Monoclonal Antibodies Shake Up Myeloma Paradigm

Paul Richardson, MD

The introduction of monoclonal antibodies into the treatment of relapsed/refractory multiple myeloma is one of the most important advances made in recent years, said Paul G. Richardson, MD. However, headway has also been made with small molecule inhibitors and CAR T-cell therapies, leaving investigators hopeful for the future.

“We’re seeing our patients have excellent durations of disease control, but nonetheless, once relapsed/refractory disease has become established, it is a very, very challenging space in which to try and help patients,” said Richardson, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center, and institute physician, Dana-Farber Cancer Institute. “The good news is, with various strategies we're looking at continuing to move the needle forward.”

Monoclonal antibodies such as elotuzumab (Empliciti), which received approval for use in combination with pomalidomide (Pomalyst) and low-dose dexamethasone in 2018, are among the most important advances made in the relapsed/refractory setting, according to Richardson.

Additionally in this setting, the CD38-targeted antibody daratumumab is approved as monotherapy for patients with myeloma who have had ≥3 prior lines of treatment, including a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent, or who are double refractory to a PI and an IMiD agent; in combination with lenalidomide (Revlimid) and dexamethasone, or bortezomib (Velcade) and dexamethasone, for those who have received ≥1 prior therapy; and in combination with pomalidomide and dexamethasone in patients who have received ≥2 prior therapies, including lenalidomide and a PI.

Another CD38-targeted monoclonal antibody of particular interest is isatuximab. When combined with pomalidomide and low-dose dexamethasone, this agent was found to prolong progression-free survival (PFS) in patients with relapsed/refractory disease compared with pomalidomide/dexamethasone alone, according to data from the ongoing phase III ICARIA-MM trial. Updated data are slated be presented at the 2019 ASCO Annual Meeting.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Richardson, who is also RJ Corman Professor of Medicine at Harvard Medical School, highlighted the many promising agents that have emerged in the paradigm in recent years, remaining challenges, and hope for continued progress.

OncLive: What recent advances have been made with immunotherapy in relapsed/refractory multiple myeloma?

Richardson: There have been numerous advances made in relapsed/refractory myeloma in the last several years. Perhaps the most important, most recently, has been the introduction of monoclonal antibodies—in particular the first-in-class monoclonal antibody daratumumab, which targets CD38. Obviously, elotuzumab, which targets SLAMF7, has been an important advance as well, particularly when used in combination with IMiDs. Those 2 antibodies have stood out, but in terms of the pipeline, what’s looking particularly exciting in the CD38 space are the current advances that have been made with isatuximab, a chimeric antibody targeting CD38.

In the context of the CD38-targeting space the results of the ICARIA-MM trial are particularly exciting and will be presented at the 2019 ASCO Annual Meeting. This is, as I've mentioned, a chimeric antibody that targets CD38 combined with pomalidomide and dexamethasone versus pomalidomide and dexamethasone. Just as we saw the success of ELOQUENT-3, which was elotuzumab/pomalidomide/dexamethasone versus pomalidomide/dexamethasone, again the primary endpoint has been met very nicely in this trial. Therefore, I'm confident of success in terms of overall approval for isatuximab, but we'll be presenting the data in that regard.

Beyond the monoclonal antibodies, we recognize the incredible impact of next-generation immunomodulatory therapy in the form of pomalidomide, as well as next-generation proteasome inhibition in the form of carfilzomib (Kyprolis), and, of course, ixazomib (Ninlaro). However, it’s important to recognize the essential nature of targeting the immune system in the relapsed/refractory space. In that regard, cellular therapy has been tremendously important, with promising beginnings seen with CAR T-cell therapy. Beyond that, there is the recognition that immunotherapeutic strategies more broadly hold great promise. That doesn't just include [targets such as] CD38 or SLAMF7; it goes beyond that as you think about BCMA-targeting strategies. [For example, there are] antibody-drug conjugates like GSK2857916, which is a particularly promising agent under development. It is also important to note that we have this emerging strategy of bispecific T-cell engagers, which we think may be very promising in the future. That is some of the excitement around immune therapy.

Could you speak to other approaches focused on targeting mutational burden?

Beyond immunotherapy, it's very important to recognize the continued benefit of targeting mutational burden. In particular, some of the promise around venetoclax (Venclexta), which has really been focused on the (11;14) translocations that are seen in a subset of patients with myeloma. There has been a recent safety concern with venetoclax, but I'm confident that especially in the t(11;14) population, the clinical benefit is substantial. I'm very hopeful that the drug will continue to have momentum and make progress in that space.

In the other setting of mutational burden, there are a variety of novel small molecules under evaluation. Perhaps one of the most exciting ones is the selective inhibitor of nuclear export small molecule, selinexor. This drug is fascinating; it's an oral agent that's administered once or twice a week. [When administered] once weekly in combination it appears to be very active, particularly [when combined with] other drugs such as bortezomib.

This particular drug works by blocking the export of proteins that would otherwise normally suppress the malignant genome, and in that regard, suppress oncogenic thrust. In that context, it allows for a stabilization of the malignant genome in a way that is proapoptotic and triggers a control of the malignant cell. This whole construct around this agent is particularly fascinating because it may be very important, especially in high-risk disease. It seems to be very effective when used in combination and early trials have been promising, particularly in the single-arm setting. Randomized data are coming, but I'm very hopeful that selinexor will make its way into FDA approval later this year.

Are there any other promising agents that you would like to highlight?

There are several other small molecule inhibitors under study, and one that is not necessarily a small molecule, but more of a targeted chemotherapeutic, is melflufen. This agent is activated by aminopeptidases and is particularly important in the way that it targets the tumor selectively, and targets the nucleus of the myeloma selectively versus normal tissue. Early studies with that particular drug have been very promising. There are a variety of novel agents and several new strategies, which are important in relapsed/refractory disease. [We want] to bring these together and improve patient outcomes in the longer-term.

What are some challenges that still need to be addressed?

With all of these strategies, we're seeing clear clinical benefit in disease control and high response rates in certain settings and more modest responses in others, but nonetheless, in a very refractory population. However, the fundamental challenge is the fact that myeloma is incurable.

Where do you see future research headed?

I am very hopeful of continued progress. We have to be realistic that there isn’t necessarily a “home run” in any particular setting, [progress] is more incremental. For example, if you think about CAR T-cell therapy, [we have seen] incredible response rates and wonderful proof-of-principle that enhancing harnessing the immune system is critical to success in myeloma. People have been a little bit disappointed that the duration of disease control with CAR T has been less than we would have hoped, given from what we have seen with leukemia and lymphoma in contrast.

However, I don't see that as a failure or a disappointment, I see it as something that we would expect with myeloma, given how the disease is incredibly resilient. The hope is that with newer agents, we can add to this. We can build on these types of successes and [induce] responses that last longer. In that spirit, in terms of what new directions lie, there are very exciting [CELMods]. CC-220 and CC-480 are two that come to mind, both of which are very promising. These are basically the most powerful IMiD drugs that we've used to date.

Isatuximab Phase 3 Trial Meets Primary Endpoint of Prolonging Progression Free Survival in Patients With Relapsed/Refractory Multiple Myeloma. Sanofi. Published February 5, 2019. https://bit.ly/2HUKkNT. Accessed February 5, 2019.