#WHEREISDRJOE Is It Time to Bring the CAR Home Early?

By Dr. Joseph Mikhael IMF Chief Medical Officer

Chimeric antigen receptor (CAR) T-cell therapy is already having a profound impact in many blood cancers, including in myeloma. Two CAR T-cell therapies are approved by the U.S. Food and Drug Administration (FDA) for use in myeloma.

In March 2021, Abecma® (generic name “idecabtagene vicleucel” or “ide-cel” for short) became the first CAR T-cell therapy approved by the FDA for patients with myeloma, and it is the first CAR T-cell therapy that targets the B-cell maturation antigen (BCMA), a protein involved in myeloma cell growth and survival. Abecma is approved for the treatment of adult patients with relapsed or refractory myeloma after 4 or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

In February 2022, the FDA approved Carvykti® (“ciltacabtagene autoleucel” or “cilta-cel” for short) for the treatment of patients with relapsed or refractory myeloma after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The CAR T-cell approach to treating myeloma is an immunotherapy that enhances the immune system, our body’s natural defense designed to destroy infected and malignant (cancerous) cells, and to remove cellular debris. CAR T-cell therapy takes the patient’s own T cells and engineers them to attack and destroy the myeloma cells. To achieve this goal, the T cells are “harvested” from the bloodstream of the patients, then sent to a highly specialized manufacturing laboratory to be engineered and multiplies until enough active T cells have been manufactured for the therapy to be effective. Then the T-cell product is administered to the patient by way of an infusion. The infused T cells immediately begin attacking the myeloma cells.

We are seeing response rates more than 3 times higher than prior therapies in heavily pretreated myeloma, even up to nearly 100%! But not only are the response rates high, we are seeing those responses last for a very long time. Some patients have had durable responses lasting for years. However, both Abecma and Carvykti are FDA-approved to be used in patients with at least 4 prior lines of therapy. That may change soon. Two large clinical trials, one with Abecma and one with Carvykti, are using CAR T-cell therapy in earlier-line treatment settings, including in newly diagnosed myeloma.

The KarMMa-3 clinical trial is evaluating Abecma in patients with 2 to 4 prior lines of therapy by comparing it to one of 5 standardof-care (SOC) regimens currently used in relapsed myeloma:

1. Darzalex® (daratumumab) + Pomalyst® (pomalidomide) + dexamethasone (DPd),

2. Darzalex + Velcade® (bortezomib) + dexamethasone (DVd),

3. Ninlaro® (ixazomib) + Revlimid® (lenalidomide) + dexamethasone (IRd),

4. Kyprolis® (carfilzomib) + dexamethasone (Kd), or

5. Empliciti® (elotuzumab) + Pomalyst + dexamethasone (EPd). With follow up of just over 18 months, the median progressionfree survival (PFS) was 13.3 months in the Abecma study arm vs. 4.4 months in the SOC study arm, and the response rate was 71% vs. 42%, respectively. This is truly a remarkable difference in favor of CAR T-cell therapy.

Data from the CARTITUDE-4 clinical trial of Carvykti was recently presented at the annual meetings of the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA). Carvykti was evaluated in patients with 1 to 3 prior lines of therapy vs. SOC regiments DPd and DVd. With approximately 16 months of follow-up, the PFS for the SOC regimens study arm was 11.8 months vs. the Carvykti study arm where PFS has not yet been reached. The difference in the PFS curves is quite striking. There was also a significant difference in response rates, with 85% in the Carvykti study arm vs. 63% in the SOC regimens study arm.

In both studies it appears that giving CAR T-cell therapy earlier in the myeloma disease course resulted in less toxicity: less cytokine release syndrome (CRS), neurological toxicity, and low blood counts. This is not entirely surprising as novel treatments tend to be more effective in earlier lines of therapy, but the degree of improvement is noteworthy. It may also be that the patients’ T cells are more effective and safer when used earlier.

So what does this mean for patients with myeloma? It is gratifying to see these impressive results, and we anticipate that in the near future the FDA approvals for both CAR T-cell therapy products will change to allow their use earlier in the disease course. Having said that, many myeloma patients are experiencing difficulties with access to CAR T-cell therapy. This is a complex problem that includes production issues, slots at treatment centers, race and ethnicity, socio-economic status, and geography – some myeloma patients simply do not live anywhere near where CAR T-cell therapy is being done.

There is hope in sight as production increases and more treatment centers are beginning to offer CAR T-cell therapy. The results of the KarMMa-3 and CARTITUDE-4 clinical trials are truly very exciting. We are now evaluating CAR T-cell therapy in the frontline setting, and even comparing it to autologous stem cell transplant. We may soon see the CAR being brought home even earlier! MT

Stay tuned for Dr. Mikhael’s next #WHEREISDRJOE column and contact the IMF InfoLine with your myeloma-related questions and concerns. Phone lines are open 9 a.m. to 4 p.m. (Pacific) Monday through Thursday, and 9 a.m. to 2 p.m. on Friday at 1.800.452.CURE in the U.S. and Canada and 1.818.487.7455 worldwide. To submit your query electronically, email InfoLine@myeloma.org