Dr Mailankody Discusses When and How to Use CAR-T Therapy for MM

During the Lymphoma, Leukemia & Myeloma (LL&M) Congress, Sham Mailankody, MBBS, Myeloma Service and Cellular Therapeutics Service, Memorial Sloan Kettering Cancer Center, New York, discusses when and how to use CAR-T cell therapy for multiple myeloma (MM).

Dr Mailankody said in the last 10 to 15 years, progress has been made in multiple areas of myeloma drug discovery. Currently, there are 7 emerging immunotherapies for myeloma, including CAR-T cells like ide-cel; monoclonal antibodies such as daratumumab, elotuzumab, and isatuximab; antibody drug conjugates like belantamab; bispecific T cell engagers; bispecific antibodies; checkpoint inhibitors including nivolumab or pembrolizumab; and CAR natural killer cells.

Dr Mailankody then overviewed data from 3 key trials of BCMA-directed CAR-T cells, including ide-cel, cilta-cel and orva-cel. Of these, ide-cel is the only BCMA-directed CAR-T therapy approved by the FDA. However, Dr Mailankody said, there’s a strong expectation that cilta-cel will be approved in the coming months. Orva-cel, which has good response rates and an acceptable safety profile, is no longer in clinical development.

“I should start by saying ide-cel and cilta-cel have not been tested head-to-head in any comparative, randomized clinical trials. Both products have been tested though, in phase I clinical trials with patients with 3 or more prior lines of therapy in refractory disease,” Dr Mailankody said.

Thus, Dr Mailankody compared the clinical data of 2 trials, idel-cel in the KarMMA trial and cilta-cel in the CARTITUTE-1 trial. The trials, he said, are comparable, but there was a higher proportion of patients with extramedullary disease (ide-cel 39%, cilta-cel 13%) and patients with high-risk cytogenetics (35% vs 24%) in the ide-cel study compared to cilta-cel. The median age, R-ISS stage 3 disease, number of prior lines, and triple -refractory disease, were all similar in both trials.

In both trials, cytokine release syndrome (CRS) was common—somewhere between 84 percent to 95 percent of patients had any grade CRS, Dr Mailankody said. Rates of grade 3 or higher CRS was less than 5 percent in both. Immune cell-associated and neurologic events (ICANS) were seen in 18 percent of patients in the ide-cel group compared to 21 percent of patients in the cilta-cel group. The one notable difference between the studies, Dr Mailankody said, was the rates of grade 3 or higher ICANS—3 percent in ide-cel and 9 percent in cilta-cel. Lastly, non-relapse deaths within the first 12 months were 7 percent and 9 percent, respectively.

“With cilta-cel, not only was there the classic ICANS but also delayed neurologic toxicity seen several weeks to months after the CAR-T cell, which accounts for the somewhat higher rate of neurologic events,” Dr Mailankody said.

In terms of efficacy, Dr Mailankody said the overall response rate (ORR) was 73 percent in the ide-cel group and 97 percent for the cilta-cel group. Similarly, the CR rates in bone marrow and MRD-negativity rates were lower for ide-cel, 33 percent versus 67 percent, and 79 percent versus 93 percent, respectively. The median follow-up in the 2 studies was similar. The duration of response (DOR) and median PFS were not reached with cilta-cel. However, with ide-cel, the DOR was 10.7 months and the median PFS was 8.8 months. At 18 months of follow-up, 56 percent of patients were still progression-free.

Dr Mailankody then compared these 2 studies to other FDA-approved treatments. As of the last 2 years, 3 drugs have been approved for advanced myeloma, including melphalan flufenamide, belantamab mafodotin, and selinexor.

“Compared to these 3 treatments, ide-cel and cilta-cel have higher response rates, higher complete response rates, better PFS, and better OS at the time of reporting. Obviously, none of these treatments have been compared head-to-head. This is a cross-trial comparison and it comes with all of the caveats that exist for these kinds of comparisons,” Dr Mailankody said.

To summarize, Dr Mailankody said both products have impressive responses in relapse or refractory (R/R) MM, particularly when focusing on response rates, complete response (CR), DOR, PFS, and MRD negativity rates. There are also delayed neurologic events with cilta-cel.

There are currently about half a dozen different BCMA-directed bispecific antibodies—T-cell engaging therapies that are not CAR-T cell—in clinical development, Dr Mailankody said. There’s an obvious advantage over CAR-T cell since bispecific antibodies can be given off-the-shelf or as a weekly IV or subcutaneously in an outpatient setting. That data, however, is somewhat premature, Dr Mailankody said, as most studies are only at dose escalation or early phase 2. The overall response rates (ORR) at the higher doses are between 30 percent and 80 percent. DOR is still too early to look at, but in some cases, like the AMG420 study, the DOR was 8 months.

Turning back to CAR-T cells, Dr Mailankody said there is only 1 FDA-approved treatment for patients with more than 3 lines of therapy. Ongoing trials with both ide-cel and cilta-cel are evaluating the possibility of moving the treatments to earlier lines of therapy. The potential advantages of using CAR-T cell therapy early are that T-cells are likely to be less exhausted. Patients are also likely to have less refractory disease, and thus, fewer comorbidities, all of which may predict a better response, Dr Mailankody said.

There are many different combinations being evaluated for CAR-T cells, he said, including immunomodulating drugs like lenalidomide and pomalidomide, and checkpoint blockades like nivolumab or pembrolizumab.

Dr Mailankody highlighted one of the them—gamma-secretase inhibitors (GSI). These are enzymes that cleave the surface BCMA and lead to lower expression of BCMA on the cell surface and higher soluble BCMA levels.

This clinical trial, by Dr Cohen et al at Fred Hutch, looked at 10 patients with R/R MM who were treated with GSI and BCMA-directed CAR-T cell therapy. Each patient had impressive responses, he said, and showed that the treatment of GSI prior to the CAR-T cells can increase the cell surface expression of BCLA, “thereby providing a mechanism rationale for efficacy with BCMA-directed CAR-T cell therapy,” he said.

“BCMA therapies are clearly at the forefront of immune approaches for multiple myeloma but they're certainly not the only target for CAR-T cell therapy,” Dr Mailankody said.

Other targets include SLAMF7, GPRC5B, FcRH5, CD38, and more are in clinical development for CAR-T cell therapies in multiple myeloma. There is a non-overlapping correlation between GPRC5D-positive cells and BCMA-positive cells, Dr Mailankody said, suggesting that the expression of these 2 antigens is complementary, and therefore, there is a role for GPRC5D-directed therapy for patients with MM who have low expression of BCMA or in addition to BCMA-directed therapies.

Based on this, Dr Mailankody said there’s a phase 1 clinical trial at MSKCC looking at MCARH109, a GPRC5D-directed CAR-T cell therapy for patients with R/R MM. The trial allows for prior CAR-T cell and BCMA therapies and is treating patients with multiple dose levels at a standard 3+3 dose escalation, starting at 25 million cells all the way up to 800 million cells. Patients are initially screened followed by leukapheresis and then standard lymphodepletion with fludarabine and cyclophosphamide followed by a single infusion of MCARH109. Currently, there’s no clinical data but the hope is soon at upcoming meetings, he said.

Switching gears to allogeneic CAR-T cells, Dr Mailankody said it has limitations, including how to address graft-versus-host disease (GVHD) and host-versus-graft disease (HVGD), but also advantages, including bulk manufacturing, repeat dosing, no need for bridging, and cell quality.

A clinical trial on allogenic CAR-T cell therapy is currently underway. ALLO-715 is a first-in-class allogeneic BCMA CAR-T cell therapy that uses a human-derived scFv targeting BCMA with a 4-1BB costimulatory domain and CD3zeta signaling domain. In this product, GVHD is overcome by using TALEN-mediated technology to knock out the T-cell receptor. HVGD is overcome by knocking the CD52 gene, which allows for lymphodepletion with an anti-CD52 antibody called ALLO-647.

Results from this study were presented at ASH last year, Dr Mailankody said. Preliminary efficacy data of patients who were treated with the higher dose of 320 million with the lymphodepletion of fludarabine cyclophosphamide and ALLO-647. Six out of 10 patients at this dose level had a response, with 4 patients achieving a fairly-good partial response or better. ORR was achieved in 6 patients with 4 VGPR+ rate for the FCA 230 million cell dose group. Five of the 6 VGPR+ patients were assessed for MRD status and all were negative.

“Obviously, very preliminary. We still need to know if these responses are curable. More patients need to be treated at this higher dose level but as proof-of-concept, does show that it's feasible to do allogeneic CAR-T cells with acceptable safety and preliminary promising efficacy,” Dr Mailankody said.

In conclusion, Dr Mailankody said, the first BCMA CAR-T cell therapy is now FDA approved and EMA approved. He said he anticipates additional approvals in the next coming months and years. With the autologous CAR-T cells, both cilta-cel and ide-cel have high, overall responses and promising DOR. There are also several other potential immune approaches emerging, such as allogeneic CAR-T cells and bispecific antibodies.—Emily Bader