Expansion of Treatment Options for Patients with Multiple Myeloma

Over the past 3 years, many new FDA-approved therapies have emerged for the treatment of patients with multiple myeloma. Prior to the COVID-19 pandemic, FDA approvals came through for belantamab mafodotin (Blenrep), melphalan flufenamide (Melflufen), as well as chimeric antigen receptor T-cell therapies consisting of idecabtagene vicleucel (ide-cel; Abecma), and ciltacabtagene autoleucel (cilta-cel; Carvykti).

Paul G Richardson, MD, clinical program leader and director for Clinical Research, Jerome Lipper Multiple Myeloma Center, institute physician at Dana-Farber Cancer Institute, and RJ Corman professor of Medicine at Harvard Medical School, explained the updates in this space during a presentation at the 3rd Summit of the Americas on Immunotherapies for Hematologic Malignancies. 

Upfront treatment options and the management of relapsed disease in the context of both approved agents and emerging monoclonal antibodies were the focus of his discussion.

Richardson noted that despite all of the positive updates in the field, challenges remain and various unmet medical needs still exist, including how to strategically think when treating patients with myeloma. Understanding how to further refine therapies will be the next step in properly treating patients at an earlier rate as well as learning how patients will be affected later down the line.

In an interview with Targeted OncologyTM, Richardson discussed the many changes seen in the multiple myeloma space over previous years and what is expected for the future.

TARGETED ONCOLOGY: Can you provide a brief overview of the discussion you gave on multiple myeloma during the the summit?

Richardson: There are 2 of us speaking, myself, and Dr. Adam Cohen, and what we're covering between us is the incredible excitement in the multiple myeloma space despite all the challenges that we have faced over the last 3 years with a pandemic, in terms of continued progress with new therapies in myeloma.

I focused on upfront treatment, and the management of relapse disease, in the context of the approved agents that we're lucky to currently have, as well as the more emerging monoclonal antibodies that we're developing. Adam is going to be focusing on the cellular therapy platforms in particular, and novel strategies like targeting BCMA. Between the 2 of us, we're hoping to really bring together the excitement in myeloma, from a research point of view that's translating into real world practice now with multiple recent approvals, and at the same time, being in position to therefore improve patient outcome.

Can you discuss some of the recent approvals seen in this space over the past few years?

Over the last several years we've seen a number of drugs approved, we start really just before the pandemic or just around the pandemic with belantumab mafadotin. At the same time, we then had Melflufen approved. Subsequent to that, and most recently, we had in addition to ide-cel’s approval, which was critical, which is the first CAR T platform, then the second CAR T platform, which was cilta-cel approved, which is extremely exciting.

Also, multiple approvals around certain indications, for example, selinexor combined with bortezomib in the early relapse setting and other further indications for either isatuximab [Scarlisa] as a CD38-targeting antibody, and additional indications for CD38-targeting with daratumumab in different settings as well. I think there are multiple approvals, but probably the highlights would be the successes in the CAR T space, in particular either ide-cel and then very excitingly, and very recently cilta-cel.

In the terms of belantumab mafadotin which targets BCMA as an antibody-drug conjugate, that was some years ago now, but continuing to gain momentum. And then we did have the impressive approval of now Melflufen, a targeted peptide drug conjugate, although that's currently gone into a holding pattern pending some interpretation of important phase 3 data from a trial that showed different benefits in different subgroups of patients, which caught the regulator's attention appropriately and has generated some discourse and discussion about how to best go forward with that platform.

Irrespective of that, we've got incredible work coming from bispecifics. These are antibodies that harness the immune system from within as it were, by basically targeting BCMA but at the same time harnessing a DT cell response dramatically to the target. And the bispecifics space I think is probably in the next to see an exciting new approval hopefully this year.

How have treatment approaches evolved from the ways they were a few years ago?

I think significantly with these new agents, but I do want to emphasize that we've got multiple new agents in the pipeline. One of the features of my presentation is around the exciting new class of drugs, called the CELMoD which are extremely powerful oral agents. That's an important practical point to share, that we're looking for real world options for our patients as well. Exciting platforms like CAR T are important, but they require hospitalization. Bispecifics are perhaps less complicated in terms of their modality, but nonetheless, they still require hospitalization, at least initially.

When you put this all together, having the availability of oral options that we can take off the shelf in the absolute sense of the word, and deliver them to our patients in the outpatient setting, particularly in the context of the pandemic, is vital. I think that there's a lot of excitement coming with these new agents that are that much more convenient to use, and practical, as well as recognizing in myeloma anyway, that our patients, unfortunately, are uniquely vulnerable to COVID-19. For that reason, practical approaches that don't increase vulnerability to COVID-19, in every sense, are particularly important.

What unmet needs still need to be filled in this space?

There's a lot of unmet medical needs. One of the most interesting areas that we're looking at is how to further refine therapies strategically, so 1 aspect of my presentation today is looking at the evolving position of transplant. Recognizing that high dose melphalan has been a mainstay of therapy and targeting stemness in myeloma has been absolutely critical. Melflufen, for example, provides a very targeted way of trying to exploit that platform.

The challenge with transplant is that for a while, we realize that whilst is very effective at improving response, improving progression-free survival, it doesn't appear to have a meaningful impact on overall survival, which is interesting in the era of novel therapies. We're trying to make sense of that and the reason I'm really focusing on that is because we're learning that what you do early in the patient's course of treatment can affect what happens later. We need to think strategically about myeloma.

Obviously, the goal is a functional cure. Recognizing that myeloma remains, unfortunately, still incurable in a practical sense, but functional cure and driving towards long term remissions that enhance quality of life as well as quantity of life is our overriding goal. When you put that together in composite, the biggest unmet medical need, in my opinion, is how do we further deal with resistance and relapse? To that end, not only have we talked about BCMA and existing standard agents, but very importantly, we have new targets that we're going after, and these are particularly important in the relapse setting.

The unmet medical needs in myeloma remain complex, but an important takeaway is that, in the last 22 years, the prognosis of myeloma has improved from a median survival of around 2-3 years to about 7-10 and 10-15. That's dramatic in the same period of time. We've had 2 approvals that have been pulled back, so we're at 14, but we've had 14 approvals in the last 20 years. This is remarkable progress and we're hoping that that progress will continue.

What other research excites you in this field?

In myeloma, what really excites me is the continued development of cellular therapies until continued development of immune strategies that can overcome immune dysfunction in myeloma, which is important not only for the disease itself, but also for complications such as infection. As we think about new approaches, we have to be thinking about approaches that are real world, practical, deliverable, and take away from complicated intensive care, hospital type settings, and deliver care directly to our community practices so that they can be most effective in making an impact in the broader sense in the disease. That's an area of research, particularly given the pandemic, that has become very important.