Sequencing Bispecifics and CAR T-Cell Therapy in Myeloma and AL Amyloidosis

CancerNetwork® spoke with Ralph V. Boccia, MD, FACP, founder of The Center for Cancer and Blood Disorders, clinical associate professor at MedStar Georgetown University Hospital, and medical director of the International Oncology Network Clinical Research Program, about how he chooses and sequences T-cell–redirecting therapies for patients with relapsed multiple myeloma, including those receiving lenalidomide (Revlimid)–based maintenance. Boccia discussed why chimeric antigen receptor (CAR) T-cell therapy may ideally precede bispecific antibodies, how he selects between teclistamab-cqyv (Tecvayli) and talquetamab (Talvey) after relapse on CAR T-cell therapy, and when fixed-duration therapy may be appropriate for patients with deep, sustained responses.

He also compared minimal residual disease (MRD) data with teclistamab plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) from the phase 3 MajesTEC-3 trial (NCT05083169)¹ and talquetamab plus daratumumab from the phase 1b TRIMM-2 trial (NCT04108195),² and looked ahead to the role of B-cell maturation antigen (BCMA)–targeted bispecifics in light chain (AL) amyloidosis after daratumumab plus cyclophosphamide, bortezomib (Velcade), and dexamethasone in the frontline multiple myeloma setting.

CancerNetwork: At first relapse, perhaps after a triplet or quadruplet with or without transplant, for patients who are on lenalidomide or daratumumab/lenalidomide maintenance, how do you decide between CAR T-cell therapy and bispecifics? Should CAR T always come first, given concerns that prior BCMA-targeted bispecifics may reduce CAR T effectiveness?

Boccia: This is always a challenge, for many reasons: patients are different, their needs are different, their desires are different, their geography is different, and their disease is different. There are a lot of factors that go into choosing. Everything today is made by shared decision-making, so that has to be a big part of it as well. If you look purely at the science, it’s now becoming clearer that, due to T-cell exhaustion after bispecifics, moving from bispecifics to CAR T is much less effective than the so-called one-and-done CAR T, where there’s an opportunity for T-cell rejuvenation that allows better efficacy for bispecifics afterward. Ideally, it would be CAR T followed by bispecifics at the time of relapse.

When second-line CAR T-cell therapy fails a patient, which bispecific do you choose, for example, teclistamab vs talquetamab, given the different prior exposure criteria in the clinical trials?

Boccia: There’s a difference in the adverse event profile between teclistamab and talquetamab. The length of time since the patient had their CAR T helps me quite a bit. Some people can now measure soluble BCMA, and that’s also very helpful if you can do that. Most of us don’t, and most in the community won’t have that access. For patients who relapsed 6 months or more after CAR T, there’s plenty of time for those T cells to rejuvenate and grow back. I tend to use teclistamab in that population, and for those who relapse sooner or who have already had teclistamab, I would then go to talquetamab. Between the taste changes and the nail and skin changes, which result in weight loss and other less favorable effects, I tend to save talquetamab for later. Or, if it’s a patient who has a large extramedullary plasmacytoma burden, I will go to the combination [of teclistamab and talquetamab].³

Is there ever a point where you discuss stopping treatment? Could fixed-duration therapy work for patients with rapid, deep responses, such as MRD negativity, to reduce severe infection risk without compromising long-term outcomes?

Boccia: Today we’re moving toward fixed-duration therapies in everything we do, and multiple myeloma is no exception. The answer is yes for those who have very deep responses, and especially those who have deep, sustained responses, meaning at least a year, maybe 2 years, according to some of the studies. I think it’s very reasonable to stop therapy in those patients. Remember, multiple myeloma is often a relatively indolent disease, at least until you get to very late lines of therapy, and we’re talking about fourth-, fifth-, sixth-, or eighth-line therapy. Patients can relapse and still get nice treatment-free holidays, even if they weren’t MRD negative to begin with. If you look at the science now and where we’re going, we have begun to use MRD as an end point as opposed to response rates, and it’s going to be the norm, probably within the next 2 to 4 years, that everyone is offered fixed-duration therapy.

How does the MRD negativity rate with teclistamab/daratumumab compare with talquetamab/daratumumab? Is one higher than the other?

Boccia: The teclistamab/daratumumab and talquetamab/daratumumab data look relatively similar.^1,2 The teclistamab/daratumumab data were in a slightly earlier population of patients compared with those who got talquetamab/daratumumab, so it’s a little unfair to compare the two. I would say those are 2 extraordinarily effective agents, and the response rates are very similar, but the adverse event profiles are very different.

How is sustained MRD negativity reshaping how the oncology community defines long-term disease-free survival and potential cure in standard-risk multiple myeloma?

Boccia: In the research and academic community, it has become a hallmark of all our clinical trials, but it has also shaped how we treat patients who aren’t on clinical trials and are receiving standard of care. We’ve learned over the last 15 years that the deeper the response, the longer the progression-free survival. Typically, if you get patients into a relatively deep response, which in the old days meant a very good partial response or better and today means a sustained MRD-negative state, then we see progression-free survivals in late-stage patients as long as those of some earlier-stage patients with previous therapies.

How are BCMA-targeted bispecifics filling the treatment gap in AL amyloidosis after relapse or progression on Dara-CyBorD, and what activity and safety have trials shown in the relapsed/refractory setting?

Boccia: Amyloidosis really has been a problem for us until daratumumab came along. In the old days, it was melphalan and prednisone and then an autologous transplant. More recently, it was daratumumab, cyclophosphamide, bortezomib, and dexamethasone and then sometimes transplant. For the last several years now, we’ve had daratumumab approved to be given with daratumumab, cyclophosphamide, bortezomib, and dexamethasone,⁴ and we’ve seen significant improvement in amyloid deposits, improvement even in cardiac and renal function, and much longer progression-free survival.

With AL amyloidosis, which is light chain amyloidosis, even daratumumab plus daratumumab, cyclophosphamide, bortezomib, and dexamethasone is not a home run. It’s not much more than a base hit, maybe a double. Now we have a [triplet] when we can add bispecifics, because they are so much more effective than any of the therapies we’ve had so far. That is the wave of the future. Maybe even CAR T after that. T-cell therapy works.

What efforts are underway to test BCMA-targeted bispecifics in the frontline setting against standard regimens like Dara-CyBorD?

Boccia: We have now done a couple of studies. We just closed the phase 3 MajesTEC-7 trial (NCT05552222),⁵ which [randomly assigned patients] to DRd, which is daratumumab, lenalidomide, and dexamethasone, vs teclistamab plus DR vs talquetamab plus DR. We’re hoping to see some of that data at this year’s [American Society of Hematology] meeting and see how we did. T-cell therapy in the frontline setting is coming, and it will soon be here and will soon be a standard of care.

References

1. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2026;394(8):739-752. doi:10.1056/NEJMoa2514663
2. Chari A, van de Donk NWCJ, Dholaria B, et al. Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study. Blood. 2025;146(24):2902-2913. doi:10.1182/blood.2025029360
3. Kumar S, Mateos MV, Ye JC, et al. Dual targeting of extramedullary myeloma with talquetamab and teclistamab. N Engl J Med. 2026;394(1):51-61. doi:10.1056/NEJMoa2514752
4. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385(1):46-58. doi:10.1056/NEJMoa2028631
5. A study of teclistamab in combination with daratumumab and lenalidomide (Tec-DR) and talquetamab in combination with daratumumab and lenalidomide (Tal-DR) in participants with newly diagnosed multiple myeloma (MajesTEC-7). ClinicalTrials.gov. Accessed October 8, 2026. https://tinyurl.com/46kwwufb