High-risk smoldering multiple myeloma (HR-SMM) carries a roughly 50% risk of progression to active disease within two years. Until recently, the standard approach was observation. Even after the 2025 FDA approval of daratumumab based on the AQUILA trial, approximately 40% of patients still progressed. Deep responses remained uncommon. The CARPRISM trial cilta-cel high-risk smoldering multiple myeloma is an important new topic in this field.
The phase 2 CARPRISM trial tested a fundamentally different strategy: using ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, as primary treatment without any induction or bridging therapy in patients with HR-SMM. Notably, the CARPRISM trial cilta-cel high-risk smoldering multiple myeloma approach provides a unique opportunity to evaluate early intensive immunotherapy.
Presenting the results, Dr. Omar Nadeem (Clinical Director of the Myeloma Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute) explained the scientific rationale behind moving CAR T-cell therapy earlier in the disease course. “We aimed to see whether use of CAR T-cell therapy in the high-risk smoldering myeloma space, where the immune system is more intact, would lead to higher rates of MRD negativity without any induction therapy,” said Dr. Nadeem.
Twenty patients meeting stringent high-risk criteria (2-20-20 model, IMWG score ≥9, or select additional risk features) underwent leukapheresis, optional stem-cell collection, lymphodepletion with cyclophosphamide and fludarabine, and a single cilta-cel infusion. No bridging therapy was permitted.
Safety profile
No dose-limiting toxicities occurred in the safety run-in. Cytokine release syndrome was universal but grade 1–2 only. There were no grade ≥3 infections, ICANS, or delayed hematologic toxicities. Seven patients developed non-ICANS neurotoxicity (NINTS), four of which fully resolved (primarily cranial nerve palsies). However, the remaining three had mild, ongoing grade 1 symptoms managed with steroids, IVIG, and supportive interventions.
Efficacy results (median follow-up 15.3 months)
All 20 patients achieved MRD negativity at 10⁻⁶ by next-generation sequencing (clonoSEQ) by two months, and it has remained sustained in every patient. The overall response rate was 100%, with 90% reaching stringent complete response or better. No patient has developed biochemical or SLIM-CRAB progression. Median progression-free and overall survival have not been reached. In summary, the CARPRISM trial cilta-cel high-risk smoldering multiple myeloma findings support a potentially disease-modifying approach.
As Dr. Nadeem highlighted, “The immune system is less altered in smoldering myeloma. Therefore, CAR T-cell therapy would have potentially even greater benefit compared to relapse-refractory myeloma patients.” He added, “This truly has potential to be one-and-done treatment for patients to prevent myeloma in their lifetime.”
These data represent the first demonstration of universal, deep, and sustained MRD negativity with any CAR T-cell product in the precursor myeloma setting. They open the door to discussions about possible disease interception or even cure in selected patients with HR-SMM.
Q&A for Busy Oncologists
1. Why does cilta-cel appear far more effective in high-risk smoldering myeloma than in relapsed/refractory multiple myeloma? Dr. Nadeem noted that the intact immune system and lower tumor burden in the precursor state allow markedly better CAR T-cell expansion and persistence. This produces deeper and more durable responses than those seen in heavily pretreated patients.
2. How does the safety profile of cilta-cel in this early setting compare with its use in relapsed disease? CRS was mild and universal but never grade ≥3. ICANS was absent. The main new signal was NINTS in 35% of patients (mostly self-limited cranial neuropathies or mild grade 1 movement/neurocognitive changes). No high-grade infections or delayed cytopenias occurred.
3. How might CARPRISM results change practice relative to the recently approved daratumumab approach? Daratumumab requires three years of continuous therapy and still leaves many patients progressing without deep molecular responses. CARPRISM offers a one-time infusion with universal MRD negativity and no progressions to date. Therefore, it potentially redefines treatment goals toward disease eradication rather than chronic suppression. Thus, the CARPRISM trial cilta-cel high-risk smoldering multiple myeloma results could influence future guidelines.
4. What longer-term data are still needed before considering routine use? Durability of MRD negativity beyond 2–5 years and confirmation of a favorable risk–benefit ratio in larger, multicenter studies will determine whether early cilta-cel becomes a standard option. This is particularly important for ultra-high-risk patients who may derive the greatest absolute benefit.
Presented by Dr. Omar Nadeem. Biography and full profile: https://www.dana-farber.org/find-a-doctor/omar-nadeem