What is The Case for Earlier CAR T-Cell Referral in Multiple Myeloma?

CAR T-cell therapy has moved from a last-line option to a second-line consideration for select patients with relapsed/refractory multiple myeloma. That shift is changing how clinicians sequence therapy, manage late toxicities, and coordinate care between academic centers and community practices.

In a special CancerNetwork^® podcast series, Matthew J. Frigault, MD, clinical director of the Cellular Immunotherapy Program at Mass General Brigham Cancer Institute, and Adam D. Cohen, MD, director of Myeloma Immunotherapy and professor of medicine at the Hospital of the University of Pennsylvania, discussed updated guidelines, long-term trial data, and the practical steps that can help more patients benefit from CAR T-cell therapy. They emphasized that timing matters in patient care.

Guidelines Support CAR T-Cell Therapy in Early Relapse

The National Comprehensive Cancer Network (NCCN) recently updated its Clinical Practice Guidelines in Oncology for multiple myeloma to recommend referral for CAR T-cell therapy as early as the second line in patients with lenalidomide (Revlimid)-refractory disease, with products such as ciltacabtagene autoleucel (cilta-cel; Carvykti) supported as therapeutic options.¹

Frigault said the update reflects maturing trial data showing that the benefits of CAR T-cell therapy carry over, and may grow, when it is given earlier. The guidelines also call for more aggressive infection prophylaxis, including intravenous immunoglobulin (IVIG), for patients receiving BCMA-directed CAR T-cell therapy or bispecific antibodies. Frigault explained the rationale behind these recommendations, noting that the “number 1 cause of nonrelapse mortality in most of these patients is actually infection.”

Five-Year Data Point to Durable, Treatment-Free Remissions

Cohen reviewed updated results from cohort A of the phase 2 CARTITUDE-2 trial (NCT04133636), which were presented at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition.² The cohort enrolled 20 patients with lenalidomide-refractory multiple myeloma after 1 to 3 prior lines of therapy, a population similar to that of the phase 3 CARTITUDE-4 trial (NCT04181827), which supported approval of cilta-cel in earlier lines.³

After a median follow-up of 60.7 months, 10 of the 20 patients were alive and progression free at 5 years after a single cilta-cel infusion without any further therapy. The 5-year progression-free survival (PFS) rate was 54.2% (95% CI, 30.3%-73.0%).

“It’s obviously a very small number of patients, and we need to wait for the long-term follow-up from CARTITUDE-4 to confirm this,” Cohen said. “But it does suggest that we might be getting an even higher proportion of patients into that long-term disease-free population when we treat earlier than what we saw with CARTITUDE-1 [NCT03548207].”

Managing Late Toxicities and High-Risk Disease

Late toxicities remain a concern, including neurotoxicities apart from immune effector cell-associated neurotoxicity syndrome (ICANS) such as parkinsonism and late-onset enterocolitis after cilta-cel. Cohen said these events may be less frequent in patients with less heavily pretreated disease and in those with good disease control before infusion, which makes bridging therapy increasingly important.

Some toxicities emerge within 30 days of infusion, while others appear 90 days or more afterward. Frigault urged community clinicians to stay in contact with the treating center rather than wait. Any personality change, neurologic change, weakness, sensory change, or new-onset diarrhea should prompt a call, he said.

For patients with high-risk features, including extramedullary disease, high-risk cytogenetics, or progression within 18 to 24 months of initial therapy, Cohen recommended moving to T-cell–directed therapy early. These patients may not have outcomes quite as good as those with standard-risk disease, he said, but they fare much better with CAR T-cell therapy or bispecific antibodies than they did historically with triplet regimens.

Sequencing CAR T-Cell Therapy and Bispecific Antibodies

With bispecific antibodies now also available in early relapse, Frigault called the current landscape “a wealth of riches” but stressed that the clinical situation should drive the choice. “If you have a patient with rapidly progressive, symptomatic disease and you have a bispecific available to you, it makes total sense to reach for that bispecific and get disease control,” he said.

Still, earlier therapy can affect later options. Frigault noted that the NCCN guidelines suggest avoiding BCMA-targeted therapy before CAR T-cell therapy when possible, and that American Society of Clinical Oncology (ASCO) guidelines prefer cilta-cel for BCMA-naive populations who are eligible for CAR T-cell therapy.⁴ At the same time, patients treated with teclistamab-cqyv (Tecvayli) plus daratumumab in the phase 3 MajesTEC-3 trial (NCT05083169) are “doing fantastically many years down the road,” he said.⁵

Refer Early, Refer Often

Both experts urged community oncologists to refer patients for CAR T-cell evaluation as early as first relapse, without necessarily pausing treatment. A patient starting daratumumab, carfilzomib (Kyprolis), and dexamethasone, for example, could later consolidate that response with CAR T-cell therapy.

The manufacturing slot shortages that once delayed treatment have largely eased, Frigault said, and turnaround times continue to shorten. He pointed to the investigational BCMA-directed CAR T-cell therapy anitocabtagene autoleucel (anito-cel), evaluated in the phase 2 iMMagine-1 trial (NCT05396885), which he said has a turnaround time of 14 to 17 days.⁶

Earlier referral can also change the patient experience. Patients with lower disease burden and better functional status tend to have fewer toxicities, and at Frigault’s center, most cilta-cel infusions are now given in the outpatient setting. “We see them, they’re there for 30 minutes, and then they’re back walking along the Charles [River],” he said.

A Co-Management Model Spanning Consult to Survivorship

Frigault described CAR T-cell therapy as “a co-management strategy,” noting that no single center could handle the volume of patients with multiple myeloma. Once patients clear the acute window for cytokine release syndrome and ICANS, Cohen’s team uses a handoff checklist. It covers continued antiviral and Pneumocystis prophylaxis, blood count monitoring and growth factor support for delayed cytopenias, IVIG, surveillance for late complications such as enterocolitis, and age-appropriate cancer screening given signals of second primary malignancies.

Recent FDA changes to the Risk Evaluation and Mitigation Strategy (REMS) program have also reduced the burden on patients, Frigault noted. The time patients must remain near the treating center is now 2 weeks, and the driving restriction has been shortened from 8 weeks to 2 weeks.⁷

What Comes Next

Looking ahead, Frigault highlighted several areas of development: dual-targeting CAR T-cell products, including BCMA/CD19 constructs and BCMA/GPRC5D constructs; first-line trials comparing CAR T-cell therapy with autologous stem cell transplant; in vivo CAR T-cell approaches that skip apheresis and manufacturing by infusing a viral vector or mRNA; and combinations of T-cell engagers with CAR T-cell therapy.

“It’s going to be a good problem to have with so many options in front of us to pick from,” Frigault said. “The next challenge will be figuring out which one to use and when.”

Cohen agreed, describing his fortune to be involved in the modern multiple myeloma research field. “I think dual-antigen targeting is really exciting, and I’m really looking forward to seeing some of the longer-term follow-up data for that.”

References

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 2.2027. National Comprehensive Cancer Network. September 24, 2026. Accessed October 21, 2026. https://tinyurl.com/47x35wch
2. Cohen AD, Mateos M-V, Cohen YC, et al. Long-term (≥5-Year) remission and survival with ciltacabtagene autoleucel (Cilta-Cel) in relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy: CARTITUDE 2 Cohort A. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Poster PA-288.
3. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed October 21, 2026. https://tinyurl.com/45uewvez
4. Treatment of Multiple Myeloma: ASCO Living Guideline. Version 2026.1.3. September 14, 2026. Accessed October 21, 2026. https://tinyurl.com/mupax9zt
5. 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
6. Patel K, Dhakal B, Kaur G, et al. Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: updated results from iMMagine-1. Blood. 2025;146(suppl 1):256. doi:10.1182/blood-2025-256
7. FDA eliminates risk evaluation and mitigation strategies (REMS) for autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA. June 26, 2025. Accessed October 21, 2026. https://tinyurl.com/mrx2yxjm