On February 10, 2023 Bristol Myers Squibb (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) reported the first publication and presentation of positive results from KarMMa-3, a pivotal Phase 3, open-label, global, randomized, controlled study evaluating Abecma (idecabtagene vicleucel) compared with standard combination regimens in adults with relapsed and refractory multiple myeloma after two to four prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and who were refractory to their last regimen (Press release, Bristol-Myers Squibb, FEB 10, 2023, View Source [SID1234627055]). Data from KarMMa-3 are being published in The New England Journal of Medicine and simultaneously presented at the EBMT and the European Hematology Association (EHA) (Free EHA Whitepaper)’s (EHA) (Free EHA Whitepaper) 5th European CAR T-cell Meeting on Friday, February 10 in an oral presentation during the Best Abstract Session.
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At a median follow up of 18.6 months, treatment with Abecma (n=254)demonstrated a clinically meaningful and statistically significant improvement in the primary endpoint of progression-free survival (PFS) compared with standard regimens (n=132), with a median PFS of 13.3 months (95% CI: 11.8-16.1) vs. 4.4 months (95% CI: 3.4-5.9), respectively (HR:0.49; p<0.0001). This represents a 51% reduction in risk of disease progression or death with Abecma. Based on results from KarMMa-3, Abecma is the first and only chimeric antigen receptor (CAR) T cell therapy to demonstrate superiority over standard regimens in triple-class exposed relapsed and refractory multiple myeloma in a randomized, controlled Phase 3 trial.
"In earlier lines of treatment for multiple myeloma, regimens consisting of immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies are often used to help manage the disease. This shift in the treatment paradigm leaves many patients who are triple-class exposed with relapsed and refractory disease and in need of new treatment options sooner," said Paula Rodriguez-Otero, M.D., Ph.D., Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain. "Results from the KarMMa-3 study with Abecma clearly demonstrate the benefit of earlier use of a CAR T cell therapy in providing the longest progression-free survival for patients with relapsed and refractory multiple myeloma compared to current standard regimens for these patients."
"With Abecma, our first-in-class anti-BCMA CAR T cell therapy, we sought to deliver a personalized therapy that provides durable outcomes with a single infusion to advance the multiple myeloma treatment paradigm for patients," said Anne Kerber, senior vice president, Cell Therapy Development, Bristol Myers Squibb. "This represents the third New England Journal of Medicine publication for Abecma, showing the clear clinical benefit of using Abecma across lines of therapy for patients with triple-class exposed relapsed and refractory multiple myeloma to provide the best chance for lasting disease control."
Results for the key secondary endpoint of overall response rate also met statistical significance with the majority of patients (71%) treated with Abecma achieving a response, and 39% achieving a complete response or stringent complete response. In comparison, less than half of patients (41%) who received standard regimens achieved a response, with 5% experiencing a complete response or stringent complete response (p<0.0001). Responses with Abecma were durable with a median duration of 14.8 months (95% CI: 12.0-18.6) compared with 9.7 months (95% CI: 5.4-16.3) for standard regimens. Clinical benefit with Abecma was consistently observed across difficult-to-treat subgroups.
"For relapsing triple-class exposed multiple myeloma patients, median progression-free survival is just 4.6 months and there is no established standard treatment approach that provides durable responses," said Sergio Giralt, M.D., Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center. "In this study, we are seeing efficacy among a population with historically difficult-to-treat disease, with a significant improvement in progression-free survival and deep and lasting responses. These results from KarMMa-3 introduce the potential for this anti-BCMA CAR T cell therapy to become a standard of care earlier in the treatment course for relapsed and refractory multiple myeloma."
Abecma exhibited a consistent and generally predictable safety profile, including no new safety signals, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurotoxicity. In patients treated with Abecma, 88% experienced any grade CRS, with Grade 3/4 events occurring in 4% of patients. Two patients (1%) experienced a Grade 5 CRS event. Median time to onset of CRS was 1 day (range: 1-14) and median duration of CRS was 3.5 days (range: 1-51). Any grade neurotoxicity occurred in 15% of patients, with Grade 3/4 neurotoxicity occurring in 3% of patients, and no Grade 5 events reported. Median time to onset of neurotoxicity was 3 days (range: 1-317) and median duration of neurotoxicity was 2 days (range: 1-37).
"The KarMMa-3 study is the first with a BCMA-directed CAR T therapy to demonstrate superiority versus standard regimens for patients with relapsed and refractory multiple myeloma, illustrating the potential of Abecma to change the standard of care of triple-class exposed multiple myeloma in early lines," said Steve Bernstein, M.D., chief medical officer, 2seventy bio. "We are pleased to present and have these data published to build on the compelling efficacy profile of Abecma demonstrating significant improvement in progression-free survival and we look forward to working with regulatory authorities to make Abecma available to more myeloma patients who could benefit from this important treatment option."
Bristol Myers Squibb and 2seventy bio intend to include these data in a planned supplemental Biologics License Application submission to the U.S. Food and Drug Administration (FDA) in 2023. Abecma is the first-in-class B-cell maturation antigen (BCMA)-directed CAR T cell immunotherapy approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is also approved in the European Union, Switzerland, Japan, Canada, the United Kingdom and Israel for adult patients with triple-class exposed relapsed or refractory multiple myeloma after three to four or more prior lines of therapy.
Memorial Sloan Kettering Cancer Center disclosures: Dr. Giralt and Memorial Sloan Kettering Cancer Center have financial interests associated with the research described in this release.
About KarMMa-3
KarMMa-3 (NCT03651128) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and were refractory to the last treatment regimen. Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen based on their most recent treatment regimen and investigator discretion. The primary endpoint evaluated in this study is progression-free survival, defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first. Key secondary endpoints include overall response rate and overall survival.