SPOTLIGHT: Cilta-Cel Shows Sustained MRD Negativity; Leads to Prolonged PFS in Multiple Myeloma

At the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, Yi Lin, MD, PhD, a hematologist and oncologist at Mayo Clinic in Rochester, Minnesota, shared findings from the phase 3 CARTITUDE-4 (NCT04181827) trial. In the study, ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor (CAR) T-cell therapy sold as Carvykti, showed a much longer progression-free survival than standard-of-care treatments. In an interview with The American Journal of Managed Care (AJMC), Lin said even more promising were the high rates of sustained minimal residual disease (MRD) negativity observed with cilta-cel, which translated to over 93% of patients remaining progression-free for more than 30 months.

AJMC: Can you provide a brief overview of the study?

Lin: CARTITUDE-4 is the phase 3 randomized controlled study comparing ciltacabtagene autoleucel or cilta-cel for patients with multiple myeloma against standard-of-care triplet options in patients who’ve had 1 to 3 prior lines of therapy. So, this trial already met its primary end point, which demonstrated that cilta-cel CAR T as a single infusion has a much-prolonged progression-free survival compared [with] standard-of-care options, and that led to the FDA approval for the use of this CAR T in earlier lines of therapy.

It is now approved for patients who have been treated with an IMiD [immunomodulatory drug] and a proteasome inhibitor and are refractory to lenalidomide and have had at least 1 prior line of therapy. Now, with the patients treated on [the] CARTITUDE-4 trial, we have continued to follow these patients for bone marrow MRD assessments, and we do know, with myeloma treatment, that if patients can reach that deep response—meaning we cannot detect this minimum residual disease in the bone marrow, that is sustained for at least 1 year—these patients can have an even longer progression-free survival period. And so that is what we are now seeing on this trial.

What we reported at ASH this year is that for the patients who are treated with cilta-cel on the CARTITUDE-4 study, the sustained MRD negative rate is much higher than the patient who received standard-of-care treatment; in fact, up to 6 times higher.1 We are seeing correspondingly [that] those patients treated with cilta-cel have reached this MRD negativity sustained for 1 year and longer. The majority of these patients, more than 93% of these patients, have remained progression-free for more than 30 months of follow-up. So, this is again speaking to the power of this CAR T treatment, that you can reach a very deep response with a single dose of treatment, and that can translate into a very long remission-free period for our patients.

AJMC: Given the significant MRD negativity rates observed with cilta-cel compared with standard of care, how do you see MRD negativity evolving as a surrogate end point in clinical trials for multiple myeloma, particularly in regulatory decisions or clinical practice?

Lin: Absolutely, that is a great question. I think many clinicians in
practice have recognized the importance of MRD negativity, and
particularly with CAR T therapy. That is something that can be seen early on after treatment. Of course, you know that needs to be followed to ensure that patients remain in MRD-negative status. So earlier this year, it was a landmark decision with the ODAC [Oncologic Drugs Advisory Committee] meeting that the FDA is now recognizing the utility of MRD status as an end point that could be used for fast-track designation clinical trials.²

So, that would allow us to say if a therapy has already demonstrated this MRD-negative status, and it could take longer for that benefit of prolonged PFS [progression-free survival], it could take longer for that to read out. We could use that MRD-negative status to consider for rapid approval of these therapies so that these can be more accessible for patients early on.
Now, of course, that is with the caveat that we need to continue with the definitive clinical trial to demonstrate the validity of this approach, but this is very important for our patients, especially, as I mentioned, if the benefit of the sustained MRD negativity could be [the] majority of these patients remaining in remission for close to 3 years or longer. We certainly don’t want to wait that long for those results to read out before we consider that for approval. So, I think this would be important in how we test novel therapies in our patient population.

AJMC: The study showed consistent MRD negativity benefits with cilta-cel across subgroups. Were there any specific patient characteristics or biomarkers that seemed to correlate with greater or lesser efficacy of cilta-cel, and how might this guide personalized treatment approaches?

Lin: At this time, we are seeing the benefit of cilta-cel with the prolonged progression-free survival for all patients [who] have these various high-risk features; for example, patients who may have high-risk cytogenetics or extramedullary disease, and so on. We have not yet identified, for example, a patient population that we would consider the CAR T to be potentially less beneficial. And so, if a patient is medically eligible to be considered for CAR T, we would say, please consider that at the earliest opportunity for that patient so that they can have this benefit of having a potentially very prolonged treatment-free period while staying in remission from multiple myeloma.

AJMC: Sustained MRD negativity at 12 months was a key finding. How does achieving sustained MRD negativity translate into real-world clinical benefits for patients, particularly regarding quality of life and long-term outcomes? Could this lead to adjustments in treatment duration or intensity?

Lin: The way that cilta-cel CAR T is currently approved for use in practice by the FDA is as a single-dose treatment with no maintenance therapy, and this is really the only class of treatment. CAR T is the only class of treatment in multiple myeloma that is currently approved to be given without some type of continuous treatment, even if patients are in remission. So, we have some results already reporting out from CARTITUDE-4 trials, showing that this can translate into benefits for quality of life.

As patients recover from some of the initial, very reversible [adverse] effects of CAR T, over the course of the year and longer, generally, there is an improvement in their quality of life. And so, I think it’s very important that we have this tool with MRD testing, [so] that we can reassure patients that we can monitor them for any potential risk of relapse, so they could continue without the need of adding any treatment, as long as they’re demonstrating this remission and enjoy that quality of life benefit that this therapy would bring.

References
1. Popat R, Oriol A, Cavo M, et al. Ciltacabtagene autoleucel (cilta-cel) vs standard of care (SoC) in patients with lenalidomide (len)-refractory multiple myeloma (MM) after 1-3 lines of therapy: minimal residual disease (MRD) negativity in the phase 3 CARTITUDE-4 trial. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Abstract 1032.
2. Seymour C. FDA’s ODAC recognizes MRD as an accepted end point for accelerated approval in multiple myeloma. OncLive. April 12, 2024. Accessed October 15, 2024. https://www.onclive.com/view/fda-s-odac-recognizes-mrd-as-an-accepted-end-point-for-accelerated-approval-in-multiple-myeloma