Cilta-cel CAR T: Myeloma ‘Cure' and Conjecture

Medscape

3 days ago

Not a day goes by in clinic without a patient asking about the recent New York Times article on multiple myeloma: "Doc, is there really a cure now? I want this treatment." The article was boldly titled "From No Hope to a Potential Cure for a Deadly Blood Cancer." But did we truly leap from "no hope" to "potential cure"?
In this commentary, I explore what the article got right, where caution is warranted, and how I think about the notion of a cure for myeloma.
Manni Mohyuddin, MD
Historically, patients with heavily pretreated, relapsed myeloma had grim prognoses, often with less than a year of survival. The arrival of BCMA- and GPRC5D-directed therapies has rewritten expectations for this population. Cilta-cel, a BCMA-targeted chimeric antigen receptor (CAR) T-cell product, is a standout.
A recent long-term follow-up study in Journal of Clinical Oncology (JCO) reported that one third (32 of 97) of patients remained progression-free 5 years after a single cilta-cel infusion. It's a remarkable outcome, one worthy of celebration, yet we must interpret these results with care.
Of the 113 enrolled patients, only 97 received cilta-cel, and only the outcomes of those 97 are described, with the unfortunate ones whose disease progressed before cilta-cel infusion omitted from this narrative. Patients with rapidly progressing or unstable disease often don't make it to CAR T — a natural selection bias.
Moreover, heavy censoring at the tail end of the Kaplan-Meier survival curve, a statistical method used to track patient outcomes over time, and where many patients drop out or are lost to follow-up, introduces uncertainty about what the results will be with even longer follow-up. A real-world study of cilta-cel showed 12-month progression-free survival (PFS) at just 68%, making it unlikely that we will see such outcomes with 5 years of follow-up in the real world, and highlighting the gap between clinical trial efficacy and real-world effectiveness.
This discrepancy is not new. The MAIA study reported a median PFS beyond 5 years for newly diagnosed patients treated with daratumumab, lenalidomide, and dexamethasone (DRd). Yet, in real-world cohorts, PFS is closer to 2-3 years. Differences in censoring, progression definitions, and patient selection drive this gap.
Given these dynamics, a 30% five-year PFS in real-world practice for this patient population seems unlikely. While some patients, perhaps 10%-15%, may experience truly durable responses, presenting the trial's cure fraction as broadly achievable would be misleading.
The word "cure" featured prominently in both the JCO publication and the New York Times article. However, the most recent definition of cure in myeloma includes sustained measurable residual disease (MRD) negativity off all therapy for at least 5 years. When asked, patients have clearly indicated that they do not consider themselves cured while still on treatment (as is often the case in myeloma), no matter what the disease response is. I celebrate this trial for many reasons, but one important one is that it gave patients such valuable time off from treatment.
However, during long-term follow-up of this trial, MRD negativity was not routinely assessed. At one center, 12 patients were evaluated serially and found to be MRD negative. But this was a post hoc analysis, and data from other centers weren't reported. Given the nuanced ways that relapse is defined in myeloma (with markers having to be above a certain threshold), we must be cautious in declaring these patients cured.
Some of them may already have signs of relapse that has not yet reached a certain threshold to call it as progression. I also must admit to feeling distressed that a top-notch journal allowed the authors to make such bold statements based on post hoc analysis from a single center. Such post hoc data mining — where researchers look for patterns after seeing the results — carries a high risk for false discoveries and should not support definitive claims about cure.
The article implies that these long-term remissions and cure are unprecedented. That's simply not true. Long-term follow-up from studies using intensive upfront therapy have shown that many patients — especially those with standard-risk disease — achieve long remissions, are off treatment, and remain alive for years. To claim that we've gone from "no hope" to "potential cure" neglects this important context. Myeloma had seen sustained, incremental progress across multiple drug classes well before cilta-cel emerged.
Cilta-cel is a powerful therapy, but it is not without risk — something the article omits. It has horrendous, unpredictable toxicities that were not mentioned in the New York Times article. These include secondary cancers, a horrible diarrhea due to immune-mediated gut damage, and often irreversible neurologic damage. Thankfully, these are not experienced by the majority of patients, but we are imperfect at predicting to whom they do happen, and many of these toxicities are currently permanent.
Despite these critiques, I view the New York Times story as a net positive. It raises awareness about the progress we've made and offers patients hope. I do believe we are curing some patients with myeloma, and cilta-cel is part of that story. However, the 30% cure rate cited in the article is probably an illusion among such a heavily pretreated population (although I am hopeful for an even higher cure rate in the newly diagnosed setting).
I envision a future with safer therapies that more reliably increase the cure fraction. And while I appreciate how this article shined a spotlight on myeloma, I hope that future media coverage embraces the nuance that this disease — and its patients — deserve.