User login
Stored CD34 cells for multiple myeloma patients largely unused
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
REPORTING FROM TCT 2020
FDA approves new drug for relapsed/refractory multiple myeloma
The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.
Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.
“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.
The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.
In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.
The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.
Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).
The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.
The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.
The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.
This article originally appeared on Medscape.com.
The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.
Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.
“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.
The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.
In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.
The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.
Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).
The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.
The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.
The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.
This article originally appeared on Medscape.com.
The U.S. Food and Drug Administration today approved isatuximab (Sarclisa, Sanofi) in combination with pomalidomide (Revlimid, Celgene) and dexamethasone for the treatment of adult patients with multiple myeloma who have received two or more prior therapies including lenalidomide and a proteasome inhibitor.
Isatuximab is an anti-CD38 monoclonal antibody administered by intravenous infusion that works by helping the immune system attack multiple myeloma cancer cells.
“While there is no cure for multiple myeloma, Sarclisa is now another CD38-directed treatment option added to the list of FDA-approved treatments of patients with multiple myeloma who have progressive disease after previous therapies,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“In the clinical trial, there was a 40% reduction in the risk of disease progression or death with this therapy,” he added.
The new approval is based on results from ICARIA-MM, an open-label, randomized phase 3 clinical trial of isatuximab among 307 patients in this setting.
In the trial, at a median follow-up of 11.6 months, median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group versus 6.5 months in the pomalidomide-dexamethasone group (hazard ratio, 0.60; P = .001), as reported last year. Overall response rates were 60.4% for the triplet-treated group versus 35.3% for the doublet-treated group.
The most common side effects for isatuximab included neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia.
Deaths because of treatment-related adverse events were reported for one patient (less than 1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two patients (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).
The drug can also cause serious side effects, including IV infusion-related reactions. In the case of a grade 3 or higher reaction, the drug should be permanently discontinued and health care professionals should institute appropriate medical management.
The FDA notes there have been higher incidences of second primary malignancies observed in a controlled clinical trial of patients with multiple myeloma receiving the drug.
The FDA also highlighted that laboratory test interference may be caused by isatuximab and that blood banks should be informed that patients are receiving the drug. Isatuximab may interfere with, for example, antibody screening for patients who need a blood transfusion. Isatuximab may also interfere with the assays used to monitor M-protein, which may impact the determination of complete response.
This article originally appeared on Medscape.com.
New CAR T-cell therapy eliminates MM and tumor propagating cells without fratricide in lab study
These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.
This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.
Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.
Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.
“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.
The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.
SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.
These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.
This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.
Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.
Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.
“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.
The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.
SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.
These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.
This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.
Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.
Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.
“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.
The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.
SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.
FROM NATURE COMMUNICATIONS
CRISPR-engineered T cells may be safe for cancer, but do they work?
according to a report in Science.
The results of no harm support this “promising” area of cancer immunotherapy, according to study investigator Edward A. Stadtmauer, MD, of the University of Pennsylvania in Philadelphia and colleagues.
However, there was no evidence of benefit in this trial. One patient transfused with CRISPR-engineered T cells has since died, and the other two have moved on to other treatments.
“The big question that remains unanswered by this study is whether gene-edited, engineered T cells are effective against advanced cancer,” Jennifer Hamilton, PhD, and Jennifer Doudna, PhD, both of the University of California, Berkeley, wrote in an accompanying editorial.
The study enrolled six patients with refractory cancer, and three of them received CRISPR-engineered T cells. Two patients had multiple myeloma, and one had metastatic sarcoma.
Dr. Stadtmauer and colleagues drew blood from the patients, isolated the T cells, and used CRISPR-Cas9 to modify the cells. The T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC and TRBC (genes encoding the T-cell receptor chains TCR-alpha and TCR-beta) as well as PDCD1 (a gene encoding programmed cell death protein 1). The T cells were then transduced with a lentiviral vector to express a transgenic NY-ESO-1 cancer-specific T-cell receptor.
The investigators expanded the cell lines and infused them back into the patients after administering lymphodepleting chemotherapy. The sarcoma patient initially had a 50% decrease in a large abdominal mass, but all three patients ultimately progressed.
The editorialists noted that gene disruption efficiencies in this study were “modest,” ranging from 15% to 45%, but the investigators used a protocol from 2016, when the study was given the go-ahead by the National Institutes of Health and the Food and Drug Administration. With current protocols, gene disruption efficiencies can exceed 90%, which means patients might do better in subsequent trials.
There was no more than mild toxicity in this trial, and most adverse events were attributed to the lymphodepleting chemotherapy.
There was concern about potential rejection of infused cells because of preexisting immune responses to Cas9, but it doesn’t seem “to be a barrier to the application of this promising technology,” the investigators said.
They noted that “the stable engraftment of our engineered T cells is remarkably different from previously reported trials ... where the half-life of the cells in blood was [about] 1 week. Biopsy specimens of bone marrow in the myeloma patients and tumor in the sarcoma patient demonstrated trafficking of the engineered T cells to the tumor in all three patients” beyond that point. The decay half-life of the transduced cells was 20.3 days, 121.8 days, and 293.5 days in these patients.
The editorialists said the details in the report are a model for other researchers to follow, but “as more gene-based therapies are demonstrated to be safe and effective, the barrier to clinical translation will become cell manufacturing and administration.”
This work was funded by the National Institutes of Health and others. Dr. Stadtmauer didn’t report any disclosures, but other investigators disclosed patent applications and commercialization efforts. Dr. Doudna disclosed that she is a cofounder or adviser for several companies developing gene-editing therapeutics.
SOURCE: Stadtmauer EA et al. Science. 2020 Feb 6. doi: 10.1126/science.aba7365.
according to a report in Science.
The results of no harm support this “promising” area of cancer immunotherapy, according to study investigator Edward A. Stadtmauer, MD, of the University of Pennsylvania in Philadelphia and colleagues.
However, there was no evidence of benefit in this trial. One patient transfused with CRISPR-engineered T cells has since died, and the other two have moved on to other treatments.
“The big question that remains unanswered by this study is whether gene-edited, engineered T cells are effective against advanced cancer,” Jennifer Hamilton, PhD, and Jennifer Doudna, PhD, both of the University of California, Berkeley, wrote in an accompanying editorial.
The study enrolled six patients with refractory cancer, and three of them received CRISPR-engineered T cells. Two patients had multiple myeloma, and one had metastatic sarcoma.
Dr. Stadtmauer and colleagues drew blood from the patients, isolated the T cells, and used CRISPR-Cas9 to modify the cells. The T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC and TRBC (genes encoding the T-cell receptor chains TCR-alpha and TCR-beta) as well as PDCD1 (a gene encoding programmed cell death protein 1). The T cells were then transduced with a lentiviral vector to express a transgenic NY-ESO-1 cancer-specific T-cell receptor.
The investigators expanded the cell lines and infused them back into the patients after administering lymphodepleting chemotherapy. The sarcoma patient initially had a 50% decrease in a large abdominal mass, but all three patients ultimately progressed.
The editorialists noted that gene disruption efficiencies in this study were “modest,” ranging from 15% to 45%, but the investigators used a protocol from 2016, when the study was given the go-ahead by the National Institutes of Health and the Food and Drug Administration. With current protocols, gene disruption efficiencies can exceed 90%, which means patients might do better in subsequent trials.
There was no more than mild toxicity in this trial, and most adverse events were attributed to the lymphodepleting chemotherapy.
There was concern about potential rejection of infused cells because of preexisting immune responses to Cas9, but it doesn’t seem “to be a barrier to the application of this promising technology,” the investigators said.
They noted that “the stable engraftment of our engineered T cells is remarkably different from previously reported trials ... where the half-life of the cells in blood was [about] 1 week. Biopsy specimens of bone marrow in the myeloma patients and tumor in the sarcoma patient demonstrated trafficking of the engineered T cells to the tumor in all three patients” beyond that point. The decay half-life of the transduced cells was 20.3 days, 121.8 days, and 293.5 days in these patients.
The editorialists said the details in the report are a model for other researchers to follow, but “as more gene-based therapies are demonstrated to be safe and effective, the barrier to clinical translation will become cell manufacturing and administration.”
This work was funded by the National Institutes of Health and others. Dr. Stadtmauer didn’t report any disclosures, but other investigators disclosed patent applications and commercialization efforts. Dr. Doudna disclosed that she is a cofounder or adviser for several companies developing gene-editing therapeutics.
SOURCE: Stadtmauer EA et al. Science. 2020 Feb 6. doi: 10.1126/science.aba7365.
according to a report in Science.
The results of no harm support this “promising” area of cancer immunotherapy, according to study investigator Edward A. Stadtmauer, MD, of the University of Pennsylvania in Philadelphia and colleagues.
However, there was no evidence of benefit in this trial. One patient transfused with CRISPR-engineered T cells has since died, and the other two have moved on to other treatments.
“The big question that remains unanswered by this study is whether gene-edited, engineered T cells are effective against advanced cancer,” Jennifer Hamilton, PhD, and Jennifer Doudna, PhD, both of the University of California, Berkeley, wrote in an accompanying editorial.
The study enrolled six patients with refractory cancer, and three of them received CRISPR-engineered T cells. Two patients had multiple myeloma, and one had metastatic sarcoma.
Dr. Stadtmauer and colleagues drew blood from the patients, isolated the T cells, and used CRISPR-Cas9 to modify the cells. The T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC and TRBC (genes encoding the T-cell receptor chains TCR-alpha and TCR-beta) as well as PDCD1 (a gene encoding programmed cell death protein 1). The T cells were then transduced with a lentiviral vector to express a transgenic NY-ESO-1 cancer-specific T-cell receptor.
The investigators expanded the cell lines and infused them back into the patients after administering lymphodepleting chemotherapy. The sarcoma patient initially had a 50% decrease in a large abdominal mass, but all three patients ultimately progressed.
The editorialists noted that gene disruption efficiencies in this study were “modest,” ranging from 15% to 45%, but the investigators used a protocol from 2016, when the study was given the go-ahead by the National Institutes of Health and the Food and Drug Administration. With current protocols, gene disruption efficiencies can exceed 90%, which means patients might do better in subsequent trials.
There was no more than mild toxicity in this trial, and most adverse events were attributed to the lymphodepleting chemotherapy.
There was concern about potential rejection of infused cells because of preexisting immune responses to Cas9, but it doesn’t seem “to be a barrier to the application of this promising technology,” the investigators said.
They noted that “the stable engraftment of our engineered T cells is remarkably different from previously reported trials ... where the half-life of the cells in blood was [about] 1 week. Biopsy specimens of bone marrow in the myeloma patients and tumor in the sarcoma patient demonstrated trafficking of the engineered T cells to the tumor in all three patients” beyond that point. The decay half-life of the transduced cells was 20.3 days, 121.8 days, and 293.5 days in these patients.
The editorialists said the details in the report are a model for other researchers to follow, but “as more gene-based therapies are demonstrated to be safe and effective, the barrier to clinical translation will become cell manufacturing and administration.”
This work was funded by the National Institutes of Health and others. Dr. Stadtmauer didn’t report any disclosures, but other investigators disclosed patent applications and commercialization efforts. Dr. Doudna disclosed that she is a cofounder or adviser for several companies developing gene-editing therapeutics.
SOURCE: Stadtmauer EA et al. Science. 2020 Feb 6. doi: 10.1126/science.aba7365.
FROM SCIENCE
Start of myeloma therapy may be delayed for women, minorities
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
FROM JCO ONCOLOGY PRACTICE
Key clinical point:
Major finding: Patients with delays in treatment were more likely to be women (odds ratio, 1.15) and more likely to be non-Hispanic blacks (OR, 1.21).
Study details: Retrospective analysis of 74,722 patients in the National Cancer Database diagnosed with multiple myeloma between 2004 and 2015.
Disclosures: Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
Source: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Inhibitor appears to strengthen anti-BCMA CAR T cells in myeloma patients
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
REPORTING FROM ASH 2019
D-RVd for frontline myeloma looks robust in GRIFFIN trial update
ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.
D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.
Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.
“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.
Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.
In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.
Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.
With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.
The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.
Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.
Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 106 cells/kg for D-RVd and 9.4 x 106 cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”
Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.
SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.
ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.
D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.
Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.
“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.
Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.
In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.
Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.
With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.
The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.
Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.
Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 106 cells/kg for D-RVd and 9.4 x 106 cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”
Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.
SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.
ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.
D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.
Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.
“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.
Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.
In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.
Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.
With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.
The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.
Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.
Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 106 cells/kg for D-RVd and 9.4 x 106 cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”
Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.
SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.
REPORTING FROM ASH 2019
Myeloma patients over age 70 can benefit from auto-HC transplant
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
REPORTING FROM ASH 2019
Bispecific CAR T-cells yield high response rate in relapsed/refractory myeloma
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
REPORTING FROM ASH 2019
High complete response rate seen with novel CAR-T for myeloma
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
REPORTING FROM ASH 2019