Despite Progress With CAR T-Cell Therapy, Transplant Retains Role in Myeloma

Deepu Madduri, MD

The influx of novel therapies into the multiple myeloma treatment armamentarium continues to challenge the role of transplant; however, Deepu Madduri, MD, explained that this approach is still recommended for eligible patients, as much remains unknown with chimeric antigen receptor (CAR) T-cell therapy.

“If we feel that a patient is transplant-eligible, even if they do not necessarily want to do a transplant at that time, it’s important to harvest their stem cells and store them for the future, because you never know when you may need them,” said Madduri, an assistant professor at Mount Sinai Hospital.

In terms of CAR T-cell therapy, the next-generation B-cell maturation antigen (BCMA)-targeted product, bb21217, an enhanced version of bb2121, showed preliminary efficacy in results reported at the 2018 ASH Annual Meeting. Data showed that the objective response rate was 83.3% and the very good partial response or better rate was 75% in heavily pretreated patients with relapsed/refractory disease.

“People do well on CAR T-cell therapy,” said Madduri, although it is unknown whether it can be moved into earlier lines of treatment. “We need to learn what we can do about T-cell persistence and how long T cells last after CAR T-cell therapy.”

OncLive^®: Are transplants still the recommended treatment for eligible patients?

In an interview during the 2018 OncLive^® State of the Science Summit^™ on Multiple Myeloma, held prior to the 2018 ASH Annual Meeting, Madduri discussed the status of transplant for eligible patients and the developments that are being made with CAR T-cell therapy in multiple myeloma.Madduri: In terms of current induction treatment, the IFM 2009 study [results] showed that transplant is better [in these patients] than no transplant. The other important [area] will be with regard to consolidation, maintenance, and minimal residual disease (MRD) negativity as we move toward the MRD-negative world. We’re looking at all patients to see whether they’re MRD negative or not.

What are the optimal maintenance regimens for high- and low-risk patients?

Is MRD status being used to direct treatment?

What is the biggest challenge in this patient population?

In terms of consolidation, we’re investigating the importance of consolidation posttransplant. Some studies have shown a progression-free survival (PFS) benefit, but not as much of an overall survival (OS) benefit. In terms of maintenance, we use lenalidomide (Revlimid) following transplant. There are studies that have shown that bortezomib (Velcade) maintenance is a good idea for high-risk patients and for those with renal insufficiency.We look at cytogenetics, which is playing an important role right now with the revised International Staging System. Generally, patients who are high risk following transplant end up getting a triplet regimen or at least a proteasome inhibitor plus an immunomodulatory agent versus lenalidomide alone.All studies are incorporating MRD automatically. We know that patients who are MRD negative posttransplant tend to have better OS rates compared with patients who are not. At the same time, there’s a lot about MRD we don’t know. There was a trial that looked at MRD status in patients who had lenalidomide, bortezomib, and dexamethasone (RVd) versus transplant. Patients had the same PFS benefit, so we still have a lot to learn about MRD.It’s a matter of getting the referrals to the institutions where they do the transplants. We have a lot of patients who come from the community who have been on lenalidomide for longer than 4 to 6 cycles. Ideally, the best time to harvest [a patient’s cells] is within 4 to 6 cycles of lenalidomide therapy. Being on lenalidomide beyond that can decrease the stem cell harvest. We have to look at the patient when they come into the clinic to determine whether they’re transplant eligible or ineligible.

What CAR T-cell products are being investigated in myeloma? What are the latest data with bb2121?

Are other targets being explored?

Does CAR T-cell therapy have the potential to be introduced as a frontline treatment?

Where would you like to see research focused moving forward?

C. Ola Landgren, MD, PhD, of Memorial Sloan Kettering Cancer Center, recently published a paper showing that they do 4 to 6 cycles of induction, at which time everybody has a bone marrow biopsy. If patients are MRD negative, they continue their current induction therapy as part of consolidation. If they’re MRD positive, they undergo transplant and are then put on maintenance.The most recent data were published at the 2018 ASCO Annual Meeting. There was an overall PFS of about 11.7 months and a PFS of about 17.7 months for patients who were MRD negative. We are moving toward a cure.There are ongoing trials [exploring] CD19 as a target. CD138 is also being used as a target, but these are all in early phases. We don’t really have much data to say what’s going to happen. They’re thinking about SLAMF7 as a potential target as well. There’s quite a few, but they haven’t been publicly announced yet.We still have a long way to go. We still have to get data on the current CAR T-cell products. When are these patients relapsing? Then we can slowly move it up. The phase II KarMMa-2 and phase III KarMMa-3 trials are ongoing. The phase III trial is going to compare CAR T with daratumumab (Darzalex) and pomalidomide (Pomalyst), so [those results will] be interesting to see.We don’t know what to do [after] CAR T. A lot of these targets are BCMA targets. Now we have BCMA antibody—drug conjugates, and we’re getting BCMA bi-specific T-cell engagers (BiTEs). The [important question] is whether patients who relapse on CAR T-cell therapy lose the BCMA antigen. If so, can they try one of these other targets? Additionally, if a patient relapses on a BiTE, will they have a response to CAR T-cell therapy? There is a lot more we don’t know about BCMA and CAR T-cell therapy.

Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next-generation anti Bcma CAR T therapy. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 488. ash.confex.com/ash/2018/webprogram/Paper116953.html.