Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: A Real-World Experience
Authors: Mohan Lal Bhavesh , Pandey Toshali , Alzubi Marah , Alrawabdeh Jawad , Shaughnessy, Jr John D , Zhan Fenghuang , Siegel Eric , Schinke Carolina , Thanendrarajan Sharmilan , Zangari Maurizio , van Rhee Frits , Al Hadidi Samer 
Published: December 2024

Introduction: Chimeric antigen receptor T-cell (CAR T) therapy has revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, in real-world settings, patients face lengthy wait times, and not all who are listed for CAR T-cell therapy receive it.
Methods: In this single-center retrospective observational study performed at the University of Arkansas for Medical Sciences, we analyzed the outcomes for all patients listed for B-cell maturation antigen (BCMA) CAR T-cell therapy for RRMM, including those who did not receive it.
Results: 152 patients with RRMM were listed to receive CAR T-cell therapy on or before November 1, 2023. The median age of the patients at the time of listing was 66 years (range: 33-85 years), with a median of 6 years from initial diagnosis to listing. The patients had a median of 7 (range: 1-15) lines of therapy prior to listing. Patients had a median of two prior autologous stem cell transplants. All the patients had received at least one immunomodulatory drug (IMiD) and proteasome inhibitor, and 143 (93%) patients received anti CD-38 monoclonal antibody. 53 (35%) patients received prior anti-BCMA therapy. At the time of listing, 83 (55%) patients had at least one factor that would exclude them from the KarMMa trial, with prior anti-BCMA therapy being the most common reason.
Out of 152 patients, 72 (47%) completed apheresis, and 70 (46%) patients received CAR T-cell therapy. The remaining 82 patients received alternative treatment regimens. Cyclophosphamide-based regimens and daratumumab-based regimens were the most frequently used regimens in these patients. The two most common reasons for not receiving CAR T-cell therapy while on the waitlist were the need for interval disease control and death, which together comprised 78% of cases. Patients who received CAR T-cell therapy were similar to those who did not receive it, except that the group who received CAR T-cell therapy had a higher number of patients with active disease on PET scans and a lower incidence of del(17p) mutation at the time of listing.
Among patients who received CAR T-cell therapy, the median time from listing to CAR T-cell infusion was 194 (range: 54-691) days. 62 (89%) patients received ide-cel, 7 (10%) patients received cilta-cel, and 1 (1%) patient received investigational BCMA CAR-T. The median duration of follow-up after CAR T-cell infusion was 11.9 months. 62 (89%) patients developed cytokine release syndrome (CRS), with grade III CRS occurring in 3 (4%) patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 11 (16%) patients, with 1 (1%) patient developing grade III ICANS. Any grade of neutropenia, anemia, and thrombocytopenia occurred in 66 (94%), 68 (97%), and 60 (86%) patients, respectively in the first month after CAR T-cell therapy. 64 (91%) patients had grade 3 or higher neutropenia, 31 (44%) patients had grade 2 or higher anemia, and 45 (64%) patients had grade 3 or higher thrombocytopenia.
Outcomes were calculated in two ways: an ‘intention to treat’ analysis including all patients from the time of listing regardless of CAR T-cell infusion status, and a ‘per treatment’ analysis calculated from the date the patient received a treatment to progression/death (PFS) or death (OS). The overall response rate (ORR) for all patients listed was 48%. Patients who received CAR T-cell therapy had a higher ORR compared to patients who did not receive CAR T-cell therapy and received an alternative regimen (63% vs. 39%). In the per-treatment analysis, the median progression-free survival (PFS) and overall survival (OS) for patients who received CAR-T were 12.8 months and OS not reached, respectively, compared to a median PFS of 5.4 months and OS of 15.4 months in patients who did not receive CAR T-cell therapy and received alternative treatment regimens.
Conclusions: In conclusion, more than half of the patients listed for CAR T-cell therapy did not receive it. There was an association between receiving CAR T-cell therapy and improved PFS and OS compared to those who did not receive the CAR T-cell therapy. This real-world analysis uniquely follows an intent-to-treat CAR T cohort, including patients who did not receive CAR T-cell therapy. Previous real-world studies have focused on intent-to-manufacture cohorts, lacking a comparison with patients having similar baseline disease who received contemporary alternative therapies instead of CAR T-cell therapy.