Expert Addresses Advances and Challenges in Myeloma

Triplet regimens have emerged as the standard of care for patients with relapsed multiple myeloma. Specifically, a 3-drug combination that stands out is daratumumab (Darzalex), lenalidomide (Revlimid), and bortezomib (Velcade), according to Andrew Kin, MD.

Chimeric antigen receptor (CAR) T-cell therapy has also shown promising activity in patients with relapsed/refractory disease. In a heavily pretreated patient population, updated data presented at the 2018 ASCO Annual Meeting showed that the BCMA-directed therapy bb2121 induced a complete response rate of over 50%. The median progression-free survival (PFS) was 11.8 months, with an over 10.8-month duration of response with bb2121. Phase II of the CRB-401 trial is ongoing.

“With a group of patients who were refractory and heavily pretreated, to see that level of response was almost unheard of,” said Kin of bb2121, adding that the plethora of available agents in this setting is a “good problem.”

Moreover, Kin explained the importance of sequencing the available therapies, which comprise monoclonal antibodies, proteasome inhibitors, and immunomodulatory agents, for the best possible outcomes.

OncLive: Please provide an overview of the relapsed multiple myeloma landscape.

In an interview during the 2018 OncLive State of the Science Summit™ on Hematologic Malignancies, Kin, an oncologist at Karmanos Cancer Institute, shared insight on the treatment landscape for multiple myeloma and the challenges that remain.Kin: Myeloma has been blessed and cursed in recent years. We've had so many new therapies available and so many combinations have developed from those therapies. We are fortunate in myeloma that these agents synergize and work well together. In the frontline setting, you’re starting to get some clarity as to a standard regimen and how we can apply that in a relapsed setting. In the relapsed setting, there are so many options.

The key thing to look at is, to some extent, the art of the medicine and how to utilize it. You want to look at the specifics of their disease—how quickly is it coming back, its aggression, and factors like that. We have so many classes of medication available now. You want to also get the patient's side of things—do they have any comorbidities? This will influence you toward or away from any individual agent.

With this in mind, there are a couple generalizations that we can make. The trials we have done in the relapsed setting have been testing 3 drugs against 2 drugs—adding either regimen to a backbone of lenalidomide/dexamethasone, or pomalidomide (Pomalyst)/dexamethasone. Across the board, they all showed improvement in 3 drugs versus 2 drugs. If your patient is fit enough and doesn't have any toxicities, it is clear that a 3-drug combination in the relapsed setting is what you should be shooting for.

With that said, if you don't have any specific indications, the data with daratumumab in combination with lenalidomide or bortezomib have been very interesting. We are seeing deep responses. I tend to prefer that combination. In the second-line setting, there are a number of great agents, such as carfilzomib (Kyprolis). There are also ongoing trials with daratumumab and pomalidomide. Therefore, if a patient didn't get daratumumab in the second-line setting, that would be an option. There are so many triplet options available.

What is a key consideration moving forward in terms of sequencing these agents?

What unanswered questions remain with bb2121?

What potential does elotuzumab (Empliciti) have in this setting?

Are there other trials you are particularly excited about?

With clinical trials overall, there are so many new classes of drugs coming out. Venetoclax (Venclexta) is a great example and BCMA-targeted agents are another. CAR T cells and antibody-drug conjugates have also been huge for [this field]. Most of these clinical trials start with patients who have up to 2 prior lines of therapy. Therefore, if you are in relapse, I would consider a clinical trial. Some of the most important things lie in how they did with their prior therapies and, of course, what these prior therapies were. Toxicity is especially important. For example, if a patient had neuropathy with bortezomib, you might want to think twice [about continuing therapy] or reduce the dose. What is most impressive about bb2121 is the PFS. Just like in the lymphoma setting, with a group of patients who were refractory and heavily pretreated, to see that level of response is almost unheard of. The challenge is, where this will fall in terms of sequencing. Do we move this forward, or do we leave it with the heavily pretreated population? Costs are an issue here, so you want to be sure. Those are the biggest questions we have, and we would like to see these answered before we consider moving bb2121 into an earlier setting.Its role will increase. Elotuzumab was approved in combination with lenalidomide and dexamethasone in a setting in which nearly all patients were exposed to lenalidomide maintenance at the time of their progression—so it didn’t have much of a role. It was kind of a drug without a niche. Now that we have some data in combination with pomalidomide, it will become more important. Carfilzomib in combination with pomalidomide and dexamethasone, without a monoclonal antibody, could be effective. We should have some data reported here soon. There have been several publications recently on sequencing myeloma and targeted treatments. Some things have come up looking at BRAF V600E; it looks like approximately 5% of patients [with myeloma] have that mutation.

Raje NS, Berdeja JG, Lin Y, 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).