Ide-cel Improves PFS vs SOC in Relapsed/Refractory Multiple Myeloma

Paula Rodriguez-Otero, MD, PhD

The CAR T-cell therapy idecabtagene vicleucel (ide-cel; Abecma) improved progression-free survival (PFS) compared with standard combination regimens in patients with relapsed/refractory multiple myeloma after 2 to 4 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, according to results from the phase 3 KarMMa-3 trial (NCT03651128).^1,2

At a median follow up of 18.6 months (range, 0.4-35.4), patients treated with ide-cel (n = 254) achieved a median PFS of 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) for those who received standard of care (SOC) treatment (n = 132). This result translates to a 51% reduction in the risk of progression or death (HR, 0.49; 95% CI, 0.38-0.65; P <.0001). The 6- and 12-month PFS rates in the ide-cel group were 73% and 55%, respectively. In the SOC group, those rates were 40% and 30%, respectively.

“A PFS benefit was seen consistently across different subgroups, and, importanly, in patients with poor-risk features. So older patients, patients with high-risk cytogenetic abnormalities, high tumor burden, or the presence of extramedullary disease [experienced a benefit with ide-cel," Paula Rodriguwiez-Otero, MD, PhD, Department of Hematology, Clinica Universidad de Navarra, in Pamplona, Spain, said in an interview with OncLive^®.

In March 2021, the FDA approved ide-cel for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, based on data from the phase 2 KarMMA trial (NCT03361748).³

KarMMA-3 was an open-label, global, randomized, controlled trial evaluating ide-cel compared with standard regimens in patients with relapsed/refractory multiple myeloma who have received 2 to 4 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.²

Enrolled patients were also required to be at least 18 years of age who achieved a response to at least 1 prior treatment regimen, had an ECOG performance status of 0 or 1, recovered to grade 1 or baseline of any non-hematologic toxicities from prior treatments, and had adequate vascular access for leukapheresis.⁴

Patients were randomly assigned in a 2:1 fashion to receive ide-cel or 1 of 5 standard regimens that had been chosen before randomization based on a patient’s most recent treatment regimen and investigator discretion. These regimens included daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone (n = 43); daratumumab, bortezomib (Velcade), and dexamethasone (n = 7); ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone (n = 22); carfilzomib (Kyprolis) and dexamethasone (n = 30); or elotuzumab (Empliciti), pomalidomide, and dexamethasone (n = 30).¹

Patients in the ide-cel arm received lymphodepletion with fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 3 consecutive days, followed by 2 days of no treatment before the administration of a single infusion of ide-cel at a target dose ranging from 150 × 106 to 450 × 106 CAR+ T cells. Notably, doses of up to 540 × 106 CAR+ T cells were permitted.

Patients were stratified by 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 del17p (present vs absent or unknown). Patients were enrolled from May 2019 to April 2022 at 49 sites in 12 countries prior to the April 18, 2022, data cutoff.

Along with the primary end point of PFS, key secondary end points included overall response rate (ORR) and overall survival (OS).

The median age in both arms was 63 years. Baseline characteristics were generally balanced in the two groups, except for the proportion of patients who were Black (7% in the ide-cel group vs 14% in the SOC group). Additionally, 42% of patients in the ide-cel group had high-risk cytogenetics, compared with 46% in the SOC group. The median number of previous regimens was 3 (range, 2 to 4) in each group.

Across the combined population of both arms, 90% of patients had disease that was refractory to immunomodulatory agents, 74% had disease that was refractory to proteasome inhibitors, and 95% had disease that was refractory to daratumumab. Furthermore, 65% of patients in the ide-cel group and 67% in the SOC group were triple-class refractory.

Additional data showed that patients treated with ide-cel experienced an ORR of 71% (95% CI, 66%-77%) compared with 42% (95% CI, 33%-50%) for those given standard regimens. The complete response (CR) rate was 39% in the ide-cel arm vs 5% in the control arm.

The median time to response was 2.9 months (range, 0.5-13.0) for patients in the ide-cel group, compared with 2.1 months (range, 0.9-9.4) for those in the SOC group. The median duration of response was 14.8 months (95% CI, 12.0-18.6) for ide-cel and 9.7 months (95% CI, 5.4-16.3) for SOC.

Furthermore, 20% of patients in the ide-cel group achieved MRD-negative status within 3 months before the occurrence of at least a CR, vs 1 patient (1%) in the SOC group.

OS data were immature and remained blinded at data cutoff.

Although ide-cel is approved in the United States after for patients with relapsed/refractory multiple myeloma after at least 4 prior lines of therapy, Rodriguez-Otero explained that findings from KarMMa-3 could help push the CAR T-cell therapy into earlier settings.

"[These findings could] allow us to use this potent therapy in patients that need it, because they have already exhausted the available therapies that we have, without [waiting] until later in the treatment journey. We would be able to increase the access to potent drugs for patients with relapsed/refractory multiple myeloma," she said.

Regarding safety, Rodriguez-Otero noted that there were no new safety signals, and findings were consistent studies of ide-cel. Ninety-nine percent of patients in the ide-cel group and 98% in the SOC group experienced at least 1 any-grade adverse effect (AE). Grade 3/4 AEs were reported in 93% and 75% of patients in the ide-cel and SOC arms, respectively. Grade 5 AEs occurred in 14% and 6% of patients, respectively.

The most common any-grade hematologic AEs included neutropenia, which occurred in 78% of the patients in the ide-cel group and 44% of those in the SOC group, anemia (66% and 36%), and thrombocytopenia (54% and 29%).

Fifty-eight percent of patients treated with ide-cel experienced infection, compared with 54% treated with standard regimens. The rates of grade 3/4 infection were 24% and 18% for ide-cel and SOC, respectively, and grade 5 infection occurred in 4% and 2% of patients, respectively. The most common any-grade infections were upper respiratory tract infection (12% and 7% for ide-cel and SOC, respectively) and pneumonia (10% and 7%).

Serious AEs were reported in 52% and 38% of patients in the ide-cel and SOC groups, respectively. Grade 5 treatment-related AEs occurred in 3% in the ide-cel group and 1% in the standard-regimen group, with the most common being sepsis (2% for ide-cel and 1% for SOC).

Eighty-eight percent of patients administered ide-cel experienced any-grade cytokine release syndrome (CRS). The rate of grade 1/2 CRS was 83%, and 5% had grade 3 or higher CRS, including 2 (1%) with grade 5. The median time to the first onset of CRS was 1 day (range, 1-14), and the median duration was 3.5 days (range, 1-51).

Twenty-eight percent of the intent-to-treat population died on the trial, including 30% in the ide-cel group and 26% in the SCO group. The most common cause of death was disease progression (17% in both groups).

References

1. Rodriguez-Ortero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. Published online February 10, 2023. doi:10.1056/NEJMoa2213614
2. Abecma (idecabtagene vicleucel) reduced the risk of disease progression or death by 51% versus standard regimens in earlier lines of therapy for relapsed and refractory multiple myeloma based on results from phase 3 KarMMa-3 study. News release. Bristol Myers Squibb. February 10, 2023. Accessed February 10, 2023. https://news.bms.com/news/details/2023/
3. U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed February 10, 2023. https://news.bms.com/news/details/2021/
4. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). ClinicalTrials.gov. Updated December 15, 2022. Accessed February 10, 2023. https://clinicaltrials.gov/ct2/show/NCT03651128