CARTITUDE-4 Data, IMWG Guideline Make the Case for Second-Line CAR T in Myeloma

For patients with disease relapse after frontline multiple myeloma therapy and retain good performance status and adequate T-cell fitness, the arrival of ciltacabtagene autoleucel (Carvykti; cilta-cel) in the second-line setting has reframed the sequencing conversation. International Myeloma Working Group (IMWG) recommendations now explicitly prioritize chimeric antigen receptor (CAR) T-cell therapy over bispecific antibodies when a patient is eligible for both,¹ a position that shaped the discussion at a live Case-Based Roundtable event for oncologists.

In the event in Pittsburgh, Pennsylvania, Prerna Mewawalla, MD, hematologist-oncologist and medical director of apheresis in the Division of Hematology and Cellular Therapy at Allegheny Health Network and associate professor at Drexel University College of Medicine, reviewed CARTITUDE-4 trial (NCT04181827) data and moderated discussion of access barriers, bridging therapy, and quality-of-life considerations for CAR T–eligible patients.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event. Read part 1.

CASE SUMMARY

• A 67-year-old man with relapsed/refractory multiple myeloma presents to the clinic with evidence of disease progression after receiving a triplet regimen and autologous hematopoietic stem cell transplant (HSCT).
• ECOG performance status, 1; ISS class, I; no high-risk cytogenetics present
• The patient is retired and is spending his free time visiting his grandchildren and pursuing his hobbies.
• Patient is being considered for second-line therapy.
• Treatment history:
• April 2022, bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd)

• August 2022, autologous HSCT followed by lenalidomide maintenance (achieved complete response [CR])

• March 2026, relapse

EVENT RECAP

Before the data were presented, participants split: 4 voted for teclistamab (Tecvayli) plus daratumumab (Darzalex), 3 for cilta-cel, 1 for a daratumumab-based conventional regimen, and 1 for an isatuximab (Sarclisa)-based regimen. After reviewing the CARTITUDE-4 results, the vote was 9 for cilta-cel and 0 for everything else.

Polling results from the live event reflected the field's evolving consensus on CAR-T–eligible patients:

Mewawalla presented data from the CARTITUDE-4 trial, which randomly assigned 419 patients with lenalidomide-refractory multiple myeloma who had received one to three prior lines including a proteasome inhibitor and an immunomodulatory drug (IMiD) to either cilta-cel or standard of care (pomalidomide [Pomalyst], bortezomib, and dexamethasone or daratumumab , pomalidomide, and dexamethasone).²

At a median follow-up of 33.6 months, the 36-month progression-free survival (PFS) rate was 59.4% with cilta-cel vs 25.7% with standard of care. The CR rate was 76.9% vs 24.2% at 33.6 months follow-up, and minimal residual disease negativity in evaluable patients was 85.6% vs 18.6% at 10⁻⁶ sensitivity. Overall survival (OS) was 76.4% vs 63.8%. The benefit was consistent across subgroups, including in the 59% of patients with high-risk cytogenetics and those with prior daratumumab exposure.

Mewawalla noted that response deepened over time in the cilta-cel arm even without additional therapy, a feature of the durable T-cell engraftment not observed with conventional regimens or bispecifics. She also highlighted that cytokine release syndrome (CRS) and neurotoxicity rates were lower in CARTITUDE-4 than in earlier heavily pretreated populations: CRS occurred in 76% of patients but was grade 3 or higher in only 1%, and parkinsonism, a rare but serious concern from prior studies, was seen in 1% of patients.

Jason Bierenbaum, MD, of the University of Pittsburgh Medical Center, raised the sequencing question directly. “Do I really need to refer second-line patients?” he asked. He acknowledged the subset analyses were compelling even in patients without high-risk cytogenetics or aggressive early relapse, though he noted that high-risk cytogenetics and early relapse were not examined together in a single subgroup. In response, Mewawalla reinforced the IMWG guidance: when a patient is eligible for both CAR T and a bispecific, CAR T should come first, because T-cell fitness is better earlier and prior bispecific exposure can compromise manufacturing.

However, access to CAR T remained the most cited obstacle. When asked what they found most challenging, 5 participants identified logistical and social issues, such as travel to treatment centers, caregiver support, and reluctance to leave family, and 4 cited wait times for manufacturing and administration. None identified apheresis infrastructure, insurance delays, or eligibility criteria as their greatest concern. Mewawalla and others described how she and colleagues successfully convinced patients who initially declined for these reasons by highlighting CAR T as a one-time intervention: “It's one and done. It's OK. Someone can take care of your family for a little bit.”

On bridging therapy, one of Mewawalla's preferred approaches is to use bispecific antibody but change the target by giving talquetamab (Talvey), a GPRC5D-directed bispecific. She said it requires only step-up dosing and perhaps 1 additional cycle before CAR T-cell infusion, achieving rapid disease control without exhausting BCMA-directed options. Selinexor (Xpovio)-based regimens offer an alternative for heavily pretreated patients. The group supported a 2-week washout before both apheresis and CAR T-cell infusion and agreed to avoid BCMA-directed therapy as a bridge to prevent CAR T target interference.

When asked what proportion of referred patients ultimately receive infusion, 8 of 9 participants said approximately 75%, a figure Mewawalla called encouraging but a reminder that some patients, despite eligibility and referral, ultimately decline or cannot complete the process.

For a patient like this one, a retired man with good functional status, a long first remission, standard-risk cytogenetics, and time to pursue a potentially curative intervention, the data and the discussion converged on early referral for cilta-cel before a BCMA-directed bispecific that could deplete T cells or reduce BCMA expression.

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_{DISCLOSURES: Mewawalla previously reported advisory board roles with Pfizer and Johnson & Johnson.}

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. 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

3. Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival with ciltacabtagene autoleucel versus standard of care in lenalidomide-refractory multiple myeloma: Phase 3 CARTITUDE-4 study update. Presented at: 21^st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-65.