Bridging Before CAR T in Myeloma Should Aim For Deep Response, Not Just Stability

For a patient with early-relapsed multiple myeloma who is both eligible for and willing to pursue chimeric antigen receptor (CAR) T-cell therapy, the question is no longer whether to refer, but how to keep that patient alive, stable, and immunologically intact long enough to get there. That gap of several weeks or sometimes months is where bridging therapy makes its mark, and it is turning out to be less straightforward than guidelines suggest.

In a live Case-Based Roundtable event in Buffalo, New York, Brea Lipe, MD, clinical director of the multiple myeloma program at the Wilmot Cancer Institute, University of Rochester Medical Center, reviewed bridging strategy for early-relapsed multiple myeloma and moderated discussion of a high-risk patient weighing his transportation burden against the urgency of his disease.

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CASE SUMMARY

Patient Profile:​

• A 72-year-old man with newly relapsed multiple myeloma presents to the clinic to discuss his next treatment options.
• ECOG performance status, 2; International Staging System (ISS) III/Revised ISS II; cytogenetics notable for 17p deletion​
• ​He previously achieved a complete response with quadruplet frontline therapy, which continued through autologous stem cell transplant and lenalidomide (Revlimid) maintenance.
• He experienced disease relapse after 9 months. ​
• Although he typically prefers to minimize time spent in the hospital and has an hour-long commute to the academic center, he understands that CAR T-cell therapy requires treatment at a specialized facility. He is willing to proceed with CAR T given his aggressive relapse.​

EVENT RECAP

For treatment after first relapse, the majority of participants, 62.5%, chose daratumumab (Darzalex) plus teclistamab (Tecvayli; Dara-Tec), one of the newest FDA approvals in multiple myeloma, over referring directly for CAR T or starting a selinexor (Xpovio)-based regimen. However, Lipe noted that Dara-Tec's pivotal data came largely from daratumumab-naive patients, and because this patient had received daratumumab as part of a quadruplet induction less than a year earlier, it is not known how much a second treatment with daratumumab would contribute, and teclistamab alone in this setting has not yet been approved.

Lipe reframed the decision using recent International Myeloma Working Group sequencing guidance: patients eligible for both a T-cell engager and CAR T should generally get CAR T first, reserving the bispecific for later, unless disease is progressing so quickly that a bispecific T-cell engager's immediate, off-the-shelf availability and 80% to 90% response rate make it the safer near-term choice.¹

Access, not biology, dominated the discussion of who actually gets to CAR T. Participants described regional insurance disruptions in upstate New York, including Roswell Park Comprehensive Cancer Center in Buffalo not accepting certain Medicare Advantage plans, part of a trend where numerous health systems are doing the same because of a high rate of coverage denials and delays plus slow reimbursements.² This is forcing patients to travel further or seek other treatment options instead. Lipe described drug company-sponsored travel and caregiver-pay programs that have emerged to offset this burden, calling them ethically complicated but practically necessary given how much economic hardship can determine whether a patient from a rural area completes treatment. Polling on the biggest barrier to CAR T access was split across insurance delays, logistics and caregiver support, apheresis or manufacturing capacity, and eligibility, underscoring that no single fix would solve the problem.

The CARTITUDE-4 trial (NCT04181827), which established ciltacabtagene autoleucel (Carvykti; cilta-cel) in this earlier-relapse setting, has personal resonance for Lipe. She described working to get a rapidly deteriorating patient evaluated for the trial during the COVID-19 pandemic; with the cooperation of the trial sponsor, she was able to get the patient evaluated and randomly assigned to receive cilta-cel on Christmas Day; he lived 2 more years, long enough to see a grandchild graduate college and another born.

In the trial, patients randomly assigned to standard-of-care had a median progression-free survival (PFS) of 11.8 months, and cilta-cel improved on that substantially at a median follow-up of 33.6 months, though Lipe noted the median is skewed by 2 distinct populations: patients who relapse within the first year, and a second group whose PFS is now exceeding 5 years and still has not been reached.³ Grade 3 or higher cytokine release syndrome occurred in fewer than 2% of patients receiving cilta-cel, but neurotoxicity, including rare but sometimes fatal parkinsonism, remains a serious concern she described as “devastating” when it occurs. She also flagged that patients with bulkier disease or heavier pretreatment going into CAR T tend to have worse toxicity, which is itself an argument for using bridging therapy to debulk disease rather than merely keep patients stable until receiving CAR T.

Although early on, the principle might have been that bridging therapy should use the minimum regimen needed for disease control,⁴ the importance of debulking disease has changed that for Lipe. “I don't want the minimum,” she told the group. “I don't want them just surviving to CAR T.” With evidence now that lower disease burden before receiving CAR T predicts for better outcomes, this consideration is crucial.

Lipe’s practical approach is to use triplet bridging to keep a biochemical relapse stable and even quadruplets when tumor burden is high, arguing that quadruplets can be well tolerated and improve disease control. However, she stressed to pay close attention to mechanism of action, since bispecific-based bridging that targets B-cell maturation antigen (BCMA), the same target used by most CAR T products, can lead to BCMA loss and weaken the efficacy of CAR T. Selinexor-based regimens drew particular interest for this role, because retrospective data suggest selinexor does not impair T-cell fitness and may even increase cytotoxic T-cell activation,^5,6 and its oral administration makes it practical for patients facing long travel distances. Talquetamab (Talvey), a bispecific which targets GPRC5D rather than BCMA, offers another bridging option with strong response rates, though Lipe cautioned that it still can reduce valuable T-cell fitness before another T-cell redirection therapy.

Polling results from the live event captured the group’s approach to bridging this patient:

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DISCLOSURES: Lipe previously reported consulting or advisory roles with Bristol Meyers, Janssen Oncology, Karyopharm Therapeutics, Sanofi, Pfizer; and institutional research funding from Janssen, Cellectar, Karyopharm Therapeutics, Celgene, Amgen, and Seagen.

REFERENCES

1. Costa LJ, Banerjee R, Mian H, et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. 2025;39(3):543-554. doi:10.1038/s41375-024-02482-6

2. In Medicare Advantage plans for 2026, Roswell Park won't be in network with Independent Health. Buffalo News. October 6, 2025. Accessed August 20, 2026. https://tinyurl.com/48km3m3y

3. Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026;27(2):254-268. doi:10.1016/S1470-2045(25)00653-9

4. Ailawadhi S, Anderson LD Jr, Dhakal B, Shune L, Sborov DW, Hansen DK. Optimizing selection of bridging therapies prior to CAR-T therapy administration for multiple myeloma: clinical pearls from an expert roundtable. Clin Lymphoma Myeloma Leuk. 2026;26(2):85-93. doi:10.1016/j.clml.2025.08.005

5. Kang Y, Neff JL, Ellero A, et al. Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma. Blood Immunol Cell Ther. 2025;1(3):100009. doi:10.1016/j.bict.2025.100009

6. Khouri J, Sborov D, Rossi A, et al. Focusing on selinexor for holding and bridging prior to CAR-T in relapsed/refractory multiple myeloma. J Clin Med. 2025;14(12):4071. doi:10.3390/jcm14124071