Dr. San Miguel reported consulting for Merck and relationships with Millennium, Janssen, Celgene, Novartis, Onyx, Bristol-Myers Squibb, and Sanofi.
Prescribing a winning home-exercise plan for PAD patients
CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.
“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.
Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.
“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”
At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.
The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.
The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).
“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”
Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.
“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.
Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).
Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.
Once this is performed, Dr. McDermott recommends clinicians:
• Advise patients to walk 5 days per week.
“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.
• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.
• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.
“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.
• Increase the walk time by 5 minutes each week.
Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.
• Advise patients to write down their walking goals.
Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.
• Have patients self-monitor, but also check in with someone for support.
“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”
Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.
The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.
“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.
Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.
CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.
“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.
Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.
“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”
At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.
The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.
The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).
“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”
Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.
“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.
Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).
Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.
Once this is performed, Dr. McDermott recommends clinicians:
• Advise patients to walk 5 days per week.
“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.
• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.
• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.
“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.
• Increase the walk time by 5 minutes each week.
Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.
• Advise patients to write down their walking goals.
Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.
• Have patients self-monitor, but also check in with someone for support.
“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”
Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.
The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.
“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.
Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.
CHICAGO – Following a few simple steps can help patients with peripheral artery disease (PAD) get off on the right foot with a home-based exercise program.
“There is growing evidence that PAD patients can walk for exercise at home and improve their walking performance,” Dr. Mary McDermott said at a symposium on vascular surgery sponsored by Northwestern University.
Getting them to do so, however, can be challenging. Patients with peripheral artery disease have greater functional impairment and are at higher risk for cardiovascular disease than is the general population. They also frequently limit their activity to avoid leg problems, as their PAD progresses.
“It’s hard enough to get patients without peripheral artery disease to exercise. As a general internist, I’m well aware of that,” she said. “It’s even more difficult when walking is so painful and uncomfortable.”
At present, the American College of Cardiology/American Heart Association practice guidelines for the management of patients with PAD do not recommend advising patients with PAD to go home and walk.
The guidelines were published in 2005, however, and since 2011, three of four randomized clinical trials of home-based exercise programs have shown a significant gain in walking endurance in patients with PAD, Dr. McDermott of Northwestern University in Chicago, observed.
The most hands-off of these trials showed that patients with symptomatic PAD randomized to a supervised exercise program did the best at treadmill walking, but the home-exercise group who received a step monitor and in-person feedback just once per month did significantly better than did controls assigned light resistance training. Moreover, the home-exercise group had greater change in 6-minute walk distances than either of the other groups (J Am Heart Assoc. 2014 Oct;3[5]:e001107).
“I think the reason for this is that the home-based group was walking outside or perhaps in a mall and getting better at walking over ground,” Dr. McDermott. “The treadmill group was walking only on the treadmill.”
Supervised treadmill exercise may seem like an easier prescription to write, but it faces two major barriers, she said. Most medical insurers, including Medicare, do not pay for supervised exercise for people with PAD and intermittent claudication, and most PAD patients don’t participate. The burden of traveling to an exercise center three times weekly, week after week, to participate can be overwhelming.
“For all of these reasons, we really need to develop home-based exercise programs that work,” Dr. McDermott said.
Based on the successful trials, home-based programs should include monitoring, group support, and goal setting. Dr. McDermott and her colleagues added cognitive-behavioral therapy to group support in the Group Oriented Arterial Leg Study (GOALS), resulting in significant improvement in 6-minute walk distance at 6 months, physical activity over 7 days, and self-perception of walking endurance and speed among home walkers (JAMA. 2013 Jul 3;310[1]:57-65).
Before embarking on any home-exercise program, all patients with PAD should undergo a baseline cardiac stress test to rule out coronary artery ischemia, she cautioned. This also serves to identify any coronary ischemia that may develop during the new walking program.
Once this is performed, Dr. McDermott recommends clinicians:
• Advise patients to walk 5 days per week.
“This may seem like a lot, but it’s important to have them see this as part of their daily routine; just something they get in the habit of doing,” she said.
• Start with 10-15 minutes of walking per exercise session. Tailor the program to the individual patient.
• Walk to maximal leg pain or onset of ischemic pain. Stopping to rest is acceptable.
“A lot of patients, I find, have questions, “ ‘I can’t do this.’ ‘How can this be beneficial?’ So just letting them know that if they just walk and stop, walk and stop, and start with just 10 minutes of that and increase this over time, they really can see improvement,” Dr. McDermott said.
• Increase the walk time by 5 minutes each week.
Increase the duration until the patient is walking at least 30 minutes per session and preferably 45-50 minutes per session, excluding rest periods, she said.
• Advise patients to write down their walking goals.
Specify where they will walk, when they will walk, and the duration of walking to improve compliance, which can slip following hospitalizations or when patients experience acute illness.
• Have patients self-monitor, but also check in with someone for support.
“It doesn’t have to be a nurse,” Dr. McDermott said. “In our studies, we’ve used bachelor’s degree-level people, but told them what to look for. They can do this and the patient feels there is someone they’re accountable to.”
Dr. McDermott and her colleagues are testing the boundaries of support in the ongoing HONOR trial, which includes four weekly visits to an exercise center in phase I to meet the telephone coach, learn to use a Fitbit monitor, and learn the behavioral skills necessary for long-term adherence. Phase II, however, is entirely home based and includes only Fitbit self-monitoring, regular telephone calls from the coach for feedback, use of the study website, and optional group telephone calls.
The bottom line with any program is for patients to understand it must be indefinite to maintain improvement.
“Unfortunately, if they don’t stick with it, they will slide back,” she cautioned.
Dr. McDermott reported research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), and Novartis.
EXPERT ANALYSIS FROM THE NORTHWESTERN VASCULAR SYMPOSIUM
ASH: First shot across the bow for CAR T cells in multiple myeloma
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.
CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.
“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.
The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.
While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.
Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.
The 12 patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 106 to 9 x 106 T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.
“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”
The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2015
Key clinical point: The first clinical trial of a CAR targeting BCMA demonstrated strong antimyeloma activity in patients with at least 3 prior lines of myeloma therapy.
Major finding: Myeloma in plasma cells was reduced from 90% to 0% in one patient.
Data source: Phase I study in 12 patients with at least 3 prior lines of multiple myeloma therapy.
Disclosures: Dr. Kochenderfer reported consultancy with Bluebird Bio and off-label use of cyclophosphamide and fludarabine.
Academic hospitals offer better AML survival
ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.
Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).
One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).
The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.
“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.
Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.
Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).
Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.
Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).
Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.
In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).
The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.
During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.
ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.
Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).
One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).
The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.
“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.
Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.
Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).
Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.
Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).
Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.
In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).
The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.
During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.
ORLANDO – Patients with acute myeloid leukemia (AML) initially treated at an academic center lived significantly longer than those treated at nonacademic centers, a database analysis shows.
Median overall survival increased from 7 months at a nonacademic center to 12.6 months at an academic center (P less than .001).
One-year overall survival rates were also significantly better at 51% vs. 39% (P less than .001).
The difference remained significant even after controlling for important confounders including age, comorbidity burden, receipt of chemotherapy, transplant, and delay between diagnosis and treatment, Mr. Smith Giri reported at the annual meeting of the American Society of Hematology.
“From a policy perspective, it may be useful to know whether these results are due to higher volume of cases, more advanced technology, expanded role of specialists, or greater, round-the-clock availability of resident physicians,” said Mr. Giri of the University of Tennessee Health Science Center in Memphis.
Prior studies in cancer have suggested better overall survival among breast cancer patients treated at academic centers, but this is the first study looking at outcomes in AML, the most common acute leukemia in adults.
Using the National Cancer Database Participant User File, the investigators identified 7,823 patients with AML who received their initial therapy at the reporting facility from 1998 to 2011. The database collects information from more than 1,500 Commission on Cancer (CoC)–accredited facilities. Of the 7,823 patients, 4,681 (60%) were treated at an AC (academic/research program) and 3,142 at a non-AC (community cancer program/comprehensive community cancer program).
Patients treated at an AC were significantly younger than those treated at a non-AC (median 62 years vs. 67 years), tended to be of nonwhite race, less educated, have a lower income, and more comorbidities.
Receipt of chemotherapy (97.4% vs. 94.5%) and transplant (9% vs. 2.4%) were significantly higher at an AC than a non-AC (both P less than .001).
Kaplan Meier survival curves suggested disparate survival curves between the two groups, mainly within the first 5 years of follow-up (P less than .001), Mr. Giri said.
In multivariate model analysis, the non-AC group had significantly worse risk adjusted 30-day mortality than the AC group (odds ratio, 1.52; 95% confidence interval 1.33-1.74; P less than .001) and worse overall survival (hazard ratio, 1.13; 95% CI 1.07-1.19; P less than .001).
The study (Ab. 533) findings should be interpreted with caution because of its limitations, including the lack of information on AML risk type in the database, the fact that administrative datasets are prone to coding errors, and because the analysis did not adjust for hospital volume, which has been shown to affect survival, he said. Also, because there are more than 3,500 non–Coc approved hospitals, the sample may not be representative of overall U.S. hospitals.
During a discussion of the results, Mr. Giri acknowledged that patients treated at academic centers may have greater access to clinical trials and experimental agents. Future analyses should also distinguish patients with a diagnosis of acute promyelocytic leukemia, a distinct subset of AML.
AT ASH 2015
Key clinical point: Academic hospitals tend to have better short- and long-term mortality for patients with AML than nonacademic hospitals.
Major finding: Median overall survival was 12.6 months at an academic center vs. 7 months at a nonacademic center (P less than .001).
Data source: Retrospective analysis of 7,823 patients with AML.
Disclosures: The research was supported in part by a grant from the University of Nebraska Medical Center. The National Cancer Database is jointly sponsored by the American College of Surgeons and American Cancer Society. Mr. Giri reported having no relevant conflicts of interest.
High NLR predicts poor survival in trauma patients
CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.
The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.
“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.
The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.
The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).
In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.
Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.
The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.
Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).
A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.
On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).
In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.
“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”
During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.
When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.
The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.
The authors reported having no relevant financial conflicts of interest.
CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.
The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.
“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.
The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.
The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).
In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.
Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.
The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.
Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).
A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.
On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).
In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.
“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”
During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.
When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.
The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.
The authors reported having no relevant financial conflicts of interest.
CHICAGO – A high neutrophil to lymphocyte ratio on days 2 and 5 of surgical ICU hospitalization independently predicts increased mortality in critically ill trauma patients, an award-winning study showed.
The risk of death was two times higher for patients with a neutrophil to lymphocyte ratio (NLR) of at least 10.45 on day 2 (adjusted hazard ratio, 2.07; 95% confidence interval, 1.38-3.13; P = .001) and 5.7 times higher for those with an NLR of at least 7.91 on day 5 (adjusted HR, 5.79; 95% CI, 2.93-11.44; P less than .001) in a multivariate analysis, after adjustment for age 65 years or older, male sex, a systolic blood pressure of 90 mm Hg or less, a Glasgow Coma Scale (GCS) score of 8 or less, an Injury Severity Score (ISS) of at least 25, and operation on admission.
“The neutrophil to lymphocyte ratio is easily accessible, the calculation is simple, it adds no additional costs, and virtually all critically ill patients will have these labs,” study author Dr. Evren Dilektasli said at the American College of Surgeons annual clinical congress.
The simple calculation has been shown to be useful in the diagnosis of appendicitis and to be associated with overall survivalin metastatic colorectal cancer, but its association with mortality in trauma patients is not known, he said.
The retrospective cohort comprised 1,356 trauma patients, at least 16 years old, admitted to the Los Angeles County–University of Southern California Medical Center surgical ICU between January 2013 and January 2014. The median NLR was calculated for each day of the surgical ICU stay. At baseline, 16% of patients had an ISS of at least 25, 16.5% had a GCS of 8 or less, 4.5% had a systolic BP of 90 mm Hg or less, 74.3% were male, 23.7% were aged 65 or older, and 86% had a blunt injury. The most common operations on admission were laparotomy (39.6%) and craniectomy/craniotomy (20.7%).
In receiver operating characteristic (ROC) analysis for the first 10 days of hospitalization, the area under the curve (AUC) values for predicting mortality were between 0.55 on day 1 and a high of 0.79 on day 5, Dr. Dilektasli reported.
Starting from day 2 to day 10, the AUCs were statistically significant for predicting mortality.
The NLRs on day 2 (AUC, 0.73; P less than .001) and day 5 (AUC, 0.79; P less than .001) were selected in order to adjust for the clinical probability of early and late complications, he said.
Subsequent ROC curve analysis revealed an NLR cutoff of 10.45 on day 2 (AUC, 0.73; sensitivity, 73.2%; specificity, 61.8%) and a cutoff of 7.91 on day 5 (AUC, 0.79; sensitivity, 82.8%; specificity, 65.2%).
A high NLR on day 2 (at least 10.45) versus a low NLR (less than 10.45) was associated with significantly more ventilator days (5 days vs. 3 days), a longer surgical ICU length of stay (5 days vs. 3 days), a longer hospital stay (11 days vs. 8 days), and greater mortality (18.3% vs. 4.8%; all P values less than .001), reported Dr. Dilektasli, who was a research fellow at USC at the time of the study and has returned to Turkey to continue his training.
On day 5, a high NLR (at least 7.91) versus a low NLR (less than 7.91) was associated with significantly more ventilator days (7 days vs. 4 days; P less than .001), a longer surgical ICU stay (9 days vs. 5 days; P less than .001), and increased mortality (20.4% vs. 2.8%; P less than .001), but not a longer hospital stay (17 days vs. 14 days; P = .119).
In Kaplan-Meier analysis, a significant difference was observed between the high and low NLR groups on day 2 (log rank P less than .001) and day 5 (log rank P less than .001), he said.
“NLR may be a promising tool for assessing the risk of in-hospital mortality,” Dr. Dilektasli concluded. “Prospective external validation is warranted in a larger heterogeneous trauma population.”
During a discussion of the study, it was noted that the ROC curves were impressive, but that other biologic markers known to be associated with poor survival such as C-reactive protein level and class II major hepatitis C expression should have been included in the analysis.
When asked whether any patients with a low NLR on day 2 went on to have a high NLR on day 5, Dr. Dilektasli said there were such patients and that they also had an increased risk of death.
The findings of the study, which earned an excellence in research award, are only an “observation” at this point and are not being used in clinical practice, he added.
The authors reported having no relevant financial conflicts of interest.
AT THE ACS CLINICAL CONGRESS
Key clinical point: A high neutrophil to lymphocyte ratio on day 2 and day 5 of surgical ICU admission may be a useful predictor of poor survival in trauma patients.
Major finding: The adjusted hazard ratios for mortality were 2.07 with a neutrophil to lymphocyte ratio of at least 10.45 on day 2 (95% CI, 1.38-3.13; P = .001) and 5.79 with an NLR of at least 7.91 on day 5 (95% CI, 2.93-11.44; P less than .001).
Data source: A retrospective study involving 1,356 trauma patients.
Disclosures: The authors reported having no relevant financial conflicts of interest.
Anti-PD-1, IMiD combo immunotherapy active in heavily pretreated myeloma
ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.
This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.
Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.
“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.
The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).
The primary goal of the ongoing study is to establish the safety of the combination therapy.
In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.
At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.
Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.
Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].
The median number of cycles was six and median follow-up short at 7.4 months.
The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.
The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.
“We reported a lot, actually, of immune-related adverse events,” he said.
In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.
The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.
Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.
A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.
Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.
The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.
Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.
ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.
This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.
Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.
“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.
The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).
The primary goal of the ongoing study is to establish the safety of the combination therapy.
In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.
At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.
Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.
Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].
The median number of cycles was six and median follow-up short at 7.4 months.
The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.
The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.
“We reported a lot, actually, of immune-related adverse events,” he said.
In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.
The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.
Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.
A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.
Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.
The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.
Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.
ORLANDO – Partnering the PD-1 antibody pembrolizumab with pomalidomide and dexamethasone induced responses in 60% of 27 patients with heavily pretreated relapsed and/or refractory multiple myeloma in a phase II trial.
This included 1 stringent complete response, 4 very good partial responses (VGPR), and 11 partial responses (PR). Eight patients had stable disease and 3 progressed.
Further, the overall response rate was 55% (2 VGPR, 9 PR) in patients double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 50% (1 VGPR and 5 PR) in those with high-risk cytogenetics.
“The regimen shows promising anti-myeloma activity in heavily pretreated patients” and had a “predictable and manageable side-effect profile,” Dr. Asraf Badros of University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, said at the annual meeting of the American Society of Hematology.
The investigators hypothesized that blocking signaling of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 with pembrolizumab (Keytruda) would activate multiple myeloma-specific cytotoxic T cells that could be further enhanced by the immunomodulator pomalidomide (Pomalyst).
The primary goal of the ongoing study is to establish the safety of the combination therapy.
In all, 33 patients received 28-day cycles of pembrolizumab 200 mg intravenous every 2 weeks plus pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly (20 mg for patients older than 70 years). After 24 months, responders will continue pomalidomide and dexamethasone alone until progression.
At enrollment, patients had to have relapsed and/or refractory disease after at least two lines of prior therapy including an IMiD and a PI, an ECOG performance status of less than 2, and adequate organ function.
Key exclusion criteria are an active autoimmune disease requiring systemic treatment or a history of severe autoimmune disease such as interstitial lung disease or active, non-infectious pneumonitis.
Patients received a median of three prior lines of therapy, 67% had prior autologous transplant, 89% were refractory to lenalidomide, and 70% were double-refractory to both IMiDs and PIs. The median age was 65 years (range 42-81 years), 73% were male, and 42% had high-risk deletion 17p and/or a translocation of chromosomes 14 and 16 [t(14;16)].
The median number of cycles was six and median follow-up short at 7.4 months.
The most common adverse events reported in 10% of all grades were fatigue and hypoglycemia, mostly grades 1 and 2.
The most serious adverse events in the study were pneumonia and infection, including one death due to sepsis, Dr. Badros said. Two other patients died as a result of disease progression and one because of a cardiac event.
“We reported a lot, actually, of immune-related adverse events,” he said.
In 10% of patients, the investigators noted pneumonitis, one of which was grade 3, as well as hyperthyroidism and autoimmune hepatitis. Pembrolizumab was not stopped and the pneumonitis was treated with steroids until symptoms resolved. Patients resumed the assigned doses, though one patient withdrew consent.
The pneumonitis did not appear to be associated with prior therapy and it “responded extremely quickly and well to the steroids, indicating it might be a cytokine release issue,” Dr. Badros said.
Five patients required pomalidomide dose reductions due to neutropenia in two, and one case each of rash, palpitations, and fatigue. After the septic death, antibiotic prophylaxis was started in all patients, he said.
A total of 22 patients remain on study, with 7 patients discontinuing because of disease progression.
Given the short follow-up, it is “too early to talk about progression-free and overall-survival, but the signal we are getting is quite impressive,” Dr. Badros said.
The investigators also tried to look at PD-L1 expression in bone marrow samples collected at screening and on day 1 of cycle 3. No PD-L1 expression was found on plasma cells in the first patient, about 40% expression in the second, and 100% expression in the third, which is consistent with the heterogeneity of PD-L1 expression reported previously in the literature, Dr. Badros said. PD-L1 expression on bone marrow biopsies was very hard to standardize and they are exploring various methods to assess the impact of fixation and decalcification on level of expression, he added.
Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.
AT ASH 2015
Key clinical point: Pembrolizumab in combination with pomalidomide and dexamethasone has shown strong clinical activity in heavily pretreated relapsed or refractory multiple myeloma.
Major finding: The overall response rate was 60% in 27 evaluable patients.
Data source: Ongoing phase II study of 33 patients with relapsed/refractory multiple myeloma.
Disclosures: Dr. Badros disclosed off-label use of pembrolizumab and no relevant conflicts of interest.
Keep canthopexy, canthoplasty in your sights for periorbital aging
CHICAGO – Canthopexy and canthoplasty are simple, minimally invasive procedures that are often overlooked when treating periorbital aging, Dr. Cameron D. Chesnut said at the annual meeting of the American Society for Dermatologic Surgery.
“In a simple procedure you can do in the office in literally 5 or 10 minutes under local anesthesia, you can restore the integrity of the lower lid, which in addition gives some improvement in the upper lids by lifting the globe back up,” he said.
Canthopexy and canthoplasty are very commonly performed with blepharoplasty, but can be useful on their own or in combination with fillers in mild cases of retinacular aging or lower-lid ectropion where you don’t need or want a true, full-blown blepharoplasty.
There is a labyrinth of connective tissues attached to Whitnall’s tubercle and as patients age, there is laxity of the septum, retinaculum, and orbicularis; rounding of the lateral canthal angle; and a negative intercanthal tilt that develops as the lateral canthus drops in relation to the medial canthus, said Dr. Chesnut, who is in private practice in Spokane, Wash.
In the canthopexy, the lateral canthal tendon is folded over and stabilized with a stitch, but not dispensed with. “Yes, this is surgical, but this is literally a stab incision with an 11 blade to access this,” he noted.
The key to a successful canthopexy is to release the tarsal strap, which is relatively resistant to aging laxity and tethers the lateral canthus inferiorly. “While everything else around it becomes lax, it tends to stay pretty strong and pulls down the whole lateral canthal complex,” he observed.
The canthoplasty creates more tension on the lower lid, but is more invasive. The lateral canthal tendon is cut, releasing the retinaculum. The eyelid opening is then shortened and the tendon reconstructed and reattached to the bone.
Particular attention should be paid in both procedures to globe position, particularly in patients with a negative vector in which the globe protrudes beyond their malar eminence and lower eyelid, Dr. Chesnut pointed out.
“You need to be careful with these patients because if you tighten the lower lid too much, the lower lid margin will take the path of least resistance and descend down the globe instead of up,” he said. “These are the patients that may need volume or face lifting to increase that malar support.” Complications can include overtightening, but this is nearly impossible to do with a canthopexy and usually relaxes with a canthoplasty, Dr. Chesnut said in an interview. “Avoiding it all boils down to proper preoperative planning of the amount of tightening needed.”
Likewise, proper planning can avoid undercorrection.
“This can occasionally be from failure of the reconstructed or plicated lateral canthal tendon, but this is a very robust structure, and when properly fixated to the periosteum of Whitnall’s tubercle, failure is unlikely,” Dr. Chesnut explained. “The tendon will continue to age normally, so a canthopexy patient may require or want more tightening with a canthoplasty years down the road.”
Lower-lid laxity should be assessed in all patients prior to either procedure and can be determined by performing the distraction test, in which the eyelid is grasped and pulled anteriorly. If the eyelid can be distracted by more than 6 mm to 8 mm, then laxity is present. The snapback test, where the lower lid is pulled toward the inferior orbital rim and then released, can also be used to identify poor lid tone.
Dr. Chesnut reported having no conflicts of interest.
CHICAGO – Canthopexy and canthoplasty are simple, minimally invasive procedures that are often overlooked when treating periorbital aging, Dr. Cameron D. Chesnut said at the annual meeting of the American Society for Dermatologic Surgery.
“In a simple procedure you can do in the office in literally 5 or 10 minutes under local anesthesia, you can restore the integrity of the lower lid, which in addition gives some improvement in the upper lids by lifting the globe back up,” he said.
Canthopexy and canthoplasty are very commonly performed with blepharoplasty, but can be useful on their own or in combination with fillers in mild cases of retinacular aging or lower-lid ectropion where you don’t need or want a true, full-blown blepharoplasty.
There is a labyrinth of connective tissues attached to Whitnall’s tubercle and as patients age, there is laxity of the septum, retinaculum, and orbicularis; rounding of the lateral canthal angle; and a negative intercanthal tilt that develops as the lateral canthus drops in relation to the medial canthus, said Dr. Chesnut, who is in private practice in Spokane, Wash.
In the canthopexy, the lateral canthal tendon is folded over and stabilized with a stitch, but not dispensed with. “Yes, this is surgical, but this is literally a stab incision with an 11 blade to access this,” he noted.
The key to a successful canthopexy is to release the tarsal strap, which is relatively resistant to aging laxity and tethers the lateral canthus inferiorly. “While everything else around it becomes lax, it tends to stay pretty strong and pulls down the whole lateral canthal complex,” he observed.
The canthoplasty creates more tension on the lower lid, but is more invasive. The lateral canthal tendon is cut, releasing the retinaculum. The eyelid opening is then shortened and the tendon reconstructed and reattached to the bone.
Particular attention should be paid in both procedures to globe position, particularly in patients with a negative vector in which the globe protrudes beyond their malar eminence and lower eyelid, Dr. Chesnut pointed out.
“You need to be careful with these patients because if you tighten the lower lid too much, the lower lid margin will take the path of least resistance and descend down the globe instead of up,” he said. “These are the patients that may need volume or face lifting to increase that malar support.” Complications can include overtightening, but this is nearly impossible to do with a canthopexy and usually relaxes with a canthoplasty, Dr. Chesnut said in an interview. “Avoiding it all boils down to proper preoperative planning of the amount of tightening needed.”
Likewise, proper planning can avoid undercorrection.
“This can occasionally be from failure of the reconstructed or plicated lateral canthal tendon, but this is a very robust structure, and when properly fixated to the periosteum of Whitnall’s tubercle, failure is unlikely,” Dr. Chesnut explained. “The tendon will continue to age normally, so a canthopexy patient may require or want more tightening with a canthoplasty years down the road.”
Lower-lid laxity should be assessed in all patients prior to either procedure and can be determined by performing the distraction test, in which the eyelid is grasped and pulled anteriorly. If the eyelid can be distracted by more than 6 mm to 8 mm, then laxity is present. The snapback test, where the lower lid is pulled toward the inferior orbital rim and then released, can also be used to identify poor lid tone.
Dr. Chesnut reported having no conflicts of interest.
CHICAGO – Canthopexy and canthoplasty are simple, minimally invasive procedures that are often overlooked when treating periorbital aging, Dr. Cameron D. Chesnut said at the annual meeting of the American Society for Dermatologic Surgery.
“In a simple procedure you can do in the office in literally 5 or 10 minutes under local anesthesia, you can restore the integrity of the lower lid, which in addition gives some improvement in the upper lids by lifting the globe back up,” he said.
Canthopexy and canthoplasty are very commonly performed with blepharoplasty, but can be useful on their own or in combination with fillers in mild cases of retinacular aging or lower-lid ectropion where you don’t need or want a true, full-blown blepharoplasty.
There is a labyrinth of connective tissues attached to Whitnall’s tubercle and as patients age, there is laxity of the septum, retinaculum, and orbicularis; rounding of the lateral canthal angle; and a negative intercanthal tilt that develops as the lateral canthus drops in relation to the medial canthus, said Dr. Chesnut, who is in private practice in Spokane, Wash.
In the canthopexy, the lateral canthal tendon is folded over and stabilized with a stitch, but not dispensed with. “Yes, this is surgical, but this is literally a stab incision with an 11 blade to access this,” he noted.
The key to a successful canthopexy is to release the tarsal strap, which is relatively resistant to aging laxity and tethers the lateral canthus inferiorly. “While everything else around it becomes lax, it tends to stay pretty strong and pulls down the whole lateral canthal complex,” he observed.
The canthoplasty creates more tension on the lower lid, but is more invasive. The lateral canthal tendon is cut, releasing the retinaculum. The eyelid opening is then shortened and the tendon reconstructed and reattached to the bone.
Particular attention should be paid in both procedures to globe position, particularly in patients with a negative vector in which the globe protrudes beyond their malar eminence and lower eyelid, Dr. Chesnut pointed out.
“You need to be careful with these patients because if you tighten the lower lid too much, the lower lid margin will take the path of least resistance and descend down the globe instead of up,” he said. “These are the patients that may need volume or face lifting to increase that malar support.” Complications can include overtightening, but this is nearly impossible to do with a canthopexy and usually relaxes with a canthoplasty, Dr. Chesnut said in an interview. “Avoiding it all boils down to proper preoperative planning of the amount of tightening needed.”
Likewise, proper planning can avoid undercorrection.
“This can occasionally be from failure of the reconstructed or plicated lateral canthal tendon, but this is a very robust structure, and when properly fixated to the periosteum of Whitnall’s tubercle, failure is unlikely,” Dr. Chesnut explained. “The tendon will continue to age normally, so a canthopexy patient may require or want more tightening with a canthoplasty years down the road.”
Lower-lid laxity should be assessed in all patients prior to either procedure and can be determined by performing the distraction test, in which the eyelid is grasped and pulled anteriorly. If the eyelid can be distracted by more than 6 mm to 8 mm, then laxity is present. The snapback test, where the lower lid is pulled toward the inferior orbital rim and then released, can also be used to identify poor lid tone.
Dr. Chesnut reported having no conflicts of interest.
EXPERT ANALYSIS FROM THE ASDS ANNUAL MEETING
VIDEO: High-intensity conditioning stands ground in MDS, AML
ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.
Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).
The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.
Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.
“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”
To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.
Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).
The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.
Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.
“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”
To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ORLANDO – Reduced-intensity conditioning regimens failed to show a significant survival benefit over high-intensity regimens in myelodysplastic syndrome or acute myeloid leukemia in the phase III MAVERICK trial.
Pretransplant reduced intensity conditioning (RIC) also resulted in a significantly higher risk of relapse and inferior relapse-free survival vs. myeloablative conditioning (MAC).
The findings, reported in the late-breaking abstract (LBA-8) session at the annual meeting of the American Society of Hematology, generated a lively debate over the study construct and whether its conclusion that MAC remain “the treatment of choice” in appropriate candidates should be applied to both diseases.
Session comoderator Dr. David P. Steensma, a myelodysplasia physician at the Dana-Farber Cancer Institute in Boston, said in an interview that the data will not change his practice and that physicians should continue to “push the envelope” and provide as intense a conditioning regimen as their patients can tolerate.
“The take-home message is that using a reduced conditioning regimen whatever your choice might be, even though it is gentler on the patient and may be easier for them to go through the transplant, the biggest risk is still the disease, the underlying leukemia or myelodysplasia coming back. And the benefit from reduced intensity is not enough to outweigh that risk.”
To sort out this complex trial, we spoke with study author Dr. Bart L. Scott of the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle.
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AT ASH 2015
