Landgren Explains Evolving Myeloma Landscape

C. Ola Landgren, MD, PhD

The treatment paradigm of multiple myeloma has been flooded with new agents and combinations, as well as the potential for chimeric antigen receptor (CAR) T-cell therapy, explains C. Ola Landgren, MD, PhD.

Two- or three-drug regimens have proven to be beneficial in patients with relapsed/refractory multiple myeloma, said Landgren. The triplet of the anti-CD38 antibody daratumumab (Darzalex) with lenalidomide (Revlimid) and dexamethasone, or bortezomib (Velcade) and dexamethasone, was approved by the FDA in November 2016 for relapsed disease following at least 1 prior therapy.

The quadruplet of carfilzomib (Kyprolis), lenalidomide, dexamethasone, and daratumumab has also drawn interest in the field.

Additionally, the B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy bb2121 induced complete remissions (CRs) for 56% of patients with relapsed/refractory multiple myeloma, according to updated findings from a dose-escalation trial.

OncLive: Can you please discuss your presentation?

Landgren, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, discussed the treatment of patients with relapsed/refractory myeloma during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies. In an interview during the meeting, Landgren shared his insight on CAR T-cell therapy, sequencing, and triplet and quadruplet regimens in myeloma.Landgren: I gave a presentation on the treatment landscape for patients with relapsed/refractory multiple myeloma. As illustrated in my lecture, there are many options in terms of treatment. I spoke about the fact that relapse varies greatly from patient to patient. It can be a biochemical or a symptomatic relapse. Depending on how relapse presents, there are different options to consider.

For example, if the relapse is more indolent, with a biochemical presentation, many patients would choose to do a more convenient treatment. I tried to make the case that in those patients, one could argue that using the most efficacious therapies potentially could have the longest impact or best outcome, clinically. However, there are no studies looking into that. I also spoke about the relapses that are more symptomatic or more aggressive. In those instances, we probably need to use the more efficacious treatment, because we don’t really have an option.

What was the impact of the trial of the secondgeneration CAR T-cell therapy bb2121?

Going forward, in terms of studies, we must focus on patients with indolent or biochemical relapses to see which of the options are the best. I outlined the fact that there are no new studies focusing on early intervention for patients who convert from minimal residual disease (MRD) negativity back to MRD positivity on clinical trials. We don’t know the answer to preventing clinical relapse, but studies in the near future hopefully will [provide it].I spent some time talking about the new drugs in the pipeline. The CAR T-cell therapy that targets BCMA, bb2121, was presented at the 2017 ASH Annual Meeting, and it had close to a 60% CR rate. All the current options for CAR T-cell therapy in this disease target BCMA. The sample sizes are quite small at this time and the follow-up time is restricted.

Can you discuss the importance of optimal sequencing?

My conclusion is that it looks very exciting. We have proof of principle that the therapy actually works, but we don’t know for how long, and we need larger patient series. The 2018 ASH Annual Meeting will be very important regarding the updates for this trial.When we discuss patients with relapsed/refractory myeloma, many of the newer trials focus on patients with 1 to 3 prior lines of therapy. That is where we see a significant improvement in terms of progression-free survival. I mentioned the ASPIRE trial, which also delivered an overall survival benefit of 8 months for the 3- versus 2-drug combination. Historically, patients with relapsed disease were treated with many prior lines of therapy. That is still the case for the CAR T-cell studies that we have seen so far.

Is there potential for quadruplet regimens?

There is 1 exception to the rule: the Nanjing [Legend Biotech] study, which was presented at the 2017 ASCO Annual Meeting. They reported a very high CR rate. A big question that was raised with these results was, “Is this a sign of superiority or strength of that therapy, or is it a reflection of the fact that patients were treated earlier?” A lot of investigators are now exploring how CAR T-cell therapy could potentially be rolled out earlier, and they try to address the question of whether a good, deep response with long clinical outcomes is possible for patients treated earlier.How many drugs is the optimal number? There has been a lot of discussion back and forth. If you look in the relapse setting, the field right now says 3 drugs should be given. There are multiple studies showing superiority for 3 drugs. In the newly diagnosed setting, it is the same thing—3 drugs are better than 2 drugs. Up until recently, there was some controversy, and some groups argued that there should be some risk-adaptive treatment, where they looked for the cytogenetic and fluorescence in situ hybridization profile, and they assigned patients as high risk and standard risk.

They were saying that for standard-risk patients, 2 drugs would be sufficient, but the data showed that this is not the right thing to do. You would have inferior outcomes. You are better off treating standard-risk patients, as well as high-risk patients, with the best therapies. Do not use risk-adaptive treatments unless you have to [do so] due to contraindications.

[Then] the next question: Should you use 3 drugs or 4 drugs? With the new monoclonal antibodies, people have asked whether they can be added to the 3-drug combinations. These 3-drug regimens typically include a proteasome inhibitor with an immunomodulatory drug and a low dose of steroids. Could you add a CD38-targeted antibody or some other antibody? There are many trials looking into this.

In Europe, there is bortezomib (Velcade) with lenalidomide, dexamethasone, and daratumumab. There is also a phase II trial looking at carfilzomib, lenalidomide, dexamethasone, and daratumumab. There are also permutations as well in combination with other antibodies. We need to look at the data, see what they show, and then move forward from there.

Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.