Ide-cel Demonstrates PFR and ORR Benefit Over Standard of Care in Triple-Class-Exposed R/R Multiple Myeloma
Median PFS was 13.3 months in the ide-cel arm, compared to 4.4 months for the SOC arm.
Idecabtagene vicleucel (ide-cel; Abecma; Bristol Myers Squibb, 2seventybio), a marketed BCMA-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated clinically meaningful improvements in progression free survival (PFS) and overall response rate (ORR) versus standard of care (SOC) combination regimens for patients with triple-class-exposed relapsed/refractory (r/r) multiple myeloma (MM). The data, from the phase 3 KarMMa-3 clinical trial (NCT03651128), were presented by Sergio Giralt, MD FACP, FASTCT, Memorial Sloan Kettering Cancer Center, in a late-breaking session at the 2023 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in Orlando, Florida, February 15-19, 2023.
KarMMa-3 randomly assigned patients in a 2:1 ratio to either an ide-cel arm or an SOC arm. SOC regimens were selected based on the approval and availability status of drugs in the different countries where the study was carried out. The regimens included daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone; daratumumab, bortezomib (Velcade), and dexamethasone; ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone; carfilzomib (Kyprolis) and dexamethasone; or elotuzumab (Empliciti), pomalidomide, and dexamethasone. The data cutoff was April 18, 2022, and follow-up ranged from 0.4 to 35.4 months (median, 18.6). Giralt noted that analysis was performed with 242 out of 289 planned PFS events (IF 84%) and multiplicity was controlled by O'Brien-Fleming boundaries across interim and final analyses and by hierarchical testing at each analysis.
Among the patients in the ide-cel arm, PFS ranged from 11.8 to 16.1 months (median, 13.3, 95% CI) versus PFS that ranged from 3.4 to 5.9 months (median, 4.4, 95% CI) for the patients in the SOC arm [HR, 0.49 (95% CI, 0.38-0.65) P <0.0001 based on stratified log-rank test]. Giralt noted that the PFS benefit was seen across multiple patient subgroups, including age, high-risk cytogenetic abnormalities, tumor burden, extramedullary plasmacytoma, and number of prior antimyeloma regimens. Meanwhile, the ORR for patients in the ide-cel arm was 71% (95% CI, 66-77), while the ORR for patients in the SOC arm was 42% (95% CI, 33-50). Furthermore, 51 patients (20%) in the ide-cel arm achieved a complete response (CR) or better and minimal residual disease (MRD)-negative status (95% CI, 15.2-25.0) while only 1 patient (1%) in the SOC arm achieved a CR or better and MRD-negative status (95% CI, 0-2.2). Giralt also noted that patients who received ide-cel reported significant improvements in quality of life assessments compared to patients who received SOC.
“The median time for maximum CAR T-cell expansion was approximately 11 days, but there was a significant variation in PK exposure,” Giralt stated during his presentation. “Patients who had the highest persistence of CAR T-cells as measured by droplet PCR showed the best and most prolonged response. Of note, and very important, PK persistence and expansion was not related to dose. Therefore patients at the lower dose levels could have a high expansion and a very long peristence and patients in the highest dose levels could have short expansions and short persistence."
In terms of safety, the most common toxicity was hematologic toxicity, with 87% of the patients in the ide-cel arm experiencing grade 3-4 cases of hematologic toxicity and 60% of the patients in the SOC arm experiencing grade 3-4 cases of hematologic toxicity. Giralt pointed out that for patients in the ide-cel arm who developed grade 3-4 cases of thrombocytopenia or neutropenia that persisted longer than 1 month, the median time to recovery was 1.9 months (95% CI, 1.5-2.1) for thrombocytopenia and 1.7 months (95% CI 1.5-1.9) for neutropenia. It was also noted that second primary malignancies occurred in 6% of patients in the ide-cel arm and 4% of patients in the SOC arm. Giralt stated that the most common severe toxicity was infections, with 24% of patients in the ide-cel arm experiencing grade 3-4 infections and 18% of patients in the SOC arm experiencing grade 3-4 infections. He noted that the toxicity profile of ide-cel was similar to that seen in previous studies. Incidence of grade 3 or higher cytokine release syndrome (CRS) and investigator-identified neurotoxicity (iiNT) was low and resolved within a median of 3.5 days for CRS and 2 days for iiNT. No incidence of Parkinsonism was reported.
“The toxicity was actually similar in older patients and in younger patients,” Giralt said in response to an audience question following the presentation. “I do think it's important to recognize that there were there were 3% fatal events in the ide-cel arm versus 1% in the standard control. These were primarily sepsis. There was 1 case of severe fatal CRS that was associated with Candida sepsis and another case of CRS that also was fatal. I do think that there was a learning curve as we started doing this; particularly in patients with high tumor burden, we very rapidly decided that we needed to intervene early with steroids and tocilizumab at the first sign of CRS. Particularly one of the things we learned is if CRS occurs within the first 24 hours, those patients were at high risk of developing severe CRS, and we needed to intervene early.”
Initially, 254 patients were assigned to the ide-cel group. Of these patients, 249 received leukapheresis, 213 received bridging therapy, and 225 received ide-cel (safety population). The treated population was defined as the 250 patients who received either leukapheresis or bridging therapy. Meanwhile, 132 patients were assigned to the SOC group. Among these patients, 126 actually received SOC in the trial (treated/safety population). Giralt noted that characteristics such as median age, tumor mass, and high-risk cytogenetics were similar for patients assigned to each group. He additionally pointed out that overall, 66% of patients had triple-class-refractory r/r MM and were deemed eligible for treatment within 4 years of diagnosis. The patients’ disease relapsed at a median of approximately 7 months since the last regimen.
Giralt concluded that the results presented support the use of ide-cel in patients with early-line relapse and triple-class-exposed r/r MM. “Our goal as physicians is to give patients the longest life with the best quality of life with the right amount of treatment,” Giralt added in response to another audience question. “Allogeneic transplant for myeloma can be effective, but it also is toxic and it's associated with high relapse rates. I do think that we're now at a point where we have 3 distinct immunotherapies that can be fairly effective: CAR-T cells, bispecifics, and allogeneic transplant. And we know that myeloma is very dose responsive. How we're going to integrate those strategies to be able to give patients the longest life with the best quality of life with a minimum amount of treatment is our challenge. I think if you have a young patient who failed very early, we need to try to see if we can cure them. And that means to try to use an allogeneic transplant as part of the platform. However, I think that has to be done in the context of a clinical trial.”
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