Expert Insights on Important Updates in Multiple Myeloma With Marc Braunstein, MD, PhD

Marc Braunstein, MD, PhD

Associate Professor, Department of Medicine

Fellowship Program Director, Hematology/Oncology

Codirector, Hematology-Oncology System

NYU Grossman Long Island School of Medicine

NYU Langone Health

Mineola, NY

In an interview with Peers & Perspectives in Oncology, editorial board member Marc Braunstein, MD, PhD, reviewed key updates in multiple myeloma for chimeric antigen receptor (CAR) T-cell and bispecific antibody therapy. Additionally, Braunstein discussed the importance of having a plan and team in place for transition of care from an academic to a community setting when using these new and specialized drugs.

Peers & Perspectives in Oncology: What are the most recent or important updates to CAR T-cell therapy in the multiple myeloma space?

Braunstein: There are a lot of updates, both in terms of the mechanisms of the CAR T cells that are targeting different receptors and in the phase of the myeloma disease in which these cellular therapies are approved. One of the most recent developments in the field has been the FDA’s review of the data for both of the currently available CAR T products, which are idecabtagene vicleucel [ide-cel; Abecma] and ciltacabtagene autoleucel [cilta-cel; Carvykti] in earlier lines of therapy than they were originally approved. The phase 3 CARTITUDE-4 study [NCT04181827] investigated cilta-cel in patients with 1 to 3 prior lines of therapy.¹ The phase 3 KarMMa-3 study [NCT03651128] investigated ide-cel in patients with 2 to 4 prior lines of therapy—an earlier setting than the median of 5 prior lines of therapy in which these cellular therapies were originally approved based on phase 2 data in later relapses.²

What is also interesting about those 2 studies, CARTITUDE-4 and KarMMa-3, is that they were randomized studies, and they looked at those anti-BCMA [B-cell maturation antigen] CAR T constructs compared with standard of care, multiagent, off-the-shelf therapies that contained monoclonal antibodies or proteasome inhibitors in patients who were refractory to lenalidomide. Both of those studies were practice changing and showed a progression-free survival improvement in those earlier settings compared with standard of care therapy.^1,2 The FDA reviewed these results a couple of months ago and approved these therapies in earlier lines. That is the most recent and exciting update in terms of CAR T therapy for myeloma.

Do you see CAR T-cell therapy moving into frontline treatment-naive settings for these patients?

That’s a great question. To take a step back, I think we are in the era of immunotherapy for myeloma, and it’s making tremendous strides. We started about 20 years ago with immunomodulators, and then we moved on to monoclonal antibodies. Now we’re using antibody-drug conjugates, bispecific antibodies, and CAR T cells. The story in each of those approaches has been that they get approved in later lines of therapy, and then we move them into earlier lines. Daratumumab [Darzalex] is a classic example of that, and it now has become standard of care for first-line therapy.

With CAR T-cell therapy, there are a number of ongoing studies to address your question, including in patients who are transplant eligible as well as those who are high risk, which represents a more challenging group of patients in which to achieve remissions. The phase 3 CARTITUDE-6 study [NCT05257083] is a randomized study that is examining patients with newly diagnosed, transplant-eligible myeloma. They all get induction treatment and then get randomized to CAR T or autologous stem cell transplant. I think that will be a pivotal study that will tell us how impactful CAR T-cell therapy is up front. The other phase 1 study of note is called KarMMa-4 [NCT04196491], which is looking at ide-cel in patients with newly diagnosed myeloma who are high risk, and that will also be valuable to determine [whether] giving CAR T-cell therapy up front can be effective and in higher-risk patients when the myeloma microenvironment is less resistant to immunotherapy.

How does bispecific therapy play a role in this setting?

When we think about bispecific therapy, we’re talking about immunotherapy involving antibodies that serve 2 functions. One is to do the traditional role of a therapeutic antibody, which is to bind to a target on the cancer cell. In this case, for multiple myeloma, there are 3 approved bispecific antibodies, [2] targeting [BCMA] and 1 targeting GPRC5D, an orphan receptor that is expressed on myeloma cells. Those are what the bispecific antibodies target on the myeloma, and then on the other side of that bispecific antibody, they target a receptor, CD3, which is expressed on T cells, and that circumvents the physiologic process of T-cell activation by directly activating T cells in the proximity to the plasma cells in which these antibodies also target.

There are 3 bispecific antibodies approved: teclistamab-cqyv [Tecvayli] and elranatamab-bcmm [Elrexfio], which both target BCMA, and talquetamab [Talvey], which targets GPRC5D. All of these 3 agents have been studied in nonrandomized studies that led to their approval, and studied patients who were heavily pretreated.

The phase 1 MajesTEC-1 study [NCT03145181],³ which investigated teclistamab; phase 2 MagnetisMM-3 study [NCT04649359],⁴ which studied elranatamab; and phase 1 MonumenTAL-1 study [NCT03399799],⁵ which explored talquetamab, enrolled patients with a median of 5 prior lines of therapy. There are some differences between the dosing schedules for these antibodies, but the response rates are fairly similar, in the range of 60% to 70%.^3-5 That number is particularly compelling if you view it from the perspective of these patients being very resistant to any other conventional therapy. The median progression-free survival in the MajesTEC-1 study of teclistamab was about 11 months, but it wasn’t reached in studies for elranatamab and talquetamab.

These bispecific antibodies are practice changing. They are very impactful at treating heavily pretreated patients who are resistant to any other line of therapy outside of maybe CAR T therapy. They also offer, in the case of talquetamab, a naive antigen to target in patients who may have received prior BCMA therapy such as a CAR T-cell therapy.

The take-home message is that bispecific antibodies are here to stay. We’re very likely to see them move up into earlier lines of therapy. There are ongoing studies of combining bispecific antibodies. For example, ongoing data [were] previously presented at the 2023 American Society of Clinical Oncology [ASCO] Annual Meeting, combining teclistamab and talquetamab for relapsed/ refractory multiple myeloma; that’s the phase 1/2 RedirecTT-1 study [NCT04586426].⁶ The phase 1 TRiMM-2 study [NCT04108195] is looking at talquetamab plus daratumumab in relapsed/refractory myeloma.⁷ Then we have a handful of novel bispecific antibodies as well. For example, linvoseltamab is another BCMA bispecific antibody that targets a different epitope on BCMA, and [data were] presented at 2024 ASCO in the LINKER-MM1 study [NCT03761108] of relapsed/refractory myeloma.⁸

Another take-home message is that we have a lot of work to do in the field to be able to deliver these therapies both in academic settings and community settings. I think in any setting we all have to become experts in managing the adverse events [AEs] of these bispecific antibodies and CAR T-cell therapies, even if we’re not the ones who are giving the initial infusions of the therapy. For example, a patient gets referred to a tertiary care center and then returns to their community oncologist; the primary oncologist still has to be fairly familiar with long-term AEs of these therapies and management approaches. These therapies are here to stay, and oncologists have to become experts at managing the drug-related toxicities such as cytokine release syndrome [CRS].

How do you facilitate the use of these therapies in the process of moving a patient from academic to community settings or vice versa?

It’s a work in progress because now that we have approvals of CAR T in earlier lines of therapy, the number of patients undergoing CAR T therapy is going to increase. Likewise, with 3 bispecific antibodies on the market and with more down the line, there are going to be additional patients who are receiving T cell–redirecting therapies. With that comes potential for short-term toxicities such as CRS, or immune effector cell–associated neurotoxicity syndrome [ICANS], as well as long-term toxicity such as infectious disease, neurological complications, fatigue, and other AEs that are specific to the individual agents. For example, with talquetamab, there can be mucocutaneous AEs.

When it comes to coordinating care between tertiary care centers and community oncology practices, I think that we should be on the same level where patients should be able to get bispecific antibody therapy locally in a community oncology setting, but in a setting in which they are comfortable and are expert at managing those toxicities. Half of what we do in oncology is managing drug toxicities so that patients can derive the ultimate and complete benefit of a therapy. This is a lot of what goes into training and educating our fellows as well, so we all have to be comfortable managing toxicities of novel immunotherapy approaches.

One element is being keen on how to manage the toxicities and how to give prophylactic therapy to prevent those AEs. The other thing is facilitating the transitions of care. For example, patients may get their step-up dosing in an inpatient setting and then return for the maintenance dosing in the outpatient setting. Or they may get their one-off CAR T infusion and then return to their original oncologist in the outpatient setting. Just like in the stem cell transplant field, which has been around for much longer than T cell–redirecting therapies, we have to have a team that involves multiple interprofessional levels of care to facilitate seamless communication, making sure medications are given appropriately for when the patient transitions between care levels, and making sure that everybody is familiar with and comfortable with medication management and patient monitoring, and that the patient is educated as well about the trajectory and what medications they should be on and what to report about any particular AEs. Likewise, caregiver support is very important in this process, even more so than with our conventional myeloma therapies. So all those things have to align in a very coordinated way in order to facilitate the optimal care for patients on these therapies.

What is the comfort level with continuing CAR T-cell or bispecific therapy when a patient is transferring from an academic to a community setting? Do you have advice for oncologists in this situation?

Being part of the Perlmutter Cancer Center and working within a network of cancer practices both in an academic setting but also in a hybrid community setting, I do get to work with community oncologists who want to give their patients the access to these therapies. For example, this might be a scenario where they need to refer the patient to another site within our network that has the protocol in place to give the bispecific antibodies, if not the initial step-up dosing, then the patient may return for the maintenance phase of the dosing when the risk for, let’s say, CRS is much lower. I think that there’s a mix in the community. Most patients get their cancer care in the community setting, which is why it’s so important to be able to empower community oncologists with the tools they need to give these T cell–redirecting therapies to their patients directly where they live.

To their credit, community oncologists have a lot on their plate. They may manage multiple cancer types, or even the ones who are more focused still may have a very high patient load. It would probably be very difficult for them to focus their practice on managing bispecific antibodies alone. I think that the community practices that will be best equipped to give these therapies will be those who have a lot of ancillary support—nurses, nurse navigators, or advanced practice providers who can help field phone calls, talk to the emergency department [ED] when these patients may present, and see patients more frequently in the beginning, so that when patients may present to the ED with the symptom of CRS, and not just your run-of-the-mill sepsis presentation, the ED is aware that the management will be different. I think you have to have the right infrastructure. It’s not just the comfort of the community oncologist, but how comfortable and confident is their entire team to help manage these more complex patients.

Right now, I’d say it’s probably the minority of community practices that are giving bispecific antibodies, and extremely fewer practices are giving CAR T-cell therapy, since that requires more of an inpatient setting and more of a robust standard operating protocol. The practices that give bispecific antibodies for myeloma likely have strong relationships with tertiary care centers that can give step-up dosing inpatient and a strong relationship with academic practices that transition the care back to the community. Managing CRS and ICANS or even infectious diseases from these therapies is like any anything else; once you become comfortable with it, it becomes more familiar, and it’s not as worrisome when you face it, even if it may be a high-grade AE. The more that you practice, the more you become comfortable managing these AEs and know when you have to give certain medications outpatient or when you need to admit the patient to the hospital.

What are your biggest takeaways in terms of patient care in the community and academic settings?

No matter what setting a patient is going to be treated with for these therapies, the critical factor is going to be access to care. In academia, we are privileged to be in a setting where we have so many consulting services to rely on and so much associated support.... There are practices in rural or suburban areas in the country where there is less support for patients receiving T cell–redirecting therapies, and so they may not have the infrastructure to deliver some of these therapies we’re talking about for myeloma. Access to care is so critical, and that’s why it is important for community oncologists to be able to give these therapies like bispecific antibodies.

The other matter is the cost of the therapies. We have to reconcile how we as a health care system and we in the myeloma field are going to be able to bring down the cost of these therapies so that patients have more access to them, especially for underserved or underinsured patients. I’m very excited about where the field is going. There’s more and more talk about an operational cure for myeloma where we are extending survival much longer. Every time I go back and look at the Surveillance, Epidemiology, and End Results database, which looks at the statistics for survival in myeloma, the 5-year survival percentage keeps going up month by month. I think we’re doing well, and it’s a really exciting time. There’s still a lot of work to be done, but we’re making substantial strides and it’s a great time to be in the field.

REFERENCES:

1. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379

2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614

3. Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665-674. doi:10.1016/S0140-6736(21)01338-6

4. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9

5. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591

6. Cohen YC, Morillo D, Gatt ME, et al. First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16):8002. doi:10.1200/JCO.2023.41.16_suppl.8002

7. Dholaria BR, Weisel K, Mateos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16):8003. doi:10.1200/JCO.2023.41.16_suppl.8003

8. Jagannath S, Lee HC, Richter JR, et al. Indirect comparison of linvoseltamab versus teclistamab for triple-class refractory (TCE) relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42 (suppl 16):7560. doi:10.1200/JCO.2024.42.16_suppl.7560