Clinical Review of Cellular Therapies for Multiple Myeloma Part I: A Primer on CAR-T for the Community and Rural Oncologist

Introduction

The advent of chimeric antigen receptor T-cell (CAR-T) therapy has fundamentally shifted the therapeutic landscape for hematologic malignancies, including multiple myeloma, offering durable remissions in diseases previously resistant to conventional approaches. As these therapies migrate from academic tertiary centers into broader clinical practice, the practicing oncologist in rural non-metropolitan settings faces an imperative to understand not only the mechanisms and efficacy of these agents but also the full spectrum of their toxicities, the infrastructure required to manage them safely, and the criteria by which patients must be escalated to specialized care. This two-part clinical review synthesizes available evidence to provide a framework for the community and rural oncologist managing patients who have received anti-BCMA (B-cell maturation antigen) CAR-T therapy for multiple myeloma.

Overview of CAR-T therapies

CAR-T is an immunotherapy using genetic engineering of a patient's autologous T lymphocytes to express a synthetic receptor composed of an extracellular antigen-recognition domain to target the neoplastic cell of interest. After leukapheresis to extract a patient’s T cells, they are transduced via viral vector with a CAR transgene, expanded ex vivo, and then reinfused into the patient following lymphodepleting chemotherapy (typically fludarabine and cyclophosphamide). As of the time of this publication, there are seven U.S. Food and Drug Administration (FDA)-approved CAR-T therapies in total. And currently two of them, idecbtagene vicleucel (ide-cel, Abecma by Celgene and Bristol Myers Squibb) and ciltacabtagene autoleucel (cilta-cel, Carvykti by Legend and Johnson & Johnson), are approved for use in multiple myeloma.

CAR-T therapy has demonstrated transformative efficacy across multiple hematologic malignancies. In diffuse large B-cell lymphoma, three CD19-directed products – axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel – have demonstrated long-term remissions in approximately 30–40% of patients with relapsed or refractory disease following aggressive salvage therapy. In B-cell acute lymphoblastic leukemia (B-ALL), tisagenlecleucel achieved remission rates exceeding 80% in pediatric and young adult populations. And in multiple myeloma, anti-BCMA-directed constructs have produced the most remarkable overall response rates and durability of responses offering the possibility of minimal residual disease (MRD) negativity and even raising the specter of cure in this previously incurable disease. Although once isolated to large academic centers, as the scope of CAR-T expands, the rural oncologist will increasingly encounter patients who have undergone these therapies.

Idecabtagene Vicleucel (ide-cel)

Ide-cel was the first anti-BCMA CAR-T product approved by the FDA in March 2021, employing a single anti-BCMA single-chain variable fragment. Its approval was predicated upon the single-arm phase 2 KarMMa-1 trial [1] demonstrating an overall response rate of 73% and a complete response rate of 33% in patients with triple-class refractory myeloma.

The pivotal randomized phase 3 KarMMa-3 trial [2] subsequently established ide-cel superiority over physician's choice of five standard regimens in 386 patients with triple-class–exposed relapsed and refractory myeloma who had received two to four prior lines of therapy. The primary endpoint was progression-free survival (PFS) and significantly favored ide-cel, with a median PFS of 13.3 months compared to 4.4 months in the standard-of-care arm (HR 0.49; 95% CI, 0.38–0.65; P<0.001). The overall response rate was 71% in ide cel versus 42% in standard-of-care, with complete responses in 39% versus 5%, respectively. Adverse events included expected cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), infections, and cytopenias. Overall, grade 3-4 CRS was observed in 5% of patients, and grade 3 neurotoxicity in 3%, reflecting a toxicity profile considerably more attenuated than that observed with cilta-cel.

Ciltacabtagene Autoleucel (cilta-cel)

Cilta-cel was FDA approved in February 2022 and is structurally distinguished from ide cel by the incorporation of two anti-BCMA structures on the CAR-T membrane, which ultimately offers substantially higher BCMA-binding avidity. This molecular architecture likely underlies its superior depth and durability of response relative to ide-cel but is also accompanied by a more complex toxicity profile.

The phase 1b/2 CARTITUDE-1 trial [3] established cilta cel's registrational basis, enrolling 97 heavily pretreated patients with a median of six prior lines of therapy. At a median follow-up exceeding four years, cilta cel achieved an overall response rate of 98%, with stringent complete response in 83% of evaluable patients and a median PFS of 34.9 months—response rates unprecedented in this disease setting. Any-grade CRS occurred in 95% of patients (grade 3–4: 4%). Neurotoxicity was observed in 21% of patients (grade 3–4: 9%).

Clinical details and trials data

The phase 3 CARTITUDE-4 trial [4] was an open-label, randomized trial enrolling 419 patients with lenalidomide-refractory multiple myeloma who had received one to three prior lines of therapy comparing a single infusion of cilta cel against physician's choice of pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd). In the initial analysis, cilta cel reduced the risk of progression or death by 74% (HR 0.26; P<0.001), with an ORR of 84.6% and a complete response rate of 73.1%, versus 67.3% and 21.8% in the standard-of-care arm, respectively.

Crucially, updated results [5] at a median follow-up of 33.6 months demonstrated that cilta cel reduced the risk of death compared to standard of care (HR 0.55; 95% CI, 0.39–0.79; P=0.0009), with 30-month OS rates of 76.4% versus 63.8%. This represented the first randomized demonstration of an overall survival benefit of this magnitude for CAR T therapy in myeloma. The combination of this OS benefit and the unprecedented depth of response in the second-line setting has irreversibly shifted practice expectations, with cilta-cel now FDA-approved for lenalidomide-refractory patients after as few as one prior line of therapy. 

Moreover, in a long-term analysis of the CARTITUDE-1 trial [6], 32 of the 97 cilta-cel treated patients were progression free at 5 years and 12 of these patients had evaluations to show they were MRD-negative (at a level of 10^-5). Now the forthcoming CARTITUDE-6 trial (NCT05257083) extends this investigational trajectory into the frontline setting, randomizing transplant-eligible patients with newly diagnosed myeloma 1:1 after DVRd (daratumumab, bortezomib, lenalidomide, and dexamethasone) induction to either a single infusion of cilta-cel followed by lenalidomide maintenance, or autologous stem cell transplant followed by two cycles of DVRd consolidation and lenalidomide maintenance. Dual primary endpoints are PFS  and sustained MRD-negative complete response for at least 12 months.

All in all, the data continue to support anti-BCMA CAR-T therapy in myeloma in a favorable manner leading to the expansion of its use to more and more practice centers, including non-metropolitan settings. With the extension of survival, even a patient treated at an academic, tertiary care center may venture back to a community oncology practice.

Head-to-head comparison

The absence of a prospectively randomized direct comparison between ide cel and cilta cel is a persistent evidence gap for clinicians. This was addressed by a multicenter retrospective analysis [7] using data from the U.S. Multiple Myeloma Immunotherapy Consortium across 19 academic institutions. The study examined 641 patients with relapsed/refractory myeloma who underwent leukapheresis for either standard-of-care ide-cel or cilta cel, with inverse probability of treatment weighting applied to balance baseline characteristics across cohorts.

The findings were unambiguous in their directional signal: cilta-cel was associated with a 56% reduction in the risk of progression or death in the intent-to-treat population and a 53% reduction in those who received infusion, alongside superior overall survival. Cilta-cel delivered consistently higher ORRs and deeper responses across matched subgroups. However, the toxicity differential was also worse. Cilta-cel was associated with a 5.5-fold higher incidence of severe (grade ≥3) CRS compared to ide-cel, and potentially most concerning for community oncologists there was a 21-fold higher incidence of delayed neurotoxicity (DNT), including immune effector cell-associated parkinsonism and cranial nerve palsies. These data empirically validate what experienced myeloma clinicians had long suspected anecdotally: cilta-cel is the more efficacious product, but comes at the cost of a more hazardous toxicity profile, particularly with respect to neurologic sequelae that can emerge weeks to months post-infusion and that require specialized monitoring and multidisciplinary expertise.

Based on these data and the trends of both patient and physician preference, cilta-cel has been increasingly used above ide cel and so community oncologists are likely to encounter myeloma patients treated with the former more than the latter. By extension of this, awareness of DNTs and other late toxicities is essential.

Other BCMA therapies

It is worth acknowledging that the broader anti-BCMA treatment landscape also includes three approved bispecific T-cell engaging antibodies – teclistamab, elranatamab, and linvoseltamab – as well as an antibody drug conjugate, belantamab mafadotin. The bispecific agents share broadly similar in their effect and toxicity profiles with BCMA-directed CAR-T products since they also use CD3+ T cell including CRS, ICANS, infections, and cytopenias, although they are generally of lower severity and often manageable in the outpatient setting given their intermittent administration. However, the depth and durability of response achieved with CAR T products, particularly cilta cel, appears to exceed those observed with bispecific antibodies in the relapsed/refractory setting. Because the mechanisms of action rely on T cell, both bispecific T-cell engaging antibodies (BTCE’s) and CAR-T therapies are broadly called T cell redirecting [TCR] therapies.

Clinical Use and Conclusion

As of the end of 2024, over 5,000 patients had been treated with cilta-cel globally across clinical and commercial settings, a number that has since grown to more than 9,000 patients worldwide. Ide-cel, while generating $242 million in U.S. revenue in 2024, has ceded market predominance to its successor: across U.S. treatment centers offering both therapies, cilta-cel holds approximately 80% of the CAR-T market share in myeloma, reflecting both its superior efficacy data and growing clinician and patient preference. 

Originally, both products were restricted to patients with four or more prior lines of therapy. That changed in April 2024, when the FDA simultaneously expanded the indications of both agents: ide-cel was approved for triple-class–exposed patients after two or more prior lines of therapy and as discussed above cilta-cel became the first BCMA-directed CAR-T product approved as early as second-line therapy. These parallel label expansions, grounded in the KarMMa-3 and CARTITUDE-4 trial data respectively, have substantially broadened the eligible patient population and accelerated the migration of CAR-T therapy into earlier disease states. Cilta cel is now being evaluated in Phase III trials for frontline myeloma in both transplant-eligible (CARTITUDE-6) and transplant-ineligible (CARTITUDE-5) settings, portending a future in which these cellular therapies may ultimately replace or supplant autologous stem cell transplant as consolidation in newly diagnosed disease. In the next article ( read here ), we will discuss the toxicities and management for the community and rural oncologist.

Patient Perspective / Plain-Language Summary

Multiple myeloma is a cancer of the bone marrow that has historically been difficult to treat. A newer type of treatment called CAR T-cell therapy uses a patient's own immune cells, specifically T lymphocytes, which are modified in a laboratory to seek out and destroy myeloma cells. Two CAR-T products are currently FDA-approved for myeloma: idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). Clinical studies show these treatments can produce deep, long-lasting remissions, and Carvykti in particular has been shown to extend patients' lives compared to standard chemotherapy combinations. Because these treatments are now being used more widely, patients may return to their local or rural oncologist for follow-up care after receiving CAR-T therapy at a specialized center. This article helps community oncologists orient to the basic landscape of CAR-T therapy in myeloma.

Key Takeaways

• Idecbtagene vicleucel (ide-cel), brand name Abecma by Celgene and Bristol Myers Squibb is the first FDA-approved CAR-T therapy in multiple myeloma with approval in 2021 based on the KarMMA trials

• Ciltacabtagene autoleucel (cilta-cel), brand name Carvykti by Legend and Johnson & Johnson is the second FDA-approved product, approved in 2022 based on the CARTITUDE trials, and now has a greater market share

• In retrospective review of ide-cel and cilta-cel, it appears cilta-cel is much more potent but also has more toxicity

• The current indications for both CAR-T therapies are in relapsed/refractory myeloma, potentially as early as second line treatment

References:

1. Munshi, N.C., et al., Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med, 2021. 384(8): p. 705-716.

2. Rodriguez-Otero, P., et al., Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med, 2023. 388(11): p. 1002-1014.

3. Berdeja, J.G., et al., Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet, 2021. 398(10297): p. 314-324.

4. San-Miguel, J., et al., Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med, 2023. 389(4): p. 335-347.

5. Einsele, H., 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): p. 254-268.

6. Jagannath, S., et al., Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma. J Clin Oncol, 2025. 43(25): p. 2766-2771.

7. Hansen, D.K., et al., Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma. J Clin Oncol, 2025. 43(13): p. 1597-1609.

Corresponding author: 

Adeel M. Khan, M.D., M.P.H., M.S.
Assistant Professor of Medicine & Public Health 
Harold C. Simmons Comprehensive Cancer Center & Peter O’Donnell Jr School of Public Health
University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX, USA 75390
Tel: (405) 623 3337 | E-mail: [email protected] / [email protected]

ORCiD: 

Adeel Khan: 0000-0002-9462-6316
Aimaz Afrough: 0000-0003-2645-8557
Samer Al Hadidi: 0000-0003-4297-8042 
Sean Taasan: 0000-0001-6937-0120
Larry Anderson: 0000-0002-6531-9595

Relevant Disclosures/Conflict of Interest:

• AMK: Johnson & Johnson, Legend, Sanofi, Pfizer, AbbVie
• AA: AbbVie, Adaptive Biotech, K36 Therapeutics, Johnson & Johnson, Regeneron, Bristol Myers Squibb, Karyopharm Therapeutics, Sanofi, and Pfizer
• SAH: Johnson & Johnson, Legend, Sanofi, Pfizer
• ST: none
• LDA: Johnson & Johnson, Celgene, Bristol Myers Squibb, Amgen, GSK, AbbVie, BeiGene, Karyopharm, Pfizer, Cellectar, Sanofi, Prothena, and Arcellx