Ongoing Research Aims to Bring Bispecific Antibodies to Earlier Settings and Novel Combinations in Myeloma

Joshua Richter, MD

Bispecific antibodies, including BCMA-targeted agents and drugs with other targets, have made inroads in later lines of treatment for patients with relapsed/refractory multiple myeloma, and ongoing investigations are evaluating these treatments in earlier lines of therapy and in novel combinations, according to Joshua Richter, MD, who added that expanded access to these types of therapies would be crucial from patients treated in community settings.

“Bispecific antibodies are important because approximately 80% of [patients with] myeloma in the United States are treated in the community,” Richter explained during an interview with OncLive^® at the 41st Annual CFS^®. “Therefore, there's a large need for these types of active agents that don't have to be given at academic centers.”

In the interview, Richter provided an overview of the current state of bispecific antibodies in multiple myeloma, discussed ongoing investigations of these agents, and expanded on their unique toxicities and the need for proactive management.

Richter is an associate professor of medicine in the Division of Hematology and Medical Oncology at the Tisch Cancer Institute, and the director of Multiple Myeloma for the Blavatnik Family Chelsea Medical Center at Mount Sinai in New York, New York.

OncLive: Could you expand on the current state of the treatment armamentarium with bispecific antibodies in multiple myeloma?

Richter: In the world of myeloma, in the relapse setting, we currently view things as early relapse or late relapse, [with] early relapse being 1 to 3 prior lines [of therapy], and late relapse being 4 or more prior lines. Early relapse is usually dominated by some of the classical agents in the field, such anti-CD38 monoclonal antibodies, proteosome inhibitors, and immunomodulatory drugs [IMiDs]. However, late-line relapses have been dominated by some of the T-cell–redirecting therapies, and that was what I focused on in my presentation, specifically looking at bispecific antibodies.

Bispecific antibodies have 2 arms; 1 arm reaches out to CD3, which is located on all T cells. The other arm reaches out to a specific antigen located on the myeloma cell. We grab the T cell and activate, and we grab the cancer cell. Two cells enter, 1 cell leaves.

[My presentation] focused on some of the main classes of agents right now, and in the bispecific antibody world, we have BCMA-targeted bispecifics with drugs such as teclistamab-cqvy [Tecvayli], elranatamab-bcmm [Elrexfio], linvoseltamab [REGN5458], and a number of others. Then we have the non–BCMA-targeting bispecifics, such as those that target GPRC5D, namely talquetamab-tgvs [Talvey] and forimtamig [RG6234], and the bispecific antibody targeting FcRH5, also known as cevostamab [RG 6160].

We're starting to learn [more] a lot about these agents. They're highly active, and they have a unique set of toxicities, [which] are very similar in many ways to the CAR T-cell therapies when looking at cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS]. The other important factor is monitoring and appropriately [using] prophylaxis for infectious complications, including things like pneumocystis prophylaxis, and IVIG.

Finally, I talked about some of the latest studies about combining these agents, either with anti-CD38 antibodies suchs daratumumab [Darzalex], or a study called the phase 1/2 RedirecTT-1 study [NCT04586426], where we are combining 2 bispecifics: talquetamab and teclistamab.

Are there any other investigational bispecific antibodies that have shown promise?

There are a few interesting approaches [with new targets] that are entering the clinical trial space in a phase 1 setting. Some of them are the natural killer [(NK) cell] engagers, and there's a few trispecific antibodies that seek to engage T cells [as well as] NK cells.

There is another stream of bispecific antibodies that don't engage NK cells and don't engage T cells; [rather], they engage macrophages, and these are CD47-based bispecific antibodies. This is an interesting look at these non–T cell–redirecting therapies. They may have some of the great efficacy of bispecifics without all the associated T cell–engaging toxicities like CRS or ICANS, but we're going to have to wait to see if that holds true in further study.

What research is ongoing or upcoming that could help move bispecific antibodies to earlier lines of therapy?

There are several studies that are looking at these drugs as monotherapy and in combinations in earlier lines [of treatment]. The phase 1 TIMM-2 [NCT04108195] and TRIMM-3 [NCT05338775] studies are at various combinations [featuring bispecific antibodies].

There have been a number of pushes to enhance the patient experience with these drugs in the community setting. There have been a number of studies looking at giving the prophylactic tocilizumab [Actemra] to minimize the incidence of CRS, which may allow more [clinicians] to give these drugs as an outpatient [treatment]. This was seen in the E-1 cohort of the phase 1 CaMMouflage study [NCT05722418]. We've also saw this in one of the cohorts of the phase 2 MajesTEC-1 study [NCT04557098].

The other thing that studies of cevostamab [RG 6160] are doing is looking at limited-duration treatment. There is a wonderful investigator-initiated [phase 2 trial (NCT05932680)] from Alfred Garfall, MD, of the University of Pennsylvania evaluating limited durations of treatment with teclistamab.

If we start to use prophylactic tocilizumab and limited-duration [approaches, bispecific antibodies] may be a little more user friendly for some of our community colleagues.

What could the use of bispecific antibody–based combinations look like in multiple myeloma?

There are some really interesting studies as we move from late-relapse [setting] to early-relapse [setting], but there are even some studies, including the phase 3 MajesTEC-7 trial [NCT05552222], that are looking at what happens when we move [bispecific antibodies] all the way up to frontline therapy, or when we combine them with drugs such as daratumumab and lenalidomide [Revlimid].

It may be that as we move these drugs to the frontline [setting], we could get such incredible depth of response that we may be able to stop or tailor back some of the therapy to get amazing durations of remission and even cure some people. Fingers are crossed about the next generation of clinical trials.

Regarding toxicities associated with bispecific antibodies, what are some of the management strategies currently deployed for adverse effects?

For the BCMA-directed bispecific antibodies, which [represent the greatest] share what we are using right now with teclistamab and talquetamab, we recommend prophylaxis for pneumocystis jirovecii pneumonia, either with something like trimethoprim sulfamethoxazole or with atovaquone. We recommend herpes simplex virus and varicella zoster virus prophylaxis with acyclovir or valacyclovir.

The other important utilization is Intravenous immunoglobulin [IVIG]. We've been using secondary prophylaxis for the CD38 antibodies, waiting until the patient has hypogammaglobulinemia and then develops several infections before instituting IVIG prophylaxis. However, we're currently recommending primary prophylaxis for patients [receiving] BCMA-based bispecific antibodies. You may not be able to start it at the first day of treatment, because their IgG may already be sky high in the setting of relapse, and you'd worry about hyperviscosity. Once the total IgG comes down a bit, we recommend starting either with monthly IVIG in cycle 2 or cycle 3.

What is your main message for colleagues based on your presentation?

Bispecific antibodies are here to stay in late-relapse [setting], and they are working their way up to earlier and earlier lines of therapy. The reality is that there still may be some hurdles to overcome for utilizing agents such as these in the community. I would encourage you to reach out to my institution or any myeloma institution, because we can have some type of shared therapy where we give the step-up dosing in the hospital, and then send them back to our community colleagues for ongoing maintenance of therapy. It doesn't have to be an all or nothing; we can all work together.