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Questions surround MRD assessment in MM
DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.
However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.
The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.
What we know
Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM1, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.2
Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.3
NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).
With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.
Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 105).
Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).
Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.4
What we don’t know
Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.
Another uncertainty is the optimal sensitivity threshold. In the POLLUX study5, researchers found that a threshold of 10-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.
So although 10-4 proved inaccurate, it isn’t clear if the optimal threshold is 10-5 or 10-6, Dr. Valković said.
Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.
In a study published in 2017, PET produced false-negatives in MM patients.6 In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.
Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:
- If patients don’t achieve MRD negativity, should they continue on the therapy?
- If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
- Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?
“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.
He did not declare any conflicts of interest.
1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160
2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319
3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6
4. Fernandez RA et al. Blood. 2017; 130:3098
5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282
6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422
DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.
However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.
The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.
What we know
Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM1, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.2
Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.3
NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).
With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.
Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 105).
Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).
Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.4
What we don’t know
Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.
Another uncertainty is the optimal sensitivity threshold. In the POLLUX study5, researchers found that a threshold of 10-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.
So although 10-4 proved inaccurate, it isn’t clear if the optimal threshold is 10-5 or 10-6, Dr. Valković said.
Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.
In a study published in 2017, PET produced false-negatives in MM patients.6 In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.
Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:
- If patients don’t achieve MRD negativity, should they continue on the therapy?
- If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
- Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?
“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.
He did not declare any conflicts of interest.
1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160
2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319
3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6
4. Fernandez RA et al. Blood. 2017; 130:3098
5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282
6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422
DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.
However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.
The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.
What we know
Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM1, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.2
Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.3
NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).
With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.
Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 105).
Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).
Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.4
What we don’t know
Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.
Another uncertainty is the optimal sensitivity threshold. In the POLLUX study5, researchers found that a threshold of 10-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.
So although 10-4 proved inaccurate, it isn’t clear if the optimal threshold is 10-5 or 10-6, Dr. Valković said.
Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.
In a study published in 2017, PET produced false-negatives in MM patients.6 In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.
Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:
- If patients don’t achieve MRD negativity, should they continue on the therapy?
- If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
- Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?
“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.
He did not declare any conflicts of interest.
1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160
2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319
3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi: https://doi.org/10.1016/S1470-2045(16)30206-6
4. Fernandez RA et al. Blood. 2017; 130:3098
5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282
6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422
STRO-001 receives orphan designation for MM
The U.S. Food and Drug Administration (FDA) has granted orphan designation to STRO-001 for the treatment of multiple myeloma (MM).
STRO-001 is an antibody-drug conjugate targeting CD74, a protein highly expressed in MM and other B-cell malignancies.
Sutro Biopharma, Inc., is currently studying STRO-001 in a phase 1 trial enrolling separate dose-escalation cohorts for MM and B-cell lymphoma.
Preclinical research of STRO-001 in MM was presented at the 2017 ASH Annual Meeting.
Researchers examined bone marrow samples from MM patients and detected CD74 expression in 35 of the 36 samples, including specimens from patients who were treatment-naïve and patients who had been heavily pretreated with chemotherapy and stem cell transplant.
The researchers then found that STRO-001 demonstrated cytotoxicity in MM cell lines.
STRO-001 also reduced tumor burden in two disseminated xenograft models (ARP-1 and MM.1S) and prolonged survival in one of them (MM.1S).
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The U.S. Food and Drug Administration (FDA) has granted orphan designation to STRO-001 for the treatment of multiple myeloma (MM).
STRO-001 is an antibody-drug conjugate targeting CD74, a protein highly expressed in MM and other B-cell malignancies.
Sutro Biopharma, Inc., is currently studying STRO-001 in a phase 1 trial enrolling separate dose-escalation cohorts for MM and B-cell lymphoma.
Preclinical research of STRO-001 in MM was presented at the 2017 ASH Annual Meeting.
Researchers examined bone marrow samples from MM patients and detected CD74 expression in 35 of the 36 samples, including specimens from patients who were treatment-naïve and patients who had been heavily pretreated with chemotherapy and stem cell transplant.
The researchers then found that STRO-001 demonstrated cytotoxicity in MM cell lines.
STRO-001 also reduced tumor burden in two disseminated xenograft models (ARP-1 and MM.1S) and prolonged survival in one of them (MM.1S).
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The U.S. Food and Drug Administration (FDA) has granted orphan designation to STRO-001 for the treatment of multiple myeloma (MM).
STRO-001 is an antibody-drug conjugate targeting CD74, a protein highly expressed in MM and other B-cell malignancies.
Sutro Biopharma, Inc., is currently studying STRO-001 in a phase 1 trial enrolling separate dose-escalation cohorts for MM and B-cell lymphoma.
Preclinical research of STRO-001 in MM was presented at the 2017 ASH Annual Meeting.
Researchers examined bone marrow samples from MM patients and detected CD74 expression in 35 of the 36 samples, including specimens from patients who were treatment-naïve and patients who had been heavily pretreated with chemotherapy and stem cell transplant.
The researchers then found that STRO-001 demonstrated cytotoxicity in MM cell lines.
STRO-001 also reduced tumor burden in two disseminated xenograft models (ARP-1 and MM.1S) and prolonged survival in one of them (MM.1S).
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Selinexor receives priority review for penta-refractory MM
The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.
With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.
Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.
Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.
Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.
STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.
Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.
Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.
The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).
Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.
The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.
With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.
Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.
Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.
Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.
STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.
Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.
Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.
The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).
Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.
The U.S. Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for selinexor.
With this NDA, Karyopharm Therapeutics Inc., is seeking accelerated approval for selinexor, an oral selective inhibitor of nuclear export compound, as a treatment for penta-refractory multiple myeloma (MM).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA plans to make a decision on the NDA for selinexor by April 6, 2019.
Selinexor also has orphan drug and fast track designations from the FDA for the treatment of penta-refractory MM.
Selinexor has demonstrated a clinical benefit in penta-refractory MM patients in the phase 2 STORM trial, according to researchers.
Results from this trial were recently presented at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting.
STORM included 122 patients with penta-refractory MM. They received selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.
Two patients (1.6%) achieved stringent complete responses (with minimal residual disease negativity), six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses, and 16 (13.1%) had minimal responses.
Forty-eight patients (39.3%) had stable disease, 16 (13.1%) had progressive disease, and 10 (8.2%) were not evaluable for response.
The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.
Common treatment-related adverse events included fatigue/asthenia (69.9%), nausea (69.1%), thrombocytopenia (67.5%), anorexia (52.0%), anemia (48.0%), weight loss (47.2%), neutropenia (35.8%), vomiting (35.0%), diarrhea (33.3%), hyponatremia (30.9%), leukopenia (29.3%), and lymphopenia (13.8%).
Trials of selinexor were placed on partial clinical hold in March 2017 due to a lack of information about serious adverse events. However, the hold was lifted for trials of patients with hematologic malignancies at the end of that same month.
Quadruplet therapy could be the future in MM
New York—Four-drug combinations are holding promise for the treatment of multiple myeloma (MM), although data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center.
The efficacy of multiple triplet regimens has been well documented, and data are now emerging on the potential of 4-drug combinations.
“Triplet therapy is the standard,” she said during a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies, “and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, she said, is SWOG 0777, an open label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable. The trial was recently reported in The Lancet.
The median progression free survival (PFS) was 43 months for the triplet, versus 30 months for the two-drug regimen (P=0.0018).
Likewise, median overall survival (OS) was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P=0.025).
“Very convincingly, just receiving that short exposure to bortezomib,” she said, “ended up causing a substantial increase of progression-free and overall survival.”
Effective triplet regimens include the combination of carfilzomib, lenalidomide, and dexamethasone (KRd), cyclophosphamide, bortezomib, and dexamethasone (CyBorD), and more recently, ixazomib, lenalidomide, and dexamethasone (IRd).
These regimens have “excellent” response rates and survival data, Dr. Callander noted.
Quadruplet data
The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at ASCO 2017 (abstract 8002).
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data also presented at ASCO 2017 (abstract 8000), with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr Callander conjectured.
Four versus three drug strategies are being evaluated in ongoing randomized clinical trials including patients with previously untreated myeloma, she said.
These studies include Cassiopeia (NCT02541383), which is evaluating bortezomib, thalidomide, and dexamethasone with or without daratumumab, and GRIFFIN (NCT02874742), which is looking at VRd with or without daratumumab.
Daratumumab received an additional indication in myeloma, this time as part of a 4-drug regimen, several months ago, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The U.S. Food and Drug Administration (FDA) approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE (MMY3007) study, published in The New England Journal of Medicine, showing an 18-month PFS of 71.6% for the 4-drug combination versus 50.2% for VMP alone (P<0.001).
New York—Four-drug combinations are holding promise for the treatment of multiple myeloma (MM), although data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center.
The efficacy of multiple triplet regimens has been well documented, and data are now emerging on the potential of 4-drug combinations.
“Triplet therapy is the standard,” she said during a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies, “and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, she said, is SWOG 0777, an open label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable. The trial was recently reported in The Lancet.
The median progression free survival (PFS) was 43 months for the triplet, versus 30 months for the two-drug regimen (P=0.0018).
Likewise, median overall survival (OS) was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P=0.025).
“Very convincingly, just receiving that short exposure to bortezomib,” she said, “ended up causing a substantial increase of progression-free and overall survival.”
Effective triplet regimens include the combination of carfilzomib, lenalidomide, and dexamethasone (KRd), cyclophosphamide, bortezomib, and dexamethasone (CyBorD), and more recently, ixazomib, lenalidomide, and dexamethasone (IRd).
These regimens have “excellent” response rates and survival data, Dr. Callander noted.
Quadruplet data
The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at ASCO 2017 (abstract 8002).
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data also presented at ASCO 2017 (abstract 8000), with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr Callander conjectured.
Four versus three drug strategies are being evaluated in ongoing randomized clinical trials including patients with previously untreated myeloma, she said.
These studies include Cassiopeia (NCT02541383), which is evaluating bortezomib, thalidomide, and dexamethasone with or without daratumumab, and GRIFFIN (NCT02874742), which is looking at VRd with or without daratumumab.
Daratumumab received an additional indication in myeloma, this time as part of a 4-drug regimen, several months ago, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The U.S. Food and Drug Administration (FDA) approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE (MMY3007) study, published in The New England Journal of Medicine, showing an 18-month PFS of 71.6% for the 4-drug combination versus 50.2% for VMP alone (P<0.001).
New York—Four-drug combinations are holding promise for the treatment of multiple myeloma (MM), although data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center.
The efficacy of multiple triplet regimens has been well documented, and data are now emerging on the potential of 4-drug combinations.
“Triplet therapy is the standard,” she said during a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies, “and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, she said, is SWOG 0777, an open label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable. The trial was recently reported in The Lancet.
The median progression free survival (PFS) was 43 months for the triplet, versus 30 months for the two-drug regimen (P=0.0018).
Likewise, median overall survival (OS) was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P=0.025).
“Very convincingly, just receiving that short exposure to bortezomib,” she said, “ended up causing a substantial increase of progression-free and overall survival.”
Effective triplet regimens include the combination of carfilzomib, lenalidomide, and dexamethasone (KRd), cyclophosphamide, bortezomib, and dexamethasone (CyBorD), and more recently, ixazomib, lenalidomide, and dexamethasone (IRd).
These regimens have “excellent” response rates and survival data, Dr. Callander noted.
Quadruplet data
The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at ASCO 2017 (abstract 8002).
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data also presented at ASCO 2017 (abstract 8000), with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr Callander conjectured.
Four versus three drug strategies are being evaluated in ongoing randomized clinical trials including patients with previously untreated myeloma, she said.
These studies include Cassiopeia (NCT02541383), which is evaluating bortezomib, thalidomide, and dexamethasone with or without daratumumab, and GRIFFIN (NCT02874742), which is looking at VRd with or without daratumumab.
Daratumumab received an additional indication in myeloma, this time as part of a 4-drug regimen, several months ago, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The U.S. Food and Drug Administration (FDA) approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE (MMY3007) study, published in The New England Journal of Medicine, showing an 18-month PFS of 71.6% for the 4-drug combination versus 50.2% for VMP alone (P<0.001).
Carfilzomib receives approval for once-weekly dosing
The U.S. Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) for a once-weekly dosing option in combination with dexamethasone for patients with relapsed or refractory multiple myeloma (MM).
Carfilzomib administered once-weekly at 70 mg/m2 with dexamethasone achieved a superior progression-free survival (PFS) and overall response rates (ORR) compared to twice-weekly carfilzomib at doses of 27 mg/m2.
Carfilzomib is not, however, approved for the twice-weekly 27 mg/m2 dose with dexamethasone alone, but with dexamethasone and lenalidomide.
The FDA based its approval on data from the phase 3 ARROW trial.
The FDA reviewed and approved the supplemental New Drug Application under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot program. The program is exploring a more efficient review process to ensure that safe and effective treatments are available to patients as soon as possible.
The FDA approved the carfilzomib application in just over a month.
ARROW
The ARROW study, reported at the 2018 ASCO annual meeting and published in The Lancet, evaluated 478 patients with relapsed or refractory MM who had received at least two but no more than three prior therapies. Prior therapies could include bortezomib and an immunomodulatory drug.
Patients randomized to the investigational arm receive a 30-minute infusion of once-weekly carfilzomib (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with 40 mg of dexamethasone.
Patients randomized to the comparator arm received a 10-minute infusion of twice-weekly carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with 40 mg of dexamethasone.
Patients in the once-weekly arm achieved a statistically significant 3.7-month improvement in PFS compared to the twice-weekly regimen. Median PFS was 11.2 months for the once-weekly patients and 7.6 months for the twice-weekly group (P=0.0014).
Patients in the once-weekly group had a 62.9% ORR compared to 40.8% for those treated twice weekly (P<0.0001).
More patients (7.1%) in the once-weekly group had complete responses or better than those in the twice-weekly arm (1.7%).
The safety profile of the two arms were comparable, with no new safety risks identified in the once-weekly arm.
Treatment-emergent adverse events occurring in 20% or more patients in either arm included anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.
First approved in 2012, carfilzomib has indications for the following in the U.S.:
- Treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with dexamethasone or with lenalidomide plus dexamethasone.
- As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Amgen manufactures carfilzomib for Onyx Pharmaceuticals, Inc.
Prescribing information for carfilzomib is available online.
The U.S. Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) for a once-weekly dosing option in combination with dexamethasone for patients with relapsed or refractory multiple myeloma (MM).
Carfilzomib administered once-weekly at 70 mg/m2 with dexamethasone achieved a superior progression-free survival (PFS) and overall response rates (ORR) compared to twice-weekly carfilzomib at doses of 27 mg/m2.
Carfilzomib is not, however, approved for the twice-weekly 27 mg/m2 dose with dexamethasone alone, but with dexamethasone and lenalidomide.
The FDA based its approval on data from the phase 3 ARROW trial.
The FDA reviewed and approved the supplemental New Drug Application under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot program. The program is exploring a more efficient review process to ensure that safe and effective treatments are available to patients as soon as possible.
The FDA approved the carfilzomib application in just over a month.
ARROW
The ARROW study, reported at the 2018 ASCO annual meeting and published in The Lancet, evaluated 478 patients with relapsed or refractory MM who had received at least two but no more than three prior therapies. Prior therapies could include bortezomib and an immunomodulatory drug.
Patients randomized to the investigational arm receive a 30-minute infusion of once-weekly carfilzomib (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with 40 mg of dexamethasone.
Patients randomized to the comparator arm received a 10-minute infusion of twice-weekly carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with 40 mg of dexamethasone.
Patients in the once-weekly arm achieved a statistically significant 3.7-month improvement in PFS compared to the twice-weekly regimen. Median PFS was 11.2 months for the once-weekly patients and 7.6 months for the twice-weekly group (P=0.0014).
Patients in the once-weekly group had a 62.9% ORR compared to 40.8% for those treated twice weekly (P<0.0001).
More patients (7.1%) in the once-weekly group had complete responses or better than those in the twice-weekly arm (1.7%).
The safety profile of the two arms were comparable, with no new safety risks identified in the once-weekly arm.
Treatment-emergent adverse events occurring in 20% or more patients in either arm included anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.
First approved in 2012, carfilzomib has indications for the following in the U.S.:
- Treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with dexamethasone or with lenalidomide plus dexamethasone.
- As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Amgen manufactures carfilzomib for Onyx Pharmaceuticals, Inc.
Prescribing information for carfilzomib is available online.
The U.S. Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) for a once-weekly dosing option in combination with dexamethasone for patients with relapsed or refractory multiple myeloma (MM).
Carfilzomib administered once-weekly at 70 mg/m2 with dexamethasone achieved a superior progression-free survival (PFS) and overall response rates (ORR) compared to twice-weekly carfilzomib at doses of 27 mg/m2.
Carfilzomib is not, however, approved for the twice-weekly 27 mg/m2 dose with dexamethasone alone, but with dexamethasone and lenalidomide.
The FDA based its approval on data from the phase 3 ARROW trial.
The FDA reviewed and approved the supplemental New Drug Application under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot program. The program is exploring a more efficient review process to ensure that safe and effective treatments are available to patients as soon as possible.
The FDA approved the carfilzomib application in just over a month.
ARROW
The ARROW study, reported at the 2018 ASCO annual meeting and published in The Lancet, evaluated 478 patients with relapsed or refractory MM who had received at least two but no more than three prior therapies. Prior therapies could include bortezomib and an immunomodulatory drug.
Patients randomized to the investigational arm receive a 30-minute infusion of once-weekly carfilzomib (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with 40 mg of dexamethasone.
Patients randomized to the comparator arm received a 10-minute infusion of twice-weekly carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with 40 mg of dexamethasone.
Patients in the once-weekly arm achieved a statistically significant 3.7-month improvement in PFS compared to the twice-weekly regimen. Median PFS was 11.2 months for the once-weekly patients and 7.6 months for the twice-weekly group (P=0.0014).
Patients in the once-weekly group had a 62.9% ORR compared to 40.8% for those treated twice weekly (P<0.0001).
More patients (7.1%) in the once-weekly group had complete responses or better than those in the twice-weekly arm (1.7%).
The safety profile of the two arms were comparable, with no new safety risks identified in the once-weekly arm.
Treatment-emergent adverse events occurring in 20% or more patients in either arm included anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.
First approved in 2012, carfilzomib has indications for the following in the U.S.:
- Treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with dexamethasone or with lenalidomide plus dexamethasone.
- As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Amgen manufactures carfilzomib for Onyx Pharmaceuticals, Inc.
Prescribing information for carfilzomib is available online.
Will quad therapy become the new standard in myeloma?
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES
B-cell maturation antigen targeted in myeloma trials
NEW YORK – Three novel treatment strategies that target B-cell maturation antigen (BCMA) have shown promise in recent multiple myeloma clinical trials, according to Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center in Rochester, Minn.
These strategies include B-cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR) T-cell therapies, bispecific T-cell engagers (BiTEs), and a BCMA antibody–drug conjugate, Dr. Kumar said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these three platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar said.
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent that has produced an overall response rate in 67% in a group of myeloma patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, including in a phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone, or bortezomib plus dexamethasone, in patients with relapsed or refractory disease.
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma involves bb2121, which showed durable clinical responses in heavily pretreated patients, according to data presented at the 2017 annual meeting of the American Society of Hematology.
“The overall response rate is quite significant,” said Dr. Kumar, who related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the response were lasting, he said, with five patients in ongoing response for more than 1 year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar said.
Additionally, promising results have been presented on a novel CAR T-cell product, LCAR-B38M, which principally targets BCMA and led to a significant number of patients who achieved stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and costimulatory molecules are currently undergoing clinical trials, Dr. Kumar said.
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short time frame, so having an approach that is off the shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies under investigation include AMG 420 and PF-06863135, he added.
Dr. Kumar reported one disclosure related to Dr. Reddy’s Laboratories.
NEW YORK – Three novel treatment strategies that target B-cell maturation antigen (BCMA) have shown promise in recent multiple myeloma clinical trials, according to Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center in Rochester, Minn.
These strategies include B-cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR) T-cell therapies, bispecific T-cell engagers (BiTEs), and a BCMA antibody–drug conjugate, Dr. Kumar said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these three platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar said.
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent that has produced an overall response rate in 67% in a group of myeloma patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, including in a phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone, or bortezomib plus dexamethasone, in patients with relapsed or refractory disease.
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma involves bb2121, which showed durable clinical responses in heavily pretreated patients, according to data presented at the 2017 annual meeting of the American Society of Hematology.
“The overall response rate is quite significant,” said Dr. Kumar, who related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the response were lasting, he said, with five patients in ongoing response for more than 1 year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar said.
Additionally, promising results have been presented on a novel CAR T-cell product, LCAR-B38M, which principally targets BCMA and led to a significant number of patients who achieved stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and costimulatory molecules are currently undergoing clinical trials, Dr. Kumar said.
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short time frame, so having an approach that is off the shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies under investigation include AMG 420 and PF-06863135, he added.
Dr. Kumar reported one disclosure related to Dr. Reddy’s Laboratories.
NEW YORK – Three novel treatment strategies that target B-cell maturation antigen (BCMA) have shown promise in recent multiple myeloma clinical trials, according to Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center in Rochester, Minn.
These strategies include B-cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR) T-cell therapies, bispecific T-cell engagers (BiTEs), and a BCMA antibody–drug conjugate, Dr. Kumar said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these three platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar said.
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent that has produced an overall response rate in 67% in a group of myeloma patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, including in a phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone, or bortezomib plus dexamethasone, in patients with relapsed or refractory disease.
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma involves bb2121, which showed durable clinical responses in heavily pretreated patients, according to data presented at the 2017 annual meeting of the American Society of Hematology.
“The overall response rate is quite significant,” said Dr. Kumar, who related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the response were lasting, he said, with five patients in ongoing response for more than 1 year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar said.
Additionally, promising results have been presented on a novel CAR T-cell product, LCAR-B38M, which principally targets BCMA and led to a significant number of patients who achieved stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and costimulatory molecules are currently undergoing clinical trials, Dr. Kumar said.
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short time frame, so having an approach that is off the shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies under investigation include AMG 420 and PF-06863135, he added.
Dr. Kumar reported one disclosure related to Dr. Reddy’s Laboratories.
EXPERT ANALYSIS FROM THE NCCN HEMATOLOGIC MALIGNANCIES CONGRESS
BCMA-targeted platforms could alter MM therapy
New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.
The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.
BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.
BCMA antibody-drug conjugate
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.
BCMA-specific CAR T-cell therapy
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.
“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.
Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.
BiTEs
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said.
New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.
The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.
BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.
BCMA antibody-drug conjugate
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.
BCMA-specific CAR T-cell therapy
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.
“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.
Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.
BiTEs
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said.
New York—Three novel treatment strategies that target B-cell maturation antigen (BCMA) are showing promise in recent multiple myeloma (MM) clinical trials, according to Shaji K. Kumar, MD, of Mayo Clinic Cancer Center in Rochester, Minnesota.
The strategies include B-cell maturation antigen (BCMA) antibody-drug conjugate, BCMA-specific chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTEs).
“Clearly, there are a lot of exciting drugs that are currently in clinical trials, but these 3 platforms appear to be much more advanced than the others, and hopefully we will see that in the clinic in the near future,” Dr. Kumar told attendees at the NCCN 13th Annual Congress: Hematologic Malignancies.
BCMA is required for plasma cell survival and is broadly expressed on malignant plasma cells.
BCMA antibody-drug conjugate
The antibody-drug conjugate, GSK2857916, is a humanized IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent. It produced an overall response rate of 67% at the 2 highest dose levels in 9 MM patients who had previously received multiple standard-of-care agents.
“Some of the responses were quite durable, lasting several months,” he said.
Now, GSK2857916 is being evaluated in a variety of different combinations, he said, including in an upcoming phase 2 study of the antibody-drug conjugate in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in patients with relapsed or refractory disease.
BCMA-specific CAR T-cell therapy
Some of the most “exciting” data with anti-BCMA CAR T-cell therapy in myeloma, according to Dr. Kumar, involves bb2121. bb2121 showed durable clinical responses in heavily pretreated patients, according to an ASH 2017 presentation.
“The overall response rate is quite significant,” Dr. Kumar said. He related a 94% rate of overall response that was even higher in patients treated with doses of 150 x 106 CAR+ T cells or more. Many of the responses were lasting, he said, with 5 patients in ongoing response for more than a year.
“The results are exciting enough that this is actually moving forward with registration trials,” Dr. Kumar added.
Another novel CAR T-cell product, LCAR-B38M, has demonstrated promising results. LCAR-B38M principally targets BCMA and has led to a significant number of patients achieving stringent complete response that lasted beyond 1 year.
Multiple BCMA-targeting CAR T-cell products that use different vectors and different costimulatory molecules are currently in clinical trials, Dr. Kumar said.
BiTEs
In contrast to CAR T-cell products that must be customized to each patient in a process that takes weeks, BiTEs are a ready-made approach to allow T cells to engage with tumor cells.
“In patients with advanced disease, a lot can change in that short timeframe, so having an approach that is off-the-shelf, which is not patient specific, is quite attractive,” Dr. Kumar said.
BCMA-directed BiTE therapies to watch that are under investigation include AMG 420 and PF-06863135, he said.
FDA authorizes ClonoSEQ to detect MRD in ALL, myeloma
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
First NGS assay approved for MRD detection in ALL or MM
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.