CAR T-Cell Data Call for New Strategies in Treatment of Multiple Myeloma

Advances in research around the use of chimeric antigen receptor (CAR) T-cell therapy in the field of multiple myeloma (MM) have shown potential for improving the durability of response for patients. With the majority of clinical trials focusing on BCMA-targeting CAR T-cell agents, early research is now exploring novel targets that experts believe may be curative for patients with MM.

During a presentation at the 2020 Society of Hematologic Oncology (SOHO) Virtual Annual Meeting, Andrzej Jakubowiak, MD, PhD, reviewed clinical trials of CAR T-cell therapy in MM and the emergence of CAR T cells against SMALF7, GPRC5D, and CD229.1

Jakubowiak began by noting that the majority of the data available for CAR T-cell therapy was for the BCMA-directed CAR T-cell agent, idecaptagene cicleuceb (ide-cel).

Ide-cel

In the phase 3 KarMMa trial (NCT03651128) of ide-cel as treatment of patients with relapsed or refractory MM, deep and durable response were achieved in heavily pretreated patients. The study also showed efficacy and safety results consistent with previous reports of clinical benefit with ide-cel in this patient population.2

KarMMa was positive for the primary end point of objective response rate (ORR), which was 73% in the overall population. Notably, patients in the multi-cohort study who received the highest dose of ide-cel (450 x 106 CAR T cells ) had the highest ORR at 82%, compared with 69% at the middle dose level (300 x 106 CAR T cells) and 50% at the lowest dose level (150 x 106 CAR T cells). The overall complete response (CR) rate observed with the drug was 31%. The median duration of response (DOR) in KarMMa was 10.6 months (range, 9.0-11.3), overall.

In terms of survival, the median progression-free survival (PFS) was 8.6 months (95% CI, 5.6-11.6 months).

The safety profile observed with ide-cel showed mainly low-grade toxicities. The most common toxicities were cytopenias including neutropenia (91%), anemia (70%), thrombocytopenia (63%), leukopenia (42%), and lymphopenia (27%). Only 4% of patients in the study died. Three of the deaths occurred due to adverse events (AEs) while the other 2 were due to disease progression.

The LCAR-B38M Construct

Jakubowiak explained that the Legend 2 study was the first to show results of bispecific CAR T cells against 2 epitopes of BCMA. Legend 2 evaluated LCAR-B38M in patients with relapsed or refractory MM.1

Treatment with LCAR-B38M led to an ORR of 88% in the 39 patients included. It was noted that patients with BCMA <40% had a higher ORR of 92% compared with those who had a BCMA ≥ 40% at 82%. Responses included very good partial responses (VGPRs) in 4% of patients, partial responses (PRs) in 11%, and stable disease (SD) in 7%. Two percent of patients in the study had progressive disease, and the remaining 4% were not evaluable for response.

Among the patients who received minimal residual disease (MRD) negativity, the median PFS was 24 months (95% CI, 15 - not reached). The 12-month PFS rate among this group was 87%. Among the group of patients who did not achieve MRD negativity, the median PFS was only 6 months (95% CI, 3-8) with a 12-month PFS of 6%.

The positive strategy is currently under further investigation in a phase 1b/2 clinical trial (CARTITUDE, NCT03548207).

JNJ-4528

Responses were achieved with JNJ-4528 when administered as treatment of patients with relapsed or refractory MM in the CARTITUDE study. Notably, responses occurred early-on in the course of treatment and were deep and durable.3

The ORR observed with JNJ-4528 was 100% out of 29 patients assessed. Responses included a CR rate of 86% and a VGPR rate of 97%. The median time to first response was 1 month.

The safety observed with the agent was similar to other CAR T cells with mainly low-grade cytopenias. Overall, any-grade neutropenia was seen in all patients, thrombocytopenia on 86%, anemia in 76%, leukopenia in 69%, and lymphopenia in 52%.

All of the studies of BCMA-targeted CAR T cells showed positive responses and overall safety, Jakubowiak noted. The unmet need in this area is the need for cure, he stated. The key is to understand why oncologists lose control of the disease even with the high rates of CRs and with MRD-negativity. Some causes may be CAR T-cell exhaustion and antigen escape, but these potentially explanations have not been confirmed through research. However, CAR T-cell construct improvement are underway in a phase 1/2 study (EVOLVE, NCT03430011).

Orvacabtagene Autoleucel and Solutions

The EVOLVE study is evaluating the use of orvacabtagene autoleucel (orva-cel) in relapsed/refractory MM. Preliminary results from the study showed manageable safety and compelling efficacy.4

The ORR achieved with orva-cel was 91% which included a 39% CR rate 25% VGPR rate and 27% PR rate. The median follow-up in the study was 5.9 months (range, 0.9-9.2).

Safety was evaluated in 51 patients. Only 21% of those treated with a low dose of CAR T cells (300 x 106) had a grade 3 or higher cytopenic event, compared with 55% in the middle dose group (450 x 106) and 44% with a high dose of CAR T cells (600 x 106).

In addition to the CAR T construct strategy, oncologists may be able to improve the durability of responses to CAR T-cell therapy by culturing CAR T cells with PI3kinase inhibitors or by lowering the immunosuppressive effects of the tumor microenvironment, Jakubowiak stated.

_References:

_{1. Jakubowiak, AJ. Role of CAR T Cells in Relapsed Myeloma. Presented at the 2020 SOHO Virtual Annual Meeting; September 9–12, 2020.}

_{2. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. J Clin Oncol. 2020: 38 (suppl; abstr 8503). doi: 10.1200/JCO.2020.38.15_suppl.8503}

_{3. Bordeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020: 38 (suppl; abstr 8505). doi: 10.1200/JCO.2020.38.15_suppl.8505}

_{4. Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J Clin Oncol. 2020: 38 (suppl; abstr 8504).}