Next Steps in Myeloma Include Combo Regimens and Achieving MRD

Ruben Niesvizky, MD

Over the last couple of years, a variety of new therapeutic options have emerged for patients with multiple myeloma. Moreover, even with the recent FDA approvals of the monoclonal antibodies daratumumab (Darzalex) and elotuzumab (Empliciti), as well as the oral proteasome inhibitor ixazomib (Ninlaro), other agents and approaches that have been a staple in the paradigm will continue to have pivotal roles.

For example, the immunomodulatory agent lenalidomide (Revlimid) was initially granted FDA approval for use with dexamethasone in patients with multiple myeloma who received at least 1 prior therapy. The indication was expanded in 2015 for use in combination with dexamethasone to include newly diagnosed patients who are not eligible for autologous stem cell transplant (ASCT).

Lenalidomide’s indication was expanded again in February 2017 when the FDA approved it as a maintenance therapy following ASCT. But clinical trials are studying the agent in combination as maintenance regimens and in other settings to further advance long-term outcomes.

A phase III randomized trial is exploring the triplet therapy of carfilzomib (Kyprolis), lenalidomide, and dexamethasone versus lenalidomide alone after ASCT for patients who are considered eligible for lenalidomide maintenance (NCT02659293). Researchers will compare progression-free survival (PFS) and the rate of minimal residual disease (MRD) negativity.

Additionally, the combination of lenalidomide and the PD-1 inhibitor pembrolizumab (Keytruda) is being tested in a phase II trial for patients with high-risk multiple myeloma following high-dose chemotherapy with ASCT (NCT02906332).

OncLive: What were the highlights from your presentation on multiple myeloma?

Ruben Niesvizky, MD, lectured on the evolving paradigm of multiple myeloma during the 2017 OncLive State of the Science Summit on Hematologic Malignancies. In an interview during the meeting, Niesvizky, who is director of the Multiple Myeloma Center at Weill Cornell Medicine/NewYork-Presbyterian Hospital, spoke about some of the exciting advances, the potential of chimeric antigen receptor (CAR) T-cell therapy, and emerging combination regimens on the horizon.Niesvizky: It was a pleasure to be here. The most important point I wanted to make is that there has been a large evolution in the management of patients with multiple myeloma. We have tried to change the algorithms to achieve the best response possible, even in people who have developed the CRAB criteria. We are moving toward chemoprevention and early intervention in people who have not developed active disease. This has been allowed using criteria that includes high free light chain ratio, high level of bone marrow plasma cytosis, or the presence of abnormalities in an MRI. With that, we can start doing early intervention—as already published with lenalidomide/dexamethasone, or as we are moving in the future to using more aggressive induction consolidation and maintenance type of programs. We are about to use protocols in that arena.

The second thing is that induction has also changed, and now we are changing the goals of remission. It is to not only to achieve complete remission (CR) but to achieve MRD. With MRD, you can hope for the best and longest type of PFS and overall survival. We can even start exploring potential curative therapies. We are also exploring the new data available for transplant, which remains an important tool to achieve that MRD but is not seen as [necessary]. Therefore, we can still achieve an MRD state without transplant. I utilize transplant later in the disease as a salvage therapy. It is important to still collect stem cells and do transplant in those patients who could not achieve a CR.

We are also seeing difficulties in trying to identify precision medicine vectors to initiate therapy, because multiple myeloma carries a large genomic instability and we cannot identify 1 simple gene to target. We are busy incorporating monoclonal antibodies into therapy, including daratumumab and others that can enhance the ability to achieve MRD either in the frontline or relapsed setting.

Even if you achieve an MRD state, it is still standard of care to use maintenance therapy. Currently, the standard is with lenalidomide but we are exploring it in combination with other agents, which include proteasome inhibitors, such as ixazomib (Ninlaro), or even possibly with oprozomib.

What other ongoing clinical trials could possibly change practice?

With the explosion of many agents available for myeloma, are there any concerns or challenges with sequencing now?

Those are agents that are oral and can allow us to duplicate the efficacy with very little toxicity and much more convenience for the patients. Certainly, the incorporation of monoclonal antibodies into the frontline setting [is exciting]. We and others are participating in the addition of daratumumab and elotuzumab earlier in the disease, and we are very interested to see what impact these will have on response rates, MRD state, and PFS.That is a very important question. Sequential therapy is part of the natural algorithms for the disease. Perhaps, in the future, I can foresee achieving an MRD and hopefully offer patients disease-free and drug-free states. That will only be possible once we start randomizing patients to get treatment or not, depending on the MRD state.

Is there potential for CAR T-cell therapy in myeloma?

What about immunotherapy overall—does this class of agents have a role?

What are the main points that the community oncologists in attendance took from your lecture on how the field in myeloma is moving?

We need to better define what to call MRD. That is also technology in evolution, and as we have better techniques, we will be able to better predict long-term outcomes with MRD. Imaging will be important and will be incorporated into that question. There are very preliminary results. The issue is to try to find better techniques—ones that are less toxic—and explore off-the-shelf products. At this point, there is excitement, but there are very little data. At this point, we are only seeing very preliminary information in the earlier stages. There are a lot of approaches that are being explored but are very early in development. But, listen, we have immunomodulatory drugs—those are partners to any potential immunotherapy. Now, we are combining them with antibodies so that is one of the first steps. Of course, we are going to have bispecific antibodies and checkpoint inhibitors, and we are combining all of them with lenalidomide and with pomalidomide (Pomalyst), so we are seeing some results that are still early on in the development of that, too. The efficacy of our products has increased significantly as we incorporate new agents. The MRD evaluation is also changing and we have to explore better techniques and incorporation of imaging into that. We also should not forget that transplant is important, but it is more of a tool—not an objective—and to try to participate in the clinical trials, particularly in the relapse/refractory setting, where more molecules can be explored.