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Creating Lasting Benefit With CAR T-Cell Therapy in Myeloma

Caroline Seymour
Published: Monday, Mar 11, 2019

Noopur Raje, MD
Noopur Raje, MD
Triplet and quadruplet regimens comprised of immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies are increasing the odds of transforming multiple myeloma into what has traditionally been thought of as a chronic disease to a curative disease, explained Noopur Raje, MD, adding that cellular therapy is bound to increase these chances.

“We've been using CAR T-cell therapy for the last couple of years, and we've learned a lot from what we've done so far,” said Raje. “At the 2018 ASH Annual Meeting, there were lots of different products in multiple myeloma. We've seen early data that look very promising, but we're just at the beginning of learning how these therapies are going to fit into our treatment paradigm.”

The first CAR-T product to demonstrate encouraging efficacy was bb2121 in the phase I CRB-401 trial, updated results from which were presented at the 2018 ASCO Annual Meeting. At 194 days of follow-up, the rate of complete response (CR) or stringent CR (sCR) was 50% among patients with ≥3 prior lines of therapy, with 36.4% of patients in a very good partial response.1 Furthermore, the median progression-free survival was 11.8 months with a median duration of response of 10.8 months.

At the 2018 ASH Annual Meeting, preliminary results with bb21217, an enhanced bb2121 construct, were presented. The product exposes bb2121 to the PI3K inhibitor bb007, therein enriching for T cells with a memory-like phenotype, explained Raje. The theory behind the construct is that it will extend T-cell persistence, thereby increasing response rates and remission durations. According to preliminary results from the phase I CRB-402 study, the CR/sCR rate was 25% among patients with ≥3 prior lines of therapy, with 50% of patients in a very good partial response.2

Based on these data, it has been posited that CAR T-cell therapy has the potential to be moved into earlier lines of therapy or replace stem cell transplant altogether. As this research is early, Raje emphasized that continuing clinical trials and cultivating more data on these constructs will be key in answering these questions.

In an interview with OncLive, Raje, professor of medicine at Harvard Medical School and director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, discussed the current treatment landscape of multiple myeloma, with a specific focus on available triplet regimens and the recent data with CAR T-cell therapy.

OncLive: What does the current treatment landscape for multiple myeloma look like?

Raje: We have lots of FDA-approved drugs and different combinations. In the upfront setting, the majority of us will use a triplet regimen followed by transplant in the transplant-eligible population as well as maintenance. There is a move towards giving 4-drug regimens upfront, with the goal of getting to and maintaining a minimal residual disease (MRD)-negative state. By doing that, we hope to transform what we're seeing as a chronic disease in some patients into a fraction of cured patients.

At the time of relapse, the curves have shifted somewhat so that the first relapse happens approximately 3.5 to 4 years after diagnosis. There are more data now looking at triplet regimens. A lot of what we do at the time of relapse is dictated by what the patient has already received, the nature of relapse, and the risk associated with the relapse. Typically, we tend to use a triplet regimen.

In the United States, the majority of our patients are progressing after having been on a lenalidomide (Revlimid) maintenance approach. We are mostly picking a pomalidomide (Pomalyst)-based approach, whether it's with daratumumab (Darzalex), carfilzomib (Kyprolis), or some other agent.

Could you discuss the data with these triplet regimens?

We have good data with carfilzomib, pomalidomide, and dexamethasone (KPd). This regimen has been used in the relapsed/refractory setting with about a 60% to 70% response rate. Additionally, the duration of response can be close to 8 or 9 months. The regimens with daratumumab have been very impressive. We see response rates of 60% with daratumumab, pomalidomide, and dexamethasone and a duration of response close to 8 to 10 months. That’s pretty remarkable in the relapsed/refractory setting.

How do these responses differ from those achieved with CAR T-cell therapy?

With CAR T-cell therapy, we've seen response rates greater than 90%. However, this is a very different patient population. We're not talking about first relapse. On average, these patients have had 7 prior lines of therapy. Besides CAR T-cell therapy, these patients would not have anything else. These hospice-like patients who are quad- and penta-refractory have seen both immunomodulatory agents [lenalidomide and pomalidomide], both proteasome inhibitors [carfilzomib and bortezomib (Velcade)], and have also seen the monoclonal antibody daratumumab.


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Community Practice Connections™: Addressing Post-Transplant Obstacles: Current and Emerging Strategies to Evolve the Standard of Care for Patients With Graft-Versus-Host DiseaseMar 28, 20192.0
2017 Year in Review™: Clinical Impact of Immunotherapies in the Treatment of CancerMar 30, 20191.75
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