Findings reported from the Phase III KarMMa-3 study revealed prolonged progression-free survival (PFS) and improved response for patients receiving idecabtagene vicleucel (ide-cel) therapy. This research compared ide-cel with standard treatments among patients with triple-class-exposed relapsed and refractory multiple myeloma who had received 2-4 regimens previously (NCT03651128).
As B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy, ide-cel has been approved by the FDA for the treatment of adult patients with relapsed and refractory multiple myeloma after four or more prior lines of therapy. This recent research confirmed that ide-cel is the first CAR T-cell therapy to demonstrate superiority over standard regimens in triple-class-exposed relapsed and refractory multiple myeloma in a randomized, controlled Phase III trial. Ide-cel more than tripled PFS and showed deep and durable responses. The safety profile for ide-cel was consistent with previously reported data.
These results were published in the New England Journal of Medicine (2023; doi: 10.1056/NEJMoa2213614) and were also presented at the EBMT and European Hematology Association 5th European CAR T-cell Meeting during the Best Abstract Session.
Study Background
"The treatment landscape for relapsed and refractory multiple myeloma has evolved with the use of immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies in doublet, triplet, or quadruplet combinations in the context of first-line therapy and treatment for relapsed disease," according to study investigator Paula Rodriguez-Otero, MD, PhD, and colleagues, who noted that, while these combinations have helped control disease, relapse is still common.
"Consequently," they wrote, "patients have triple-class exposure earlier in their treatment course and have limited treatment options. Responses to standard therapies in the triple-class-exposed population are suboptimal, leading to poor survival outcomes (median progression-free survival, 3-5 months; median overall survival, <13 months). A standard care approach in this patient population has not been established."
CAR T-cell therapies have recently been approved for patients with heavily pretreated relapsed or refractory multiple myeloma. The Phase II KarMMa study showed that ide-cel led to deep, durable responses among patients with triple-class-exposed, heavily pretreated, relapsed and refractory multiple myeloma (N Engl J Med 2021; doi: 10.1056/NEJMoa2024850). The researchers observed a response in 73 percent of the patients and a median PFS of 8.8 months. Findings from this study supported ide-cel's FDA approval.
The aim of the KarMMa-3 study was to evaluate the efficacy and safety of ide-cel in triple-class exposed patients in early relapse since standard-of-care options in these patients are suboptimal, noted Rodriguez-Otero, Specialist in Hematology and Hemotherapy with the Department of Hematology at the Clinica Universidad de Navarra, Pamplona, Spain.
Study Methods
This international, open-label, Phase III trial enrolled patients who have received 2-4 prior lines of therapy, including exposure to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies, and who were refractory to the last line of therapy, according to Rodriguez-Otero.
"Patients were randomized 2:1 to ide-cel (dose range: 150x106 to 450x106 CAR-positive T cells) or one of five standard-of-care regimens," she explained. "The choice between the different standard regimens was made by the investigator at the time of randomization based on refractoriness and exposure to prior drugs."
Patients who were in the standard treatment cohort received one of the following regimens: daratumumab, pomalidomide, and dexamethasone; daratumumab, bortezomib, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; carfilzomib and dexamethasone; or elotuzumab, pomalidomide, and dexamethasone.
"The regimen was continued until the occurrence of disease progression or unacceptable toxic effects or until withdrawal from the trial," the study authors explained. "Patients could not receive the same standard regimen as their last previous treatment before trial entry."
Investigators stratified randomization according to the following: patient's age (<65 vs. >=65 years), number of previous regimens (2 vs. 3 or 4), and high-risk cytogenetic profile (defined as t[4;14], t[14;16], or del[17p]; present vs. absent or unknown). The primary endpoint of the study was PFS. Secondary endpoints included overall response-partial response or better-and overall survival. Safety was also assessed.
Rodriguez-Otero and colleagues followed all patients for disease progression monthly for 24 months, then every 3 months until disease progression. For the overall survival analysis, patients were followed every 3 months after the occurrence of disease progression until the end of the trial-5 years after the randomization of the last patient.
Key Findings
From May 2019 to April 2022, patients were enrolled at 49 sites in 12 countries. A total of 386 patients were randomized on the KarMMa-3 study, 254 to the ide-cel arm and 132 to the standard regimen cohort. Of the 254 patients in the ide-cel group, 249 underwent leukapheresis and one patient received bridging therapy without undergoing leukapheresis. Therefore, the treated population in this cohort included 250 patients. Of those, three patients could not receive ide-cel because of cell manufacturing failure, according to the study authors.
"A total of 225 patients received an ide-cel infusion at a median dose of 445x106 CAR-positive T cells (range, 175x106 to 529x106)," they reported. "In the standard-regimen group, 126 patients received treatment."
When discussing the patient population, Rodriguez-Otero noted that the baseline characteristics between the two groups were generally well-balanced. The exception was for Black race, which comprised 7 percent of the patients in the ide-cel group versus 14 percent of those in the standard-regimen group. The median number of prior regimens was three in both arms. High-risk cytogenetic abnormalities were observed among 107 patients (42%) in the ide-cel group and 61 (46%) in the standard-regimen group. Patients in both cohorts had a median time since diagnosis of approximately 4 years and a median time to progression during the last previous anti-myeloma therapy of about 7 months.
"A total of 348 patients (90%) had disease that was refractory to immunomodulatory agents, 284 (74%) had disease that was refractory to proteasome inhibitors, and 365 (95%) had disease that was refractory to daratumumab," according to Rodriguez-Otero and colleagues. "In the overall trial population, 253 patients (66%; 164 [65%] in the ide-cel group and 89 [67%] in the standard-regimen group) had triple-class refractory disease."
At a median follow-up of 18.6 months, PFS was significantly longer for patients who received ide-cel with a median PFS of 13.3 months compared with 4.4 months among those who underwent a standard treatment regimen (HR for disease progression or death, 0.49; 95% CI: 0.38-0.65; P<0.001).
"Treatment with ide-cel resulted in a 51 percent reduction in the risk of progression or death," Rodriguez-Otero noted. "Notably, the progression-free survival benefit of ide-cel was observed across multiple patient subgroups, including patients with high-risk features such as high-risk cytogenetics, high tumor burden, presence of extramedullary disease, or triple-class refractory.
"Treatment with ide-cel also resulted in significantly higher overall response rates compared with standard regimens," she continued. "Overall response rate in the ide-cel group was 71 percent, including 39 percent with complete response, compared with 42 percent overall response rate and 5 percent complete response among patients treated with standard regimens. Overall survival is still immature and remains blinded."
Findings from the safety assessment showed that the most common adverse events were hematological, according to Rodriguez-Otero. Grade 3 or 4 adverse events occurred in 93 percent of the patients in the ide-cel group and 75 percent in the standard-regimen group. Thirty-six patients who received ide-cel and eight given standard regimens had Grade 5 adverse events. "Of these, 18 in the ide-cel arm and three in the standard regimens arm had Grade 5 adverse events, which were consistent with progression of myeloma," Rodriguez-Otero noted.
Among the patients infused with ide-cel, researchers observed cytokine release syndrome in 88 percent, with Grade 3 or higher events occurring in 4 percent, she reported. Any grade investigator-identified neurotoxicity occurred in 15 percent of patients, with 3 percent having an event of Grade 3 or higher.
The main limitation of the study, according to Rodriguez-Otero, is the use of five different regimens in the standard arm. However, she noted this limitation also reflects the absence of a standard unique regimen suitable for this population. The study authors also noted that the mechanisms of ide-cel resistance remain unclear. They reported BCMA antigen loss in only 3 percent of the patients in the KarMMa trial.
"Consistent with previous data, preliminary findings from the KarMMa-3 trial showed the presence of BCMA expression in tumor cells (in 6 of 6 samples [100%]) and soluble BCMA (in 82 of 84 samples [98%]) that were obtained from ide-cel-treated patients at myeloma progression-a finding suggesting that antigen loss is not the primary mechanism of ide-cel resistance in this context," they outlined in their NEJM paper.
Rodriguez-Otero and colleagues noted investigations are underway to assess potential mechanisms of resistance. "In addition, exploration of new combination therapy approaches to extend the durability of disease control that was observed with monotherapy may be warranted," they said.
This is the first Phase III, randomized trial demonstrating significant improvement in PFS and overall response rate with BCMA-CAR T-cell therapy in the setting of early-relapse triple-class-exposed, relapsed/refractory multiple myeloma, according to Rodriguez-Otero, who told Oncology Times that, "Overall, these results support the use of ide-cel in patients with early line relapse and triple-class-exposed relapsed/refractory multiple myeloma, a patient population with poor survival outcomes."
While discussing the significance of their findings, Rodriguez-Otero concluded, "This study will allow the use of ide-cel in early disease patients who have already exhausted the main anti-myeloma therapies. The next step is to wait for the potential regulatory approval of the drug to expand the indication."
Catlin Nalley is a contributing writer.
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