The results from the CARTITUDE-1 study showed the remarkable efficacy of ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, when used in patients with relapsed or refractory multiple myeloma after four or more prior lines of therapies. According to the study’s results, about one-third of the 97 patients in the study remain alive and progression-free for at least 5 years after a single infusion of ciltacabtagene autoleucel, without maintenance treatment; and 12 of these patients achieved continuing measurable residual disease (MRD)-negative myeloma, a complete response to the treatment, and were off all maintenance multiple myeloma therapy, including those with high-risk cytogenetics and extramedullary disease.1 (For a more detailed look at the CARTITUDE-1 trial, click here to see the Expert’s Corner with Peter M. Voorhees, MD, a CARTITUDE-1 investigator, as well as the July 25, 2025, issue of The ASCO Post.)
Kenneth C. Anderson, MD, FASCO
Whether this plateau in survival outcome persists and some of these patients are cured will be determined with further follow-up study. Of interest, the International Myeloma Society, for the first time, has proposed a definition of cure to include patients with a complete response from treatment; MRD negativity in the bone marrow using 10-6 threshold; at least three measurements of MRD 12 months apart between 1 and 5 years and MRD negativity at year 5; and negative positron-emission tomography/computed tomography (PET/CT) scan assessments confirmed a minimum of 1 year apart, including at year 5. This durability of response, until recently unachievable, now is a realistic goal for ongoing studies in myeloma.
Moving Ciltacabtagene Autoleucel to the Front-Line Setting
What are the implications of this study for future care in multiple myeloma and in clinical trials for the disease? The CARTITUDE-4 study (ClinicalTrials.gov identifier NCT04181827) has already shown that ciltacabtagene autoleucel treatment after one to three prior standard therapies for patients with relapsed and lenalidomide-refractory multiple myeloma has achieved increased MRD complete response and progression free-survival compared with the results found in CARTITUDE-1, indicating that treating relapse earlier in the course of disease may translate to even better outcomes.2
Moreover, the CARTITUDE-6 study (NCT05257083) is randomly assigning newly diagnosed patients with myeloma after daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) induction therapy to receive either ciltacabtagene autoleucel therapy or an autologous stem cell transplant. Whether a higher fraction of these patients experience prolonged response to ciltacabtagene autoleucel and are potentially cured when treated earlier with this therapy and whether patients who do not achieve complete response or who relapse after initial treatment (including with ciltacabtagene autoleucel) but remain responsive to current U.S. Food and Drug Administration–approved targeted and immune therapies remain to be seen.
Transforming Treatment Progress in Multiple Myeloma
There has been transformational progress seen in the initial treatment of multiple myeloma with the results from clinical trials such as the phase III PERSEUS study. This clinical trial found that D-VRd induction therapy prior to high-dose melphalan and autologous stem cell transplant, followed by lenalidomide maintenance, may achieve more than 200 months projected progression-free survival in patients with standard-risk multiple myeloma.3
And the recent results from the phase III MIDAS study, which randomly assigned patients who had achieved MRD-negative complete response after receiving isatuximab, carfilzomib, lenalidomide, and dexamethasone induction therapy to either continued quadruplet therapy or high-dose therapy and autologous stem cell transplant, showed that the frequency and extent of MRD complete response were not significantly different between the two cohorts.4
This unprecedented progress in the treatment of multiple myeloma suggests that quadruplet therapy alone may achieve high rates of MRD complete response in newly diagnosed patients and that autologous stem cell transplantation may not add value in this setting. On the other hand, early data suggest that the addition of teclistamab-cqyv, a first-in-class BCMA × CD3 bispecific T-cell engager, to DVR initial therapy achieves universal MRD negativity in newly diagnosed patients.5
Eradicating Multiple Myeloma
The appeal of incorporating CAR T-cell therapy or a bispecific T-cell engager into initial myeloma therapy to achieve MRD-negative complete response at high stringency is the potential to eradicate multiple myeloma, thereby avoiding the clonal evolution of residual disease that underlies disease relapse. Multiple ongoing and future trials will determine the durability of these responses and the curative potential of quadruplet treatment (with or without immune therapies) as well as define those treatments effective to treat relapsed multiple myeloma in this setting.
DISCLOSURE: Dr. Anderson reported no conflicts of interest.
REFERENCES
1. Jagannath S, Martin TG, Lin Y, 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. June 3, 2025 (early release online).
2. San-Miguel J, Dhakal B, Yong K, et al: Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med 389:335-347, 2023.
3. Sonneveld P, Dimopoulos MA, Boccadoro M, et al: Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 390:301-313, 2024.
4. Perrot A, Touzeau C, Lambert J, et al: Isatuximab, carfilzomib, lenalidomide, and dexamethasone induction in newly diagnosed myeloma: Analysis of the MIDAS trial. Blood 146:52-61, 2025.
5. Raab MS, Weinhold N, Kortüm KM, et al: Phase 2 study of teclistamab-based induction regimens in patients with transplant-eligible newly diagnosed multiple myeloma: Results from the GMMG-HD10/DSMM-XX (MajesTEC-5) trial. 2024 ASH Annual Meeting and Exposition. Abstract 493. Presented December 8, 2024.
Dr. Anderson is the Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston.
