Syed Ali Abutalib, MD
Ola Landgren, MD, PhD
To complement The ASCO Post’s comprehensive coverage of the 2019 ASCO Annual Meeting, here are several abstracts selected from the meeting proceedings focusing on novel therapeutic regimens for plasma cell dyscrasias, particularly multiple myeloma. For full details of these study abstracts, visit http://abstracts.asco.org.
ABSTRACT 8002: Efficacy of carfilzomib, lenalidomide, and dexamethasone (KRd) with or without autologous transplant in patients with newly diagnosed myeloma (age < 65 years) according to Revised International Staging System (R-ISS): Results from the FORTE trial (NCT02203643)1
Background:The rates of minimal residual disease (MRD, based on eight-color second-generation flow cytometry, sensitivity 10–5) negativity, stringent complete responses, at least a complete response, and at least a very good partial response were significantly higher with 4 induction cycles of KRd followed by autologous transplant and another 4 cycles of conslidation KRd as well as after 12 cycles of KRd (KRd12) without transplant vs a carfilzomib, cyclophosphamide, and dexamethasone (KCd) regimen followed by autologous transplant and KCd consolidation. No differences in MRD and overall best responses were noticed between KRd-autologous transplant-KRd and KRd12 at the time of its presentation during the 2018 American Society of Hematology Annual Meeting & Exposition.2
It seems logical to conjecture that MRD-negative patients increasingly will become candidates for delayed transplant after completed combination therapy.— Syed Ali Abutalib, MD, and Ola Landgren, MD, PhD
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Methods: The study compared the rate of at least a very good partial response, at least a complete response, stringent complete responses, and MRD negativity after KRd-autologous transplant-KRd vs KRd12 vs KCd-autologous transplant-KCd in patients with R-ISS 1 and R-ISS 2 and 3, after a median follow-up of 25 months. Since high-risk patients may sometimes respond rapidly, but then relapse early, the investigators also analyzed the rate of early relapse (up to 18 months from randomization).
Results: Rates of at least a very good partial response, at least a complete response, stringent complete responses, and MRD negativity were comparable between KRd-autologous transplant-KRd and KRd12 overall, in patients with R-ISS 1 and with R-ISS 2 and 3. A significantly fewer number of patients experienced early relapse with KRd-autologous transplant-KRd vs KRd12 (8% vs 17%; P = .015). This difference was mainly related to a significantly lower rate of early relapse in patients with R-ISS 2 and 3 receiving KRd-autologous transplant-KRd vs KRd12 (12% vs 23%; P = .05); no statistically significant difference was seen in R-ISS 1 (0 vs 2 patients).
Clinical Implications: KRd-autologous transplant-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk patients achieving protocol-defined MRD negativity. It is important to note that for patients with R-ISS 2 and 3, the KRd-autologous transplant-KRd platform reduced the risk of early relapse. Also, this study showed that incorporation of an immunomodulatory drug such as lenalidomide is superior to adding cyclophosphamide to the carfilzomib and dexamethasone platform to increase the depth of response, as evidenced by achievement of MRD negativity.
The study was not statistically designed to investigate upfront vs delayed transplant. Given the emerging data on the long-term toxicities related with high-dose melphalan therapy (ie, myelodysplastic syndrome) as well as the access to new MRD assays for multiple myeloma, it seems logical to conjecture that MRD-negative patients increasingly will become candidates for delayed transplant after completed combination therapy. This remains a controversial topic. Future studies should help to improve our understanding of this clinically relevant topic.
ABSTRACT 8005: Efficacy and safety of the randomized, open-label, noninferiority, phase III study of subcutaneous (n = 263) vs intravenous (n = 259) daratumumab administration in patients with relapsed or refractory multiple myeloma: COLUMBA (NCT03277105)3
Endpoints, Dose, and Schedule: Co-primary endpoints were overall response rate and predose cycle 3 day 1 daratumumab Ctrough (noninferiority = lower bound of 90% confidence interval [CI] for the ratio of the geometric means ≥ 80%). Subcutaneous daratumumab (1,800 mg plus recombinant human PH20 hyaluronidase [2,000 U/mL]) and intravenous daratumumab (16 mg/kg) were given weekly for cycles 1 to 2 (28-day cycles), every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter. Subcutaneous daratumumab (15 mL) was given over 3 to 5 minutes at alternating left/right abdominal sites. Patients (≥ 18 years) must have received at least 3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drugs or had double-refractory disease.
Subcutaneous daratumumab significantly decreased the rate of infusion-related reactions and administration time, with a comparable safety profile to intravenous daratumumab.— Syed Ali Abutalib, MD, and Ola Landgren, MD, PhD
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Results: The median follow-up was 7.5 months. The overall response rate was 41% for subcutaneous daratumumab and 37% for intravenous daratumumab. Subcutaneous daratumumab retained at least 89% of the benefit of intravenous daratumumab (97.5% CI). The ratio of geometric means of Ctrough for subcutaneous daratumumab over intravenous daratumumab was 108% (90% CI = 96%–122%). A significantly lower rate of infusion-related reactions was observed with subcutaneous daratumumab vs intravenous daratumumab (12.7% vs 34.5%; P < .0001). The median progression-free survival was 5.6 months with subcutaneous daratumumab vs 6.1 months with intravenous daratumumab (hazard ratio [HR] = 0.99; 95% CI = 0.78–1.26). The primary reasons for treatment discontinuation included progressive disease (43% with subcutaneous treatment vs 44% with intravenous treatment) and adverse events (7% with subcutaneous treatment vs 8% with intravenous treatment).
Clinical Implications: The efficacy, pharmacokinetics, and co-primary endpoints were met, demonstrating noninferiority of subcutaneous daratumumab compared with the intravenous formulation. Subcutaneous daratumumab significantly decreased the rate of infusion-related reactions and administration time, with a comparable safety profile to intravenous daratumumab. A reasonable speculation based on existing monoclonal antibodies for other blood disorders (eg, rituximab/hyaluronidase human in lymphoma) is that subcutaneous daratumumab will likely become part of most combination therapies for patients with newly disease multiple myeloma in the coming future. Also, it seems logical to speculate that subcutaneous daratumumab will become a maintenance therapy for many patients, perhaps given once every 1 to 2 months.
ABSTRACT 8007: Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager immunotherapy, in relapsed and/or refractory multiple myeloma (n = 42): Updated results of a first-in-human phase I dose-escalation (and dose-finding) study (NCT02514239)4
Study Objectives: Assessment of the safety and activity of AMG 420/BI 836909, which binds B-cell maturation antigen (BCMA) on multiple myeloma cells and CD3 on T cells
Methods: Eligible patients had disease progression after at least two lines of therapy (including a proteasome inhibitor and immunomodulatory drugs). Patients with plasma cell leukemia, extramedullary relapse, central nervous system involvement, or prior allogeneic transplantation were excluded. MRD was defined as up to 1 tumor cell/104 of marrow cells per flow cytometry.
Results: Patients discontinued treatment due to progressive disease (n = 24), adverse events (n = 7, including 3 dose-limiting toxicities), and death (n = 4). Patients were treated for a mean (standard deviation) of 2.5 (2.6) cycles. There were two deaths from adverse events (acute respiratory distress from flu/aspergillosis; fulminant hepatitis related to adenovirus infection); neither one was related to treatment. Of those with serious adverse events (n = 21, 50%), 18 required hospitalization. Serious adverse events occurring in more than 1 patient were infections (n = 12) and polyneuropathy (n = 2). Treatment-related serious adverse events included grade 3 polyneuropathy (n = 2) and grade 1 edema. Grade 2 to 3 cytokine-release syndrome was seen in 3 patients. No anti–AMG 420 antibody was detected.
This [first-in-human phase I] study shows that AMG 420 can deliver deep and durable responses, with minimal toxicity.— Syed Ali Abutalib, MD, and Ola Landgren, MD, PhD
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At a dose of 400 μg/d, there were 5 MRD-negative stringent complete responses, 1 very good partial response, and 1 partial response, for a response rate of 70%; at December 2018 data cutoff, responses lasted for 5.6 to 10.4 months, with 4 patients continuing treatment. As of February 2019, some responses lasted more than 1 year. Overall, there were 13 responders (6 stringent complete responses, 3 complete responses, 2 very good partial responses, 2 partial responses). The median time to any response was 1 month.
Clinical Implications: In this first-in-human study of AMG 420 in patients with relapsed and/or refractory multiple myeloma, there was a 70% response rate, with 5 of 7 responders achieving a stringent complete response at 400 μg/d (the recommended dose for further investigation). A dose of 800 μg/d was determined not to be tolerable. This study shows that AMG 420 can deliver deep and durable responses, with minimal toxicity. An expanded study size with longer follow-up will be interesting.
ABSTRACT e19537: Safety and efficacy of four drug regimens in patients with newly diagnosed multiple myeloma: Systematic review of variety of four-drug combinations5
Method: A systematic retrospective review of ongoing phase I to III clinical trials in newly diagnosed multiple myeloma (n = 1,990 in 8 trials) was performed, (Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines) using 5 databases.
Results: The combination of daratumumab, bortezomib, lenalidomide, and dexamethasone demonstrated the best treatment response (very good partial response of 100%, complete response of 63%, and 15-month progression-free survival of 94%). The combination of daratumumab, bortezomib, melphalan, and prednisone (overall response rate of 90.9%, at least a very good partial response rate of 72.9%, median progression-free survival at 27.8 months was not reached) as well as the combination of isatuximab, bortezomib, lenalidomide, and dexamethasone (overall response rate of 93%, a very good partial response rate of 71.43%, 7.5-month progression-free survival of 100%) were associated with improvement in overall response in transplant-ineligible patients. The combination of daratumumab, carfilzomib, lenalidomide, and dexamethasone showed excellent efficacy (overall response rate of 100%, at least a very good partial response rate of 86%), with 6-month progression-free survival of 100%.
Clinical Implications: Four-drug regimens have improved efficacy compared with three-drug regimens in newly diagnosed patients with myeloma, with a comparable incidence of toxicities. Prospective data with longer follow-up are required. The findings that the combination of daratumumab, carfilzomib, lenalidomide, and dexamethasone has excellent efficacy (overall response rate of 100%, at least a very good partial response rate of 86%) with a 6-month progression-free survival rate of 100% are great news for patients.
It is reasonable to speculate that such four-drug combinations will become the future standard for many patients with newly diagnosed multiple myeloma. In addition, the integration of sensitive MRD testing and modern four-drug combinations will likely impact the use of upfront vs delayed high-dose melphalan. It seems logical to believe there will be advances in treatment of myeloma in the coming few years.
ABSTRACT TPS8057: Myeloma-developing regimens using genomics (MyDRUG) master protocol (NCT03732703)6
Study Rationale: Seminal genomic-sequencing research efforts, such as the Multiple Myeloma Research Foundation (MMRF) CoMMpass study, have highlighted the fact that a large number of multiple myeloma cases harbor potentially actionable oncogenic molecular alterations. Published reports on small numbers of cases suggest that precision medicine interventions clinically targeting such actionable drivers may benefit patients with multiple myeloma. To that end, investigators have launched MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual patients’ genomics.
Methods: This study is a phase I to II, multicenter master protocol conducted in functional high-risk patients with multiple myeloma who have had one to three prior lines of therapy. The protocol defined high risk as patients experiencing disease progression from baseline treatment within 18 months without maintenance or 3 years on maintenance therapy. Patients are being screened for actionable genomic alterations. Those with a greater than 30% mutation to any of the following genes—-CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2, or t(11;14)—can be enrolled to one of the treatment arms. Such patients with actionable alterations are being assigned to the appropriate targeted agent used in combination, with a backbone regimen of ixazomib, pomalidomide, and dexamethasone, whereas patients without such alterations are being assigned to immunotherapy.
TREATMENT REGIMENS UNDER STUDY IN MULTIPLE MYELOMA
- Carfilzomib, lenalidomide, and dexamethasone: FORTE trial in newly diagnosed myeloma
- Subcutaneous vs intravenous daratumumab: COLUMBA trial in relapsed and refractory myeloma
- AMG 420 immunotherapy: First-in-human phase I trial
- Four-drug regimens in newly diagnosed myeloma:
- Daratumumab, bortezomib, lenalidomide, dexamethasone
- Daratumumab, bortezomib, melphalan, prednisone
- Isatuximab, bortezomib, lenalidomide, dexamethasone
- Daratumumab, carfilzomib, lenalidomide, dexamethasone
Endpoints: The primary objective of the study is to evaluate the overall response rate per the International Myeloma Working Group consensus criteria. Secondary objectives are to assess adverse events, progression-free survival, and overall survival. Experimental correlative aims include assessing molecular or clonal response, molecular and immune signatures of resistance or response, and MRD.
Clinical Implications:The upcoming results from this study suggest that precision medicine approaches may be possible in the future treatment of myeloma. Participation onto this (and other) myeloma clinical trials is encouraged (NCT03732703). This trial design is a creative way to develop and establish drugs with novel mechanisms of action and to offer patients with relapsed and refractory multiple myeloma access to drugs when the current U.S. Food and Drug Administration–approved agents no longer are effective. The MMRF is taking a leading role in the development of novel myeloma drugs!
ABSTRACT 8010: Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (NCT02741999)7
Study Rationale:This protocol seeks to enroll patients with MGUS and smoldering multiple myeloma with lambda light chain involvement. The hypothesis being tested with this protocol is that the presence of amyloid light chain germline genes is associated with light chain amyloidosis in patients with a preexisting diagnosis of lambda MGUS and lambda smoldering multiple myeloma.
Eligibility: SAVE is a trial for patients with lambda MGUS or lambda smoldering multiple myeloma with a kappa-lambda free light chain ratio up to 0.26 and a difference between involved and uninvolved free light chain of more than 23 mg/L. Patient recruitment is open to all eligible patients within the United States, and informed consent may be obtained in person or by phone.
Methods: Eligible patients need to submit peripheral blood or bone marrow sample(s). If the germline gene is related to AL, further evaluation will be pursued in collaboration with the treating physician.
It is reasonable to speculate that four-drug combinations will become the future standard for many patients with newly diagnosed multiple myeloma.— Syed Ali Abutalib, MD, and Ola Landgren, MD, PhD
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Results:Twenty asymptomatic patients from 18 states have been enrolled, and 23 peripheral and 4 bone marrow specimens have been obtained. A total of 17 patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 bone marrow samples. Increased risk of light chain amyloidosis was identified in seven patients, two of whom had undiagnosed light chain amyloidosis (both with IGLV2 14 germline genes). One patient with smoldering multiple myeloma (diagnosed in 2016) had AL lambda-type with gastrointestinal involvement and is 9 months post high-dose chemotherapy and autologous transplantation. The second patient with smoldering multiple myeloma (diagnosed in 2009) had cardiac AL lambda-type by heart biopsy with an N-terminal pro–B-type natriuretic peptide 171 (but with a suggestive cardiac magnetic resonance image) and is scheduled for high-dose chemotherapy and autologous transplantation.
Clinical Implications: The SAVE trial enables early diagnosis of AL lambda-type based on the lambda IGLV gene used by the clonal plasma cells. In this pilot study, reverse transcriptase polymerase chain reaction identified the clonal lambda gene 85% of the time. This trial was activated in 2016 and remains open for patient accrual (NCT02741999).
The diagnosis of light chain amyloidosis is a tissue diagnosis. If amyloidosis is suspected at any, the patient’s physician will be contacted and given recommendations regarding diagnostic tests and disease staging. Current therapy for AL amyloidosis basically focuses on managing the complications of already-present organ damage and limiting further damage driven by the disease. Unfortunately, none of the current therapies remove the established damage caused by the disease. The approach in the SAVE trial is novel and allows for early detection and treatment of the disease. This is an interesting and potentially clinically important strategy going forward. ■
Dr. Abutalib is Associate Director and Hematology and Cellular Therapy Program Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; and Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Landgren is Professor of Medicine and Chief of the Myeloma Service, Memorial Sloan Kettering Cancer Center, New York.
DISCLOSURE: Dr. Abutalib is a speaker for AstraZeneca. Dr. Landgren has received grant support from the NIH, FDA, Multiple Myeloma Research Foundation, International Myeloma Foundation, Leukemia & Lymphoma Society, Perelman Family Foundation, Rising Tides Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm; honoraria/ad boards from Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer; and Independent Data Monitoring Committee for Takeda, Merck, Janssen, and Theradex.
REFERENCES
1. Gay F, Cerrato C, Petrucci MT, et al: Efficacy of carfilzomib lenalidomide dexamethasone with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. 2019 ASCO Annual Meeting. Abstract 8002. Presented June 2, 2019.
2. Gay F, Cerrato C, Scalabrini DR, et al: Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: Analysis of the randomized Forte trial in newly diagnosed multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 121. Presented December 1, 2018.
3. Mateos MV, Nahi H, Legiec W, et al: Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous versus intravenous daratumumab administration in patients with relapsed or refractory multiple myeloma: COLUMBA. 2019 ASCO Annual Meeting. Abstract 8005. Presented June 2, 2019.
4. Topp MS, Duell J, Zugmaier G, et al: Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager immunotherapy, in R/R multiple myeloma patients: Updated results of a first-in-human phase I dose escalation study. 2019 ASCO Annual Meeting. Abstract 8007. Presented June 2, 2019.
5. Grewal US, Chakraborty R, Raziq FI, et al: Safety and efficacy of four drug regimens in newly diagnosed multiple myeloma: Systematic review. 2019 ASCO Annual Meeting. Abstract e19537. Online only.
6. Auclair D, Anderson KC, Avigan D, et al: The myeloma-developing regimens using genomics (MyDRUG) master protocol. 2019 ASCO Annual Meeting. Abstract TPS8057. Presented June 3, 2019.
7. Zhou P, Kugelmass A, Toskic D, et al: Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8010. Presented June 3, 2019.
