Expert Reflects on "Incredible" Data Seen With bb2121 in Heavily Pretreated Myeloma

Noopur Raje, MD

Noopur Raje, MD

The deep and durable phase I responses seen with the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy bb2121 in patients with relapsed/refractory heavily pretreated multiple myeloma have prompted a phase II study, which is currently ongoing, according to Noopur Raje, MD.

Data from the phase I CRB-401 trial showed bb2121 was associated with a 95.5% overall response rate. Moreover, it induced a progression-free survival (PFS) of 11.8 months, with a median duration of response of 10.8 months.

“Given that we are seeing stringent responses in patients who are minimal residual disease (MRD) negative—which we never would have expected to see in a patient population that was as refractory as it was—it’s really encouraging,” said Raje, lead author of the CRB-401 study.

While CAR T-cell therapy has shown promise, there is still a need for treatment that caters to narrower patient populations. Recent data suggest that selinexor, an emerging novel agent, could address this issue. Based on results from the phase IIb STORM trial, a rolling submission of an FDA new drug application was completed for selinexor in August 2018.

In an interview withTargeted Oncology, Raje, director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, discussed the latest treatment advances in multiple myeloma.

TARGETED ONCOLOGY:Do you have any update for the ongoing phase II study with bb2121?

Raje: We have seen the phase I data, which were recently presented. These data obviously looked very promising, which is what prompted the phase II study. We haven't seen any data yet from the phase II study, but I know that it's rapidly accruing. The trial started accruing only at the beginning of this year, and we're almost halfway through completely accruing for this trial. The hope is that we will meet our goal before the end of the year. As far as efficacy, we'll just have to wait and see.

TARGETED ONCOLOGY:What impact could bb2121 have on the treatment landscape?

It [would be] a really important addition to the armamentarium we already have. Given that we're seeing stringent responses in patients who are MRD negative—which we would have never expected to see in a patient population that was as refractory as it was in the phase I trial—it's really encouraging. The fact that we're seeing a PFS of close to 1 year in this heavily pretreated penta-refractory patient population with more than 7 prior lines of treatment—it's not what we imagined. For us to also have seen not that much toxicity was actually really reassuring. We're seeing patients who were MRD negative with a PFS of more than 17 months. These data are really incredible. We're all very excited.

The hope was that CAR T cells would cure multiple myeloma. But, now we have to be a little bit realistic. The problem with our expectations is that we've taken patients who really had no other options for treatment. Therefore, in my mind, these are still encouraging results. What impact will this have on the future of treatment? It's still a proof-of-principle study, which has shown responses—durable responses—with very little toxicity. The next step would be to move it to an earlier phase of treatment so that you can actually translate these responses into long-term disease control.

TARGETED ONCOLOGY:There have been some interesting data with triplet and quadruplet combinations. When does this play a role?

As of right now, it doesn't affect our practice because it's being used in the relapsed/refractory space. The triplet combinations are obviously better than doublets; that has been proven. In most places in myeloma, we're using triplets. I've always been an advocate of that. We're now starting quadruplets in the upfront setting, which is going to be very important. Along with these quadruplets, we are using MRD testing as an endpoint to either escalate or de-escalate treatment. By doing so with advances in technology and therapy, we may actually be curing a subset of patients with these treatments we have available already.

In the vast majority who are not cured even with the quadruplets, you would consider the use of therapy like CAR T-cell treatment. I might go even further than that. If you're seeing long-term disease control with other therapy, do you want to use quadruplets indefinitely? This remains to be tested.

TARGETED ONCOLOGY:Does the frontline combination of daratumumab (Darzalex) and VMP for newly diagnosed patients who are ineligible for stem cell transplant have any effect on your practice?

It doesn't really affect my practice because VMP is not something we use in the United States. This gives daratumumab a label in the upfront setting. If we have a patient with renal failure, for example, you could make the argument of using [daratumumab] with bortezomib (Velcade). Will I switch patients to VMP and daratumumab? The answer to that is, “Probably not.” We're waiting for the study of dexamethasone versus dexamethasone and daratumumab. This will be a more impactful study because it's more relevant to practice in the United States. Our hope is that we see some data later this year or early next year.

TARGETED ONCOLOGY:The FDA recently received a rolling submission for a new drug application for selinexor for penta-refractory patients. What impact could this have?

Selinexor is a novel drug with a completely different mechanism of action. The big question is going to be the durability of the responses in the penta-refractory patients. The fact that we are seeing responses with single-agent selinexor in this patient population is encouraging as long as it's well tolerated, and patients can stay on it. It's helpful because this is something that's right off the shelf. It would be easily accessible for patients.

TARGETED ONCOLOGY:What are your thoughts on checkpoint inhibitors?

As of right now, checkpoint inhibitors have taken a little bit of a backstage role in multiple myeloma. That's largely because of all the KEYNOTE trials. Having the FDA present their findings at the 2018 ASCO Annual Meeting was actually very instructive. If you looked at the analyses done by the FDA on the 2 big KEYNOTE trials, one was in the upfront setting and the other in the relapsed/refractory setting, one was in combination with lenalidomide (Revlimid) and the other was pomalidomide (Pomalyst).

The reason why it's gone backwards a little bit was because we saw higher mortality in patients treated with drugs such as pembrolizumab (Keytruda). Most of the deaths were related to toxicity. What it tells us is we need to appreciate the toxicity of these drugs better. However, there is a subset of patients who do better with these agents, so we need to keep working on it.

TARGETED ONCOLOGY:Where is there still an unmet need?

The biggest unmet need, number 1, is that we haven't cured myeloma. That's always the biggest unmet need until we can get there. In the meantime, we need to work on improving outcomes. The second piece is the high-risk patient population. Despite all these novel drugs, the true high-risk patients still have a median overall survival of something like 3 years at most. That needs to change. Designing trials specifically for this genetically high-risk population is critical. We also need to define this population more uniformly and not do it ad hoc.

Reference:

Raje NS, Berdega JG, Lin BY, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study.J Clin Oncol. 2018;36 (suppl; abstr 8007).