Increasing Use of BCMA-Directed Therapies in Multiple Myeloma

With the recent FDA approvals of belantamab mafodotin (BLENREP), ciltacabtaene autoleucel (cilta-cel; Carvykti), and idecabtagene vicleucel (ide-cel; Abecma), the multiple myeloma treatment landscape is hub for BCMA-directed therapies.

Each of the FDA-approved BCMA-directed therapies, and targets are being explored in ongoing studies examining response rates in patients with or without prior BCMA-directed CAR T-cell therapy.

The BCMA CAR products currently approved for patients with myeloma are specifically for those who have had at least 4 prior lines of therapy, including a proteasome inhibitor image and a CD38 antibody. While there is no age limit, patients should be in good enough condition to withstand cytokine release syndrome and are typically those without advanced heart failure, uncontrolled cardiac conditions, oxygen independence, or other severe pulmonary conditions.

During the 3rd Summit of the Americas on Immunotherapies for Hematologic Malignancies, Adam Cohen, MD, director, Myeloma Immunotherapy, and associate professor of Medicine at the Hospital of the University of Pennsylvania, presented clinical data supporting the approved agents. He noted the positive findings of the exciting new immunotherapies for myeloma which have shown high response rates, even in patients who have had prior BCMA-directed CAR T cells.

In an interview with Targeted Oncology^TM, Cohen further discussed the recent updates and advancements in BCMA-directed therapies for multiple myeloma.

TARGETED ONCOLOGY: Can you discuss your presentation on the topic of BCMA-directed therapies for patients with multiple myeloma?

Cohen: The bulk of my talk is presenting the clinical data that supports the use of both belantamab mafodotin, as well as ide-cel, and cilta-cel, which are FDA approved products. I also go through some of the exciting data coming out with the bispecific antibodies and other immune therapy that's showing a lot of promise in myeloma as well as in other cancers.

I reviewed some of the most mature data from the BCMA-targeted bispecifics as well as from 2 bispecifics hitting other targets, 1 called GPRC5D and 1 [called] FCRH5. So, there's really a lot of exciting new immunotherapies for myeloma, and these are showing high response rates, even in patients who have already had prior CAR T cells or prior BCMA-directed therapy in some cases.

Then, I finished up with a little bit of discussion of correlative analysis trying to understand mechanisms of resistance, which patients might be likely to respond, and which patients might not. I think that's going to hopefully help frame the next generation of trials if we really understand why some patients are not going to respond to these current products that are either better products that we can use, or can we combine these currently available therapies with some of our other therapies in myeloma to really start getting deeper and more durable remissions for more patients and maybe even eventually get to a cure? That's really what we're all hoping [for].

What survival response rates are being seen with other therapies for this disease?

Unfortunately, once patients had become refractory to some of our standard upfront treatments, proteasome inhibitors, IMiDs and CD-38 antibodies, we know that relapse in that relapsed refractory population, that response rates, PFS, and survivals are fairly poor. There was a large study called the MAMMOTH study that was a retrospective look back at multiple different regimens from multiple centers. Regardless of the regimen, the response rates were somewhere in the order of 30%, the PFS was only 3 to 4 months, and survival was generally in the order of 6 to 8 months. It really was an area of unmet need, and fortunately, the BCMA targeted therapies are trying to fill that niche.

Can you discuss some of the FDA approved agents? What was exciting about the study supporting these approvals?

The first BCMA-targeted drug that was approved was called belantamab mafodotin. This is an anti-BCMA antibody drug conjugate. It's a monoclonal antibody that has a microtubule poison on the end of it called MMAF, and it's given as an IV infusion every 3 weeks. It was approved based on the DREAMM-2 study which looked at 2 different doses of the drug and found that the 2.5 milligram per kilogram dose was sort of the optimal one going forward, and that's the one that got approved.

The response rate, again in that heavily refractory population of a median 6-7 prior lines of therapy was around 32%. Median PFS was only about 3 months, but the median duration of response was 11 months, meaning if you did get a response, those responses tended to be fairly durable. We've had patients on this drug going on more than 2 and a half years. So that's the first one that got approved in 2020.

The next one that was approved was ide-cel, which is a CAR T-cell product targeting BCMA, which was approved in the summer of 2021. This was based on the KARMA study, which was a multi-institution, single-arm, phase 2 study giving these BCMA-targeted CAR T cells to patients with heavily refractory myeloma. In that study, the overall response rate was 73%, with almost 40% of patients getting a CR [complete response]. The median progression-free survival for all patients was around 9 months, but in the group that got the highest dose of 450 million cells, which is the target dose approved by the FDA, median PFS was close to 12 months. This was unprecedented activity in this heavily pretreated population of patients.

The final product, that just got approved at the end of February 2022, is cilta-cel. This is another CAR T-cell product targeting BCMA. It has a distinct CAR construct compared with ide-cel cell and was also tested in a multi-institution. phase 2 study in the United States called CARTITUDE-1. In this study at 97 patients, the overall response rate was 98% with over 80% of patients achieving a complete remission. Median progression-free survival has not yet been reached with about 2 years of follow up. There are remarkable response rates, depth of response, and PFS with these CAR T-cell products in particular. I think that's what's generating a lot of excitement in the field right now, and now we have 2 different CAR products that are approved and available for our patients, which is great.

Are there currently any concerns with using BCMA-directed therapies?

Each of these approaches have their own toxicities that we need to watch out for. Belantamab, which is the antibody drug conjugate, shows one of the primary toxicities is corneal toxicity, keratopathy. The MMAF chemotherapy agent can lead to epithelial damage in the cornea that can cause blurred vision or dry eye. This is reversible, if you hold the drug and let it wash out, it does resolve and there's no permanent visual loss. It does require co-management with an eye care specialist, either an ophthalmologist or optometrist, to do eye exams and does require some dose modifications and dose holds in order to get patients through this. That's the one thing for the belantamab to keep an eye out for.

The main risks with the CAR T-cell products are similar to CAR T cells for other diseases, namely cytokine release syndrome and neurotoxicity. This tends to occur within the first week of treatment. Patients are typically hospitalized either during the CAR infusion, or shortly thereafter for monitoring for this. We've learned how to really manage these with aggressive, supportive care, and in some cases, tocilizumab or steroids to try to minimize the risk of these becoming severe. That's something we definitely need to keep an eye out for, with the CAR T-cell products, at least in the immediate post treatment period.

I think the key thing that we're learning is that these certainly can be very immune suppressive. Targeting BCMA can lead to hypogammaglobulinemia and increased risk of infections that can persist for months. These patients often need IVIG replacement, they need to be monitored closely with prophylactic antimicrobials as needed, and prompt treatment of any signs of infection.

Who is the ideal candidate for this type of treatment? What advice do you have for oncologists whose patient may not be the ideal candidate?

Right now, both BCMA CAR products in myeloma are approved for patients who have had at least 4 prior lines of therapy, which must include a proteasome inhibitor image and a CD38 antibody. There's no real upper age limit for CAR T-cell therapy. We've treated patients in their early 80s, but they do need to be robust to be able to withstand cytokine release syndrome. Typically, we would exclude patients with advanced heart failure or uncontrolled cardiac conditions, oxygen independence, COPD, or other severe pulmonary conditions or very poor performance status. We don't think renal failure necessarily is an exclusion, they were excluded from the trials, but we have been able to treat patients with commercial products even with profound renal dysfunction, just modifying the lymphodepleting chemotherapy.

I think the time to think about sending your patient into the CAR T-cell center should be when they're progressing on their third line therapy and you're thinking about starting a fourth line treatment. It would be helpful if you're thinking there would be a CAR T-cell candidate to get them into the center so we can assess them at the same time and add them to the waitlist for CAR T cells. Unfortunately, there's still limited manufacturing slots for these, so there can be a several month waitlist. That way, that patient is already in the system and if they don't respond to fourth-line treatment, or even if they are responding well but it's not a deep response, we may be able to take them to CAR T cells while they're under good disease control.

We're learning that patients who are really progressing rapidly while we're trying to collect T cells and then manage them with bridging therapy during the manufacturing process has been challenging. Some of those patients unfortunately never make it to their CAR T cells because their disease just takes off. I think it's better to send them in while they're still under some control and while we have good bridging options.