Defining the Role of Immune Therapy in Multiple Myeloma

Shebli Atrash, MD, medical oncologist at Levine Cancer Institute and clinical associate professor of Medicine at Wake Forest University

According to Shebli Atrash, MD, immune therapies, including CAR T-cell therapies, bispecific antibodies, and T-cell engagers, will play a significant role in the future of treatment in patients with multiple myeloma, as well as other solid tumors and hematologic indications and beyond.

Shebli, a medical oncologist at Levine Cancer Institute and clinical associate professor of Medicine at Wake Forest University, spoke with CancerNetwork® about immune therapies for multiple myeloma treatment following a presentation on T-cell engagers in multiple myeloma that he gave at the 2025 National Immune Cell Effector Therapy (ICE-T) Conference.1

He began by providing background for his presentation, highlighting already approved BCMA antibodies and indications for patients who are pan-refractory. Specifically, he identified trial findings that revealed an estimated 70% overall response rate evaluating these agents in multiple myeloma, as well as trials evaluating transplant-ineligible disease. To that end, he highlighted data from the phase 3 MajesTEC-7 trial (NCT05552222), noting that researchers are evaluating teclistamab-cqyv (Tecvayli) against the standard of care of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone—the phase 3 MAIA trial (NCT02252172) regimen—in this population.2,3

Shebli further touched upon the trials, including the phase 3 MajesTEC-4 trial (NCT05243797), which is exploring bispecific antibody use in the maintenance setting. The MajesTEC-4 trial evaluated teclistamab with lenalidomide vs lenalidomide alone and revealed that those characterized as minimal residual disease (MRD)–negative at baseline maintained MRD negativity at cycle 3 of treatment.

Next, Shebli outlined differences between T-cell engagers and standard therapy in multiple myeloma, highlighting advantageous response depth and durability, as well as fewer adverse effects (AEs) with the former. Suggesting that the biggest disadvantage of these therapies is infections, research is evaluating a fixed treatment duration to minimize AEs related to infections. Shebli then discussed considerations for optimizing T-cell engager efficacy across multiple myeloma populations, highlighting a need to identify why approximately 30% of patients do not respond to treatment.

Finally, he touched upon key points brought up during the overarching panel on multiple myeloma and other plasma cell disorders, as well as his closing remarks regarding immune therapies within the future oncology landscape.

CancerNetwork: What background could you provide regarding your presentation on T-cell engagers and multiple myeloma?

Atrash: We discussed bispecific antibodies for multiple myeloma. We went over the already approved BCMA antibodies [and] the indication for patients who are pan-refractory. [Trials evaluating BCMA antibodies] roughly showed us a 70% overall response rate with acceptable toxicity. The field is moving towards earlier lines; bispecific antibodies are being tested for early relapse as well as for newly diagnosed multiple myeloma. BCMA bispecific antibodies are [quite] effective for newly diagnosed multiple myeloma, whether [patients] are transplant eligible or ineligible. Trials have been testing for transplant-ineligible [disease], utilizing teclistamab in [the phase 3 MajesTEC-7 trial] against the standard of care, which is the MAIA protocol of daratumumab, lenalidomide, and dexamethasone.

For the US, we are new to the trial. [Investigators have] been enrolling [outside of the] US for some time now, and the trial is opening soon in the US. For transplant-eligible [disease], we have incorporated teclistamab enrichment with daratumumab/lenalidomide with or without bortezomib. More interesting to me is the concept of using those bispecific antibodies as a single agent for induction. It is [quite] convenient for patients as subcutaneous or [intravenous] administration, depending on the product. As a single agent, it seems to produce deep responses.

In the maintenance setting, there are a few trials that are looking at that as well. We have the [phase 3 MajesTEC-4 trial] that looked at teclistamab with lenalidomide vs lenalidomide alone, which is our standard of care. The initial safety run-in phase enrolled a few patients, but all patients who were tested for MRD negativity were MRD-negative after cycle 3. This is promising. If we believe that MRD negativity is the end point to be, especially for patients who are newly diagnosed and standard-risk, then those regimens are delivering what we ask for.

However, we must always be careful when using MRD as an end point because patients with high-risk disease could relapse quickly, and patients with standard-risk disease and slow response might also still show some [progression] that does not reflect the risk assessment for their disease.

What differentiates the T cell engagers from other standard therapies for multiple myeloma, and what advantages would these T cell engagers provide?

Atrash: T-cell engagers have changed the multiple myeloma landscape. They have produced deep responses that we have not seen with other agents. The advantages of T-cell engagers [include fewer] overall [adverse] effects, a [more] convenient administration––we are talking about one drug, [fewer] steroids––and more durable responses. The disadvantage of bispecifics is infections.

Infections have been common for BCMA-targeting bispecifics. For GPRC5D, [common] adverse effects [include] skin rash, dysgeusia, and weight loss, as well as nail changes. Those have been the determinants of treatment. Regarding infection, we have lucrative ideas that have been circulating regarding the fixed duration of treatment. This means you treat with bispecific antibodies for, say, a year or 2, and then you stop and [observe patients]. Those ideas are still premature, but [many] trials are going that way.

What would you say are the next steps for further optimizing the use and research of these T cell engager therapies for this multiple myeloma population?

Atrash: Using those bispecific [T-cell] engagers in the right setting is important. For example, utilizing talquetamab, a GPRC5D bispecific antibody, as a pre-CAR T drug to control multiple myeloma prior to administering CAR T has helped us decrease CRS and ICANS. [Additionally, regarding] my experience with teclistamab, if it is used in patients who are rapidly progressing with a large disease burden, then it might not provide as much efficacy as it does for other patients. I feel the future directions will be regarding how to use it, when to use it, [and] which population is more fit for those treatments.

We have noticed that when you start the treatment in the first month or 2, you get a drop of about 30% in the survival curves, indicating that those patients did not respond to treatment. Predicting who [make up that] 30% is important, and this has to do with the host immune system, fitness, as well as the cancer cell soluble BCMA levels. Those are the important takeaways.

What were some key points that were brought up during the panel discussion on multiple myeloma and other plasma cell disorders that stood out to you, and how could these ideas be applied to clinical practice?

Atrash: In the panel discussion, we discussed the best ways to deliver CAR T [therapy]. We discussed the idecabtagene vicleucel (Abecma; ide-cel) efficacy compared with bispecifics. When would you pick CAR T [vs] a bispecific? That discussion is still evolving, and it is [quite] important.

It will largely depend on the available socioeconomic status of the patient, and other panelists shared their opinion about using CAR T before bispecifics. This way, if a patient progresses 3 to 4 years down the road, they could still use the same target of BCMA down the road, as opposed [to starting] with the bispecific, you might wipe out the whole BCMA target; CAR T might not be an option. Sequencing of treatment was important.

I also liked the discussion around supportive care for patients, whether it is for bispecifics or CAR T; how to avoid infections and give prophylaxis treatments with acyclovir [Zovirax], with antibiotics and antifungal treatments for patients who are neutropenic with intravenous immunoglobulin [IVIG], pentamidine, or IVIG trimethoprim/sulfamethoxazole [Bactrim] for pneumocystis pneumonia [PGP] prophylaxis. I think those are important points that we learned [about] today.

What do you hope others take away from this presentation as well as this conversation?

Atrash: The main point that I was trying to deliver is immune therapy has changed cancer, and we have seen in this conference that the future [includes] immune therapy, whether it is CAR T [therapy], bispecifics, T-cell engagers, or antibody drug conjugates [ADCs]. Every oncologist needs to understand the product they are using, how to manage CRS and ICANS, and how to manage infections. [These therapies are] not only for hematology. [They are] coming to oncology and solid tumor fields as well.

References

1. Atrash S. Emerging T-cell engagers & novel immunotargets in multiple myeloma. Presented at the 2025 National Immune Cell Effector Therapy (ICE-T) Conference; July 26, 2025; Orlando, FL.
2. Krishnan AY, Manier S, Terpos E, et al. MajesTEC-7: A phase 3, randomized study of teclistamab + daratumumab + lenalidomide (Tec-DR) versus daratumumab + lenalidomide + dexamethasone (DRd) in patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant. Blood. 2022;140(suppl 1):10148-10149. doi:10.1182/blood-2022-160173
3. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249
4. Zamagni E, Boccadoro M, Spencer A, et al. MajesTEC-4 (EMN30): a phase 3 trial of teclistamab + lenalidomide versus lenalidomide alone as maintenance therapy following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2022;140(suppl 1):7289-7291. doi:10.1182/blood-2022-159756