Is that a tail? Updated results from CARTITUDE-1 in multiple myeloma

Many exciting updates in chimeric antigen receptor T-cell (CAR-T) therapy are being presented at the 2024 ASTCT / CIBMTR Tandem Meeting in San Antonio this week. Tonight in the exhibit hall, look for a compelling poster (#515) by Dr. Yi Lin of Mayo Clinic and her co-investigators regarding the CARTITUDE-1 trial. The CARTITUDE-1 trial investigated ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy that led to the drug’s US approval in February 2022 for patients with relapsed or refractory multiple myeloma (MM).

This trial enrolled heavily pre-treated patients with MM: 82% of patients had received 4 or more prior lines of therapy, while 88% were triple-class refractory to commonly used myeloma drugs like daratumumab, bortezomib, and lenalidomide. The last major publication regarding this trial’s key endpoints came with a median of 27 months of follow-up in June 2022, at which time estimated progression-free survival (PFS) was 54.9% and overall survival (OS) was 70.4%.

So what updates are we getting at the 2024 ASTCT Tandem Meeting? Now, with a median follow-up approaching 3 years, median PFS was 34.9 months while 3-year OS was 62.9%. Remarkably, of course, this is for a “one-and-done” CAR-T infusion with continued supportive care but no planned anti-MM therapy. We also see the Kaplan-Meier curves for PFS and OS below (figures used with permission):

At first glance, the OS curve seems to resemble a tail – meaning that patients who are event-free beyond a certain point subsequently remain event-free. Myeloma physicians and patients alike have long wished for a tail to our curves, similar to what is seen with lymphoma and other cancers thought to be curable in certain cases. Here, unfortunately, it’s not so simple. The sample size of eligible patients with 3 or more years of follow-up is small, and the corresponding PFS curve shows no signs of a tail. This suggests that patients continue to have MM relapses on CARTITUDE-1 with continued follow-up, although perhaps advances in new treatments (or the ability to recycle old myeloma treatments) means that they are able to stay alive.

Dr. Lin and colleagues do elegantly present correlative analyses that predict responses to cilta-cel. Some factors are unsurprising in light of what we know now about CAR-T therapy, for example that high baseline inflammation predicted poorer responses. We have long suspected that effector-to-target ratios matter with immunotherapies depending on the disease and dose range, and cilta-cel was no exception: in CARTITUDE-1, a higher ratio of CAR T-cell concentration (at its peak) divided by soluble BCMA levels predicted longer PFS.

One relatively novel finding for BCMA CAR-T therapy in myeloma was the presence of unique CAR-transduced T-cells that affected response durability. Higher numbers of stem-like CD8+ T-cells (cytotoxic CAR T-cells) were associated with longer responses, while higher numbers of CD4+ FOXP3+ regulatory T cells (CAR-positive T_reg cells) were significantly associated with shorter responses. Dividing the proportions of CAR-positive T_reg cells into two groups by their median, for example, showed dramatic differences in outcomes. The median PFS was less than one year for patients with higher numbers of CAR-positive T_reg cells; in contrast, for patients with lower numbers of CAR-positive T_reg cells, 3-year PFS exceeded 80%! This matches similar conclusions seen with T_reg cells with CD19-directed CAR-T therapy in lymphoma.

So what’s Dr. Lin’s take on this work? Her response: “The chase for the ‘tail’ on the cure may not be so elusive. The close-out analysis demonstrated impressive sustained remission for a single-dose treatment in a patient population who were heavily pretreated. The correlates for prolonged PFS give us actionable insights such as getting patients to treatment early in relapse, when disease burden would be low, and for therapeutic development of an even more potent CAR-T product.”

In conclusion, while there is admittedly no tail to be found on this poster at the 2024 ASTCT meeting, there is quite the tale: namely, a tale of two T-cell lineages and their dramatic impacts on long-term outcomes with CAR-T therapy in MM. Come stop by Dr. Lin’s poster tonight to learn more!