Name<\/strong><\/p>\n<\/div>\n\u201cThe biggest question our patients ask is: What are you waiting for?\u201d senior author Irene Ghobrial, MD,<\/b> professor of medicine at Dana-Farber Cancer Institute, said in an interview. \u201cFor any other cancer, we would never tell a patient to wait until they have end-organ damage or metastases to get treatment. Yet, for a long time, we waited for symptomatic disease because we had no good therapy.\u201d<\/p>\n
In the past decade, the FDA has approved more than a dozen new agents and nearly 30 unique regimens for multiple myeloma.<\/p>\n
\u201cMany of these drugs lead to impressive responses \u2014 and potentially cure \u2014 yet we still have been telling our patients, \u2018Wait until you have higher tumor burden, end-organ damage or fractures in your bones and then I will treat you,\u2019\u201d Ghobrial said. \u201cOur patients have told us, \u2018Treat me now with the best therapy you have.\u2019 This call from our patients really drove us to do something different.\u201d<\/p>\n
\u2018Something more\u2019<\/h2>\n
That patient-centered mission marked its first milestone in November when the FDA approved daratumumab and hyaluronidase-fihj (Darzalex Faspro, Janssen), a subcutaneous CD38-targeted therapy, for individuals with high-risk SMM.<\/p>\n
The agency based the indication on results of the randomized phase 3 AQUILA trial, which showed the therapy delayed progression to multiple myeloma by 51% at 5 years compared with active monitoring.<\/p>\n
However, the therapy is administered regularly for 3 years. Also, fewer than 10% of patients assigned the therapy in AQUILA achieved complete response and 40% developed disease progression at 5 years, suggesting limited curative potential in this setting, Nadeem said.<\/p>\n
\u201cThe question has become: Is this enough for people who are truly at high risk, or can we give them something more?\u201d Nadeem said.<\/p>\n
Nadeem, Ghobrial and colleagues conducted the CAR-PRISM trial to evaluate the efficacy and safety of ciltacabtagene autoleucel, often called cilta-cel.<\/p>\n
The CAR T-cell therapy targets the B-cell maturation antigen (BCMA), found on the surface of abnormal plasma cells.<\/p>\n
Cilta-cel already is approved for relapsed or refractory multiple myeloma. Researchers hypothesized the therapy could be even more effective in SMM given patients\u2019 immune systems would be more robust and plasma cells would be less genomically complex, potentially leading to enhanced efficacy with reduced toxicity.<\/p>\n
Investigators enrolled 20 patients (median age, 58 years; range, 37-78; 70% men) with high-risk SMM. Because participants did not receive induction or bridging therapy, trial protocol excluded patients whose plasma cells comprised more than 40% of bone marrow due to elevated potential for toxicities.<\/p>\n
Trial participants received standard lymphodepletion chemotherapy, followed by a single cilta-cel infusion at doses ranging from 0.3×106<\/sup> cells\/kg to 1×106<\/sup> cells\/kg.<\/p>\nSafety, assessed by incidence of dose-limiting toxicities, served as the primary endpoint. Objective response rate, complete response rate, MRD negativity, PFS, and incidence and severity of adverse events served as secondary endpoints.<\/p>\n
Safety and efficacy<\/h2>\n
No dose-limiting toxicities occurred.<\/p>\n
All patients experienced grade 1 (85%) or grade 2 (15%) cytokine release syndrome. No grade 3 or higher CRS or infectious adverse events occurred.<\/p>\n
All patients experienced neutropenia (grade 3\/grade 4, 90%) and leukopenia (grade 3\/grade 4, 90%). Researchers reported four cases (20%) of grade 3\/grade 4 lymphopenia, two cases (10%) of grade 3\/grade 4 anemia, three (15%) grade 3\/grade 4 thrombocytopenias, and three (15%) cases of increased lymphocyte count.<\/p>\n
No delayed hematologic toxicity occurred, and no patients developed immune-effector cell-associated neurotoxicity syndrome (ICANS).<\/p>\n
Seven patients developed non-ICANS neurotoxicity (NINTS), with median time to onset of 21 days. Four of those patients had facial nerve palsies that resolved. Three had ongoing NINTS at data cutoff \u2014 two had grade 1 movement\/neurocognitive symptoms and one had grade 1 intention tremor during fine motor tasks.<\/p>\n
\u201cThankfully, the ongoing neurological toxicities remain low grade, and they have improved without impacting patients\u2019 activities of daily living,\u201d Nadeem said. \u201cThis is one of the complications that can occur from CAR T-cell therapy. We\u2019re still learning how to use dose modification or other strategies to mitigate it and hopefully prevent it.\u201d<\/p>\n
All 20 patients achieved MRD negativity at a threshold of 10-6<\/sup> by next-generation sequencing. MRD negativity for all patients persisted through data cutoff after median follow-up of 15.3 months. Twelve patients remained MRD negative after 1 year of follow-up and six remained MRD negative after more than 18 months.<\/p>\nAll patients achieved objective response per International Myeloma Working Group criteria. Eighteen patients (90%) \u2014 including all 16 who had at least 6 months of follow-up \u2014 achieved complete or stringent complete response.<\/p>\n
No patients experienced disease progression. Median PFS and OS had not been reached.<\/p>\n
\u2018The way to cure\u2019<\/h2>\n
Researchers acknowledged study limitations, including the small cohort, short follow-up, single-arm\/single-institution design and exclusion of patients with plasma cell infiltration greater than 40%.<\/p>\n
Still, the findings support the hypothesis that administration of CAR T-cell therapy prior to symptom development and onset of active multiple myeloma can induce deep responses, researchers concluded. The approach also allows standard induction regimens to be reserved if patients do progress.<\/p>\n
CAR-PRISM represents a proof-of-concept clinical trial. Longer follow-up will be necessary to assess response durability and cilta-cel\u2019s risk-benefit ratio in this setting, according to researchers.<\/p>\n
\u201cDr. Ghobrial has made it her mission for over a decade, if not longer, to try to shift the paradigm to early therapy,\u201d Nadeem said. \u201cThe approval of daratumumab last year signaled that the tide is shifting in this area. Now, the data we\u2019re seeing with cilta-cel adds to the momentum.\u201d<\/p>\n
Researchers in Spain are evaluating cilta-cel for patients with high-risk SMM who received induction with daratumumab (Darzalex, Janssen), lenalidomide, bortezomib and dexamethasone.<\/p>\n
Results of that investigation \u2014 coupled with the CAR-PRISM data presented at AACR \u2014 could lead to even more enthusiasm about the potential value of CAR-T and other immunotherapy approaches for high-risk smoldering myeloma, Ghobrial said.<\/p>\n
\u201cThat is when a person\u2019s T cells are at their best fitness, tumor burden is low and there is less clonal evolution, so it is probably the perfect time to use this type of therapy,\u201d she said.<\/p>\n
\u201cThis has been an amazing journey,\u201d Ghobrial added. \u201cWe owe so much to the 20 patients in our trial who took the risk to try something completely new, and it is so gratifying to see the amazing responses they have had. Hopefully in our lifetime we will see myeloma as a preventable disease. We want to be able to screen early, identify it early and treat it early so a person never develops active disease, never develops bone fractures and never has renal failure. Early interception is potentially the way to cure.\u201d<\/p>\n
For more information:<\/h2>\n
Irene Ghobrial, MD, <\/b>can be reached at irene_ghobrial@dfci.harvard.edu.<\/p>\n
Omar Nadeem<\/b>, MD,<\/b> can be reached at omar_nadeem@dfci.harvard.edu.<\/p>\n\n
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Perspective<\/h2>\n
Back to Top <\/p>\n
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Smoldering multiple myeloma (SMM) is a precursor disease known to progress to symptomatic multiple myeloma \u2014 with complications such as fractures, renal failure and more \u2014 all within a brief period. The mainstay of management for SMM has been mostly observation until recently, when the FDA approved daratumumab for the treatment of high-risk SMM.<\/default:p>In this phase 2 trial, a single infusion of cilta-cel was given to patients with high-risk SMM without induction or bridging chemotherapy. Cilta-cel has been approved for the treatment of adults with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, but it has not been approved for the treatment of SMM.<\/default:p>The CAR-PRISM trial showed a 100% ORR and an unprecedented level of MRD negativity (100%) achieved within 2 months, demonstrating a fast, deep and sustained response to cilta-cel. MRD negativity is usually associated with longer PFS to a given treatment and, in this case, longer time to progression to full-blown myeloma.<\/default:p>There is no question about the effectiveness of cilta-cel in SMM, but the toxicity profile is also critical to consider when using it in a larger population of patients with SMM. There has been no new safety signal observed in this trial. About one-third of patients (n = 7) experienced non-ICANS neurologic toxicities (NINTs), predominantly at doses greater than 0.5×10. Five events were low grade and only two patients had movement and neurocognitive treatment-emergent adverse events, suggesting a lower dose (0.3×106<\/default:sup>), which was later used in the trial, might reduce NINTs.<\/default:p>This is the first study of its kind using CAR T cells in a precursor disease, with an astounding level of sustained MRD negativity that might eventually lead to a cure. If validated in subsequent studies, it will be a paradigm shift for the treatment of precursor disease for multiple myeloma.<\/default:p><\/p>\n
\n Disclosures: <\/strong> Htut reports no relevant financial disclosures.
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Sources\/Disclosures<\/h3>\n Source: <\/h2>\n
Nadeem O, et al. Abstract CT103. Presented at: American Association for Cancer Research Annual Meeting; April 17-22, 2026; San Diego.<\/p>\n
References:<\/h2>\n\n
\n Disclosures: <\/strong>
\n Johnson & Johnson supported this study. Ghobrial is a founder of and holds private equity in Predicta Biosciences. She also reports consulting roles with or honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, GSK, Janssen, Kite Pharma, Pfizer, Takeda and other companies. Nadeem reports research funding from or advisory board roles with AstraZeneca, Bristol Myers Squibb, GPCR Therapeutics, Johnson & Johnson, Kite Pharma and Sanofi. He also reports his spouse has stock ownership in Sanofi. Please see the study for all other authors\u2019 relevant financial disclosures.
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