After decades of incremental progress in the treatment of multiple myeloma, survival has increased from 3 years in the late 1990s to between 8 and 10 years today.1 Could cure for a disease that kills more than 12,000 individuals each year in the United States2 finally be within reach? The long-term results from the phase Ib/II CARTITUDE-1 trial offer compelling evidence that potential cure may already be possible, even in some patients with advanced disease.
The study findings, which were reported during the 2025 ASCO Annual Meeting3 and simultaneously published in the Journal of Clinical Oncology,4 showed that 97 heavily pretreated patients with relapsed or refractory multiple myeloma enrolled in the study experienced a 5-year progression-free survival rate of 33%, with a median overall survival of 60.7 months, after one infusion of ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy. One-third of these patients remain alive and progression-free for at least 5 years with no maintenance or subsequent antimyeloma therapy. In addition, in a subset of 12 patients at a single center who underwent serial evaluations for measurable residual disease (MRD) and positron-emission tomography/computed tomography (PET/CT) assessments, all were found to have achieved MRD negativity and were in complete metabolic response through 5+ years of posttreatment follow-up.4
In my mind, after 10 years of progression-free survival following ciltacabtagene autoleucel therapy, the cancer is not coming back.— PETER M. VOORHEES, MD
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The 32 patients who remained progression-free for at least 5 years had undergone a median of six prior lines of therapy, and they included subgroups with high-risk cytogenetics (23.3%), extramedullary plasmacytomas (12.5%), triple-class–refractory disease (90.6%), and penta-drug–refractory disease (46.9%). Severe adverse events were experienced among these patients, including two second malignancies (both solid tumors), two neurologic adverse events, and four grade ≥ 3 infections. And although previous cuts of the data have shown ciltacabtagene autoleucel therapy to be associated with a higher risk of neurotoxicity (such as cranial nerve palsies and parkinsonism), no new cases were reported in longer follow-up.
Transforming Outcomes in Multiple Myeloma
“All the advances in the treatment of multiple myeloma, including CD38 antibodies, proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplantations, have improved therapy for this cancer. The improvement has been incremental. The results we’re seeing in patients treated with ciltacabtagene autoleucel are a substantial leap forward and truly transformative,” said Peter M. Voorhees, MD, Professor of Medicine at Wake Forest University School of Medicine; Chief, Plasma Cell Disorders Division at Atrium Health, Levine Cancer Institute; Associate Director of Clinical Research at Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and an investigator on CARTinue, the long-term extension study of CARTITUDE-1.
In a wide-ranging interview with The ASCO Post, Dr. Voorhees discussed the results from the CARTITUDE-1/CARTinue trial, the potential of replacing bone marrow transplantation with CAR T-cell therapy in myeloma treatment, and achieving cure for this cancer.
Comparing Two BCMA-Directed CAR T-Cell Therapies
The results from your study are so extraordinary. Why do you think this particular BCMA-directed CAR T-cell therapy generated such durable remissions, and potential cures, in patients with advanced multiple myeloma, when the results from a clinical trial with another BCMA-directed CAR T-cell therapy, idecabtagene vicleucel, showed median duration of response, progression-free survival, and overall survival in patients with relapsed or refractory disease of 10.3, 8.8, and 34.2 months, respectively?5
Although the progression-free survival and overall survival rates with idecabtagene vicleucel are different relative to what we’re seeing with ciltacabtagene autoleucel, the two CAR T-cell therapies have never been compared head to head in a randomized trial. However, earlier this year, the U.S. Multiple Myeloma Immunotherapy Consortium reported the results of a sophisticated analysis of real-world outcomes between idecabtagene vicleucel and ciltacabtagene autoleucel and found that ciltacabtagene autoleucel demonstrated superior efficacy and overall survival. But the flip side of that is ciltacabtagene autoleucel also demonstrated a higher incidence of toxicities, particularly delayed neurotoxicities.6
These two BCMA-directed CAR T-cell therapies have different CAR constructs. The ciltacabtagene autoleucel construct uses a 4-1BB co-stimulatory domain similar to idecabtagene vicleucel. However, ciltacabtagene autoleucel has two BCMA-binding domains compared with one for idecabtagene vicleucel, allowing ciltacabtagene autoleucel to potentially bind more avidly to the myeloma cell target, which may in part explain the different results with the two products.
Achieving Long-Term Remissions
The 32 patients who remained progression-free for at least 5 years had a median of six prior lines of therapy, including autologous bone marrow transplant. After so many lines of therapy, how fit were these patients’ T cells before being genetically engineered to enhance their ability to kill myeloma cells?
What is quite remarkable about our results is that the proportion of patients with high-risk cytogenetics was the same for those who achieved progression-free survival and were alive for more than 5 years and those who relapsed before 5 years. And the percentage of patients with extramedullary disease was the same across these two groups as well. When you look at the progression-free survival of the patients with extramedullary multiple myeloma, it’s shorter than that for patients without extramedullary disease, but even within that cohort with extramedullary disease, some still experienced long-term remissions.
When we analyzed clinical variables and the correlative work, we found that having a lower burden of disease before being infused with ciltacabtagene autoleucel did impact how long patients stayed in remission. Now, whether that is the result of differences in disease biology and easier to control disease or it’s optimization of the effector-to-target ratio is unclear, and more research needs to be done on this front.
What is interesting is the immune correlates that were done as part of this study in the patients who were progression-free and alive for 5 or more years showed these patients had a higher number of circulating T cells to neutrophils in their blood prior to leukapheresis. When we looked at their CAR T-cell product after manufacturing, we found a higher proportion of CAR T cells that were naive T cells in those patients who were likely to respond for a longer period. We also found an increased expansion of the central memory CD4-positive cells after infusion in these long-term remitters. This suggests that a more immune-fit CAR T-cell product may be associated with better outcomes.
Our hope is that as we move this therapy into earlier lines of treatment, higher proportions of patients will receive more immune-fit CAR T-cell products, and we will be able to better control the burden of disease during the manufacturing process. This should translate into more patients remaining alive and progression-free and off any antimyeloma therapy for years.
Living a High-Quality Life After Myeloma
How would you describe the health status of the patients in your study?
For the one-third of patients who are progression-free and alive, they’re living as though they don’t have active multiple myeloma. In the short term after therapy, pretty intensive supportive care is required, particularly in the first 1 to 3 months. Then there is the need for extended supportive intravenous immunoglobulin (IVIG) infusions to reduce the risk of infection. But many of these patients have been able to stop IVIG infusions as their B-cell and plasma cell pools repopulate, so they are living free of treatment side effects at this point, which is remarkable. They may have some lingering side effects from prior myeloma therapies or prior complications of myeloma, for example, bone pain and neuropathy. But, for the most part, these patients are living with a good quality of life.
However, I don’t want to minimize the very real side effects some patients experienced on this study, including 17 patients who died of complications from this CAR T-cell treatment prior to disease progression and many from infections. As we move this therapy into earlier lines of treatment and control the disease better going into CAR T-cell therapy, we should be able to mitigate some of these more worrisome side effects. But there is still a lot of work to be done in identifying which patients are at greater risk for developing the unusual side effects of ciltacabtagene autoleucel, such as delayed neurotoxicities, and what we can do to reduce the likelihood of those side effects from occurring.
Replacing Bone Marrow Transplantation With CAR T-Cell Therapy?
Will CAR T-cell therapy replace bone marrow transplantation as standard of care in myeloma therapy? And should CAR T-cell therapy be moved up to the front-line setting in this cancer?
Clearly, randomized studies will need to be done to address these questions, and there are phase III randomized clinical trials investigating the use of ciltacabtagene autoleucel in current front-line therapies in myeloma. For example, CARTITUDE-6 (ClinicalTrials.gov identifier NCT05257083) is comparing the efficacy of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd), followed by ciltacabtagene autoleucel vs DVRd, followed by autologous stem cell transplant, in newly diagnosed patients with multiple myeloma.
There is a lot of enthusiasm that we will be able to replace transplant with CAR T-cell therapy. However, transplantation has performed extremely well in patients with myeloma, so the side-effect profiles of these two different approaches need to be carefully evaluated in head-to-head studies.
CARTITUDE-5 (NCT04923893) is investigating bortezomib, lenalidomide, and dexamethasone (VRd) followed by ciltacabtagene autoleucel vs VRd, followed by lenalidomide and dexamethasone, in patients with newly diagnosed myeloma for whom autologous transplant is not planned as initial therapy. We’ll probably have the results from that study sooner than those from CARTITUDE-6, and we strongly suspect there will be higher rates of MRD negativity and improved progression-free survival for those patients receiving ciltacabtagene autoleucel after their initial course of VRd. Again, we have to compare the side effects between the two approaches, because even in the nontransplant setting, newly diagnosed patients today are doing quite well.
I believe there likely will be more patients cured with the use of ciltacabtagene autoleucel as part of front-line therapy. It’s just a matter, again, of balancing the benefits and risks of some of the unusual side effects that we’re learning more about each day with ciltacabtagene autoleucel.
Defining Cure in Multiple Myeloma
What is your definition of cure in multiple myeloma? Are some patients in your study potentially cured?
That is the million-dollar question. There is a working proposal that the definition of cure in multiple myeloma is the achievement of an MRD-negative complete treatment response and complete metabolic response by PET/CT imaging sustained for 5 or more years off treatment. That’s a good place to start, and one-third of the patients in our study meet these criteria.
Do I think some of these patients in long-term remission will relapse? Yes, I do, but the CARTinue trial will go on for an additional 10 years of follow-up. It will be fascinating to see what happens to these patients over the next 5 to 10 years and what proportion of patients will remain progression-free 10 years after their ciltacabtagene autoleucel infusion. In my mind, after 10 years of progression-free survival following ciltacabtagene autoleucel therapy, the cancer is not coming back.
I do think there are some patients who are truly cured with this therapy. We just need to better identify upfront what the predictive factors are for cure and which patients will likely benefit from CAR T-cell therapy. By moving CAR T-cell therapy into an earlier line of treatment, when patients’ T-cell fitness is better, we’re hopeful the percentages of patients cured of myeloma will rise.
Unraveling the Mystery of Cure in Myeloma
After so many decades of being a stubbornly incurable cancer, is myeloma finally getting closer to becoming a curable cancer?
I believe we have the tools to cure multiple myeloma at this point. It’s just a matter of identifying the most effective way to use the different treatment modalities to reach cure. The right studies are underway to evaluate how best to get to cure in this cancer, and we are getting closer to reaching this goal.
A key piece in getting to cure is to understand why some patients relapse after T-cell–redirecting therapies, including CAR T-cell therapy or bispecific antibodies, what the mechanisms of resistance are, and how these mechanisms of resistance can be overcome. Unraveling that mystery is key to achieving cure in multiple myeloma.
DISCLOSURE: Dr. Voorhees has served as an advisor or consultant to AbbVie, Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, GSK, Johnson & Johnson, Kite, Pfizer, Regeneron, and Sanofi; and has received institutional funding from AbbVie, Johnson & Johnson, and Regeneron.
REFERENCES
1. Gulla A, Anderson KC: Multiple myeloma: The (r)evolution of current therapy and a glance into future. Haematologica 105:2358-2367, 2020.
2. American Cancer Society: Key statistics about multiple myeloma. Available at www.cancer.org/cancer/types/multiple-myeloma/about/key-statistics.html. Accessed August 13, 2025.
3. Voorhees PM, 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. 2025 ASCO Annual Meeting. Abstract 7507. Presented June 3, 2025.
4. Jagannath S, Martin TG, Cohen AD, 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).
5. Lin Y, Raje NS, Berdeja JG, et al: Idecabtagene vicleucel for relapsed and refractory multiple myeloma: Post hoc 18-month follow-up of a phase 1 trial. Nat Med 29:2286-2294, 2023.
6. Hansen DK, Peres LC, Dima D, et al: Comparison of standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel in relapsed/refractory multiple myeloma. J Clin Oncol 43:1597-1609, 2025.
