Quadruplets, Bispecific Antibodies, and CAR T-Cell Therapies Usher in Advances in Multiple Myeloma

Noopur Raje, MD

Immunotherapy and novel drug combinations contributing to a brighter future of multiple myeloma treatment, explained Noopur Raje, MD, who emphasized how these approaches coupled with supportive care can help patients achieve minimal residual disease (MRD) negativity and avoid adverse effects (AEs) such as keratopathy and neurotoxicities.

“It’s an exciting time in multiple myeloma—not just because of the therapies that we have available, but because of the technology, as well. We have tools with which we can detect disease at very low levels. Ultimately, we are aiming for MRD negativity,” Raje said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma, which she chaired.

In the interview, Raje, who is the director of the Center for Multiple Myeloma at Mass General Cancer Center, Massachusetts General Hospital, reviewed key points from each presentation shared during the meeting, including the benefits of quadruplet regimens in the up-front and relapsed settings, treatment options for relapsed/refractory disease, and the possibilities for combinations to minimize toxicities in those who receive CAR T-cell or bispecific antibody therapies. Raje also discussed recent and ongoing clinical trials evaluating patient responses to 4-drug combinations.

OncLive^®: What work has been done to incorporate MRD into future multiple myeloma treatment?

Raje: [We use] different tools to ascertain MRD negativity in patients. [Also,] some ongoing trials are using quadruplets up front. With these [regimens], we are seeing high response rates, so it makes sense for us to incorporate testing, such as MRD testing, which about 40% to 45% of patients receive. There has been remarkable progress.

I also presented on different approaches in the up-front setting. I talked about the [phase 2] MASTER trial [NCT03224507], which was an interesting trial from a hypothesis-generating standpoint. However, it also taught us is that we must refine our definition of sustained MRD negativity. [This trial defined MRD negativity as the point where patients could receive treatment-free observation and MRD surveillance [MRD-SURE]. However,] based on the International Myeloma Working Group criteria, we would consider [patients to be] MRD negative after [they have sustained MRD negativity for 1 year].

Tailoring therapy around sustained MRD negativity should be our goal. The MASTER trial taught us that, at least in the high-risk or ultra–high-risk candidates, we should not be using MRD-SURE negativity as a way of de-escalating treatment.

I am also excited about all the immunotherapeutic approaches, such as CAR-T cell therapies and bispecific T-cell engagers [BiTEs]. Some of the new novel drugs [are interesting, as well].

What would you like colleagues to take away in terms of the goals of treatment in myeloma?

There are many exciting opportunities in myeloma. Getting to MRD-negative disease should be the goal with whatever therapies we use. We are at the beginning stages of immunotherapeutic approaches and we are still learning about them. Incorporating [these strategies] early in the course of this disease is going to result in transformative care for patients with myeloma.

Your colleague, Andrew Yee, MD, of Mass General Cancer Center, spoke on updates in relapsed/refractory multiple myeloma. What has become a hallmark of relapsed/refractory disease, and what options are available to patients?

Relapsed/refractory myeloma represents an important aspect of how we treat [this disease]. There are no right answers as to how one should sequence available treatment. The good news is, we have many treatment options. The challenge is: How do you pick and what do you pick?

Dr Yee did an excellent job of explaining the criteria we should use for selecting treatments, including patient-related criteria. He also discussed the importance of determining the disease-related factors and mentioned that most of the patients we see at the time of relapse, at least in the United States, are refractory to lenalidomide [Revlimid].

He also talked about some newer treatment approaches. Regarding patients who have not yet been treated with an anti-CD38 monoclonal antibody, he talked about combinations that include CD38 monoclonal antibodies, such as [those with proteasome inhibitors] or [immunomodulatory drugs]. For example, combinations with pomalidomide [Pomalyst] or carfilzomib [Kyprolis], [are] regimens that we have seen explored in the phase 3 IKEMA [NCT03275285] and CANDOR [NCT03158688] studies.

Additionally, Dr Yee talked about several new drugs. Specifically, we have drugs like selinexor [Xpovio], which is a [selective inhibitor of nuclear export]. One challenge with this drug is its toxicity. Dr Yee laid out some combinations [that can include] selinexor. The first step is to get drugs approved. As we get drugs approved, we start learning [more about] different combinations.

Dr Yee talked about selinexor combinations with drugs like carfilzomib and daratumumab [Darzalex]. Most of these combinations use selinexor once a week. These are useful combinations wherein we can mitigate the toxicities of some of these agents.

Finally, Dr Yee discussed belantamab mafodotin-blmf [Blenrep], which is also an approved drug. Most of us who have used this agent are challenged by the possibility of keratopathy as an AE. [Dr Yee showed data supporting the use of this drug in combinations.] Specifically, when used in combination with pomalidomide, as has been demonstrated in the [phase 1/2] ALGONQUIN trial [NCT03715478], we [saw that we] can dose reduce belantamab mafodotin and give it every 4 weeks, or even every 8 weeks. By doing so, we can mitigate the keratopathy.

What sorts of questions should referring providers consider when it comes to CAR T-cell therapy in multiple myeloma, the focus of the presentation your colleague, Betsy O’Donnell, MD, of Mass General Cancer Center, gave?

Dr O’Donnell spoke about CAR T cells and BiTEs; all of us are excited about these approaches. She also shared some of the data with [idecabtagene vicleucel (ide-cel; Abecma)], [ciltacabtagene autoleucel (cilta-cel; Carvykti)], and bispecific antibodies, including teclistamab (JNJ-64007957), elranatamab (PF-06863135), and some of the newer bispecific antibodies, such as cevostamab and talquetamab.

Dr O’Donnell provided practical insights into which patients we should consider referring for CAR T cells or immunotherapeutic approaches. She discussed questions such as: What is the ideal time for referral? Who is the kind of patient who gets referred, and how do we work with community oncologists so that their patients [have access to] to some of these promising treatments? These are all practical insights into cellular therapy, as well as BiTEs.

Another one of your colleagues, Andrew Branagan, MD, PhD, of Mass General Cancer Center, also shed light on T-cell engagers in multiple myeloma. What is important to remember about the toxicities associated with these treatments?

Dr Branagan discussed some of the complications associated with both CAR T cells and bispecific antibodies. Toxicities are seen with both approaches. He talked about cytokine release syndrome, as well as the neurotoxicity that patients experience with some of these drug products.

He also provided us with good insights into [how we should navigate] infection control and long-term myelosuppression while using some of these approaches. Given that we are still battling with this pandemic, he spoke about the precautions that we should be taking regarding COVID-19, as well as the role of immunization and some of the new antibodies like [tixagevimab cilgavimab (Evusheld)].

Finally, Dr Branagan’s area of expertise at Mass General is running the Waldenström Macroglobulinemia program. He gave us an overview of Waldenström macroglobulinemia, and it is remarkable to see that have so much going on in hematologic malignancies, and advances in Waldenström macroglobulinemiaare not far behind. He talked about some of the newer approaches, as well as the new BTK inhibitors and their decreased toxicity. He also presented on some of the new monoclonal antibodies that are being tested in the context of Waldenström macroglobulinemia. Additionally, he highlighted some of the clinical trials that we have available at Mass General for patients with Waldenström macroglobulinemia.

Is there any research you or your institution are involved in that you would like to highlight?

We have much going on at Mass General Cancer Center. In the up-front setting, we are looking at quadruplets. We just completed a trial where we have used isatuximab-irfc [Sarclisa] with carfilzomib, lenalidomide, and dexamethasone. We are using this quadruplet with the help of MRD testing, and we are changing the way we maintain these patients depending on whether they are high risk. This study is being done in a transplant-eligible patient population, so if patients want the transplant, they can go to transplant.

We are also doing similar work in the elderly, non–transplant eligible patient population, still using quadruplets but with different drugs. We are using a combination of daratumumab with ixazomib [Ninlaro], lenalidomide, and dexamethasone. The goal of these trials, even in the elderly patient population, is to get to MRD negativity.

In the relapsed setting, Dr Yee is leading efforts that are investigating using 4 drugs like [those] we are studying in the up-front setting. He has several trials where he is using daratumumab with carfilzomib, pomalidomide, and dexamethasone in the relapsed setting. Those data are going to be presented at the 2022 American Society of Clinical Oncology Annual Meeting.

We have seen remarkable responses in the relapsed setting. We are very involved in the whole immunotherapy space. We are leading many efforts with CAR T-cell trials, for example, and our participation was seminal in getting some of these drug products approved.

Now, we are using CAR T cells earlier in the course of disease, and we are also working with BiTEs targeting BCMA. We work with elranatamab, and we are now doing basket studies with both CAR T cells and elranatamab to try to improve duration of response. Going to the next level, we are also combining these drugs [with] other drugs, studying maintenance therapy with iberdomide and lenalidomide, which we are excited about.

As the chair of this IPC meeting, what is the importance of meetings like these in the oncology community?

These meetings are critically important. We have so much data and so much in terms of what we can offer our patients to the point where this information can be overwhelming. Having a focused discussion and highlighting more practical approaches on how we can incorporate some of these data that we see in clinical trials into real-world treatment is crucial. Disseminating this knowledge [through platforms like this is remarkable]. A true testament to these events is the number of people who log on and stay on throughout the course of the discussion. These meetings are incredibly valuable—not only to the audience, but to us presenters, as well, because they allow us to contextualize data from clinical trials in the real-world setting.