Friday, September 22, 2023

Long-term outcomes of allogeneic stem cell transplant in multiple myeloma – Blood Cancer Journal

This study demonstrates overall poor survival outcomes in patients who underwent allo SCT for treatment of multiple myeloma with long-term survival ( >5 years) being achieved in less than 25% of patients. Nearly 75% of patients experienced disease progression or death by 2 years, and 1-year TRM was high at 22.2% Despite this, a subgroup of patients entered a durable remission after receiving an allo SCT, potentially constituting a cure. Those who saw particular benefit from allo SCT were more likely to have been in complete remission at time of allo SCT, had only one previous auto SCT, and to have undergone their allo transplant in the early 2000s. In all, allo-SCT as a treatment for multiple myeloma was minimally beneficial outside of a select few patients.

5-year OS following allogeneic transplant was poor at 22.2% with a cohort size of 85 patients and a long median follow-up of 11.5 years. As demonstrated by Fig. 1, there was a rapid survival decline immediately following transplant that did not plateau until roughly four years post-transplant and did not entirely stabilize until eight years post-transplant. 5-year PFS was 15.1%. Cumulative 1-year TRM was high at 23.5% (N = 20), exceeding the number of “cured” patients who survived 10+ years (N = 12). The largest study to examine allo SCT in MM was conducted by the Bone Marrow Transplant Clinical Trials Network (BMT CTN), and found 3-year OS and PFS to be 77% and 43%, respectively, with a TRM of 11% [23] for patients who underwent allo SCT as upfront therapy. Our overall cohort demonstrated considerably worse outcomes for the same timepoints with 3-year OS and PFS being 37.9% and 22.0%, respectively.

It is important to note that the findings of the BMT CTN study represent allogeneic transplant as upfront treatment (auto SCT to RIC allo SCT) in a group of individuals primarily with standard-risk cytogenetics and partial-response or better to previous therapy. Conversely our data represented a heterogenous and highly challenging population usually at a salvage point, with over 75% having at least 3 previous lines of therapy, and over 30% of patients in active progression at the time of transplant. The poorer survival outcomes in our study were not unexpected, given the prolonged disease history and more extensive prior therapies. Even when examining the few among our cohort who underwent auto SCT to RIC allo SCT as upfront therapy (N = 3), OS and PFS were 33% and 19%, respectively, considerably lower than the BMT CTN study.

As such, our findings more closely align with those from studies examining allo SCT as salvage therapy. Numerous studies have been conducted over the years with considerable variability in survival findings depending on pretransplant disease and patient characteristics, with estimated 2-year OS and PFS between 32–54% and 19–42%, respectively [12, 24, 25], and estimated 5-year OS and PFS between 14–26% and 2–20%, respectively [12, 24,25,26,27]. The largest allo SCT MM salvage study [28], with 413 patients, found a 5-year OS of 30% with a cumulative 1-year TRM of 21.5%, with no apparent plateau in the survival curves.

With a median follow-up of 11.5 years, our study provides unique insight into the long-term outcomes of allo SCT in MM patients. Extended follow-up revealed an OS plateau at eight years following allo SCT, with roughly 15% of patients (N = 12) surviving beyond 10 years, representing a potentially cured subgroup. Descriptive examination of patient and disease characteristics among this set of “long-term” survivors reveals them to have a higher proportion of individuals with no or one previous auto SCT, and allo SCT date between 2000 and 2010. Those receiving heavy pretreatment likely had a more aggressive or advanced disease at time of allo SCT. Regarding transplant dates, allo SCT was more commonly used as upfront therapy in the 2000s, whereas by the 2012 over two-thirds of allo SCT’s were performed as salvage therapy for progressive disease due to the advent and increased usage of novel therapeutics [7]. Of note, any patients in this study who underwent allo SCT in May 2012 or beyond had not been followed long-enough to reveal a 10-year survival at the time of analysis (May 2022). Six patients among the allo-SCT 2011-to-present analysis group were still alive at the time of analysis, five of whom underwent allo SCT from 2019 onward, and one who underwent allo SCT in 2014.

Finally, among the entire cohort, univariate analysis for prognostic factors in survival showed patients with disease progression at the time of allo SCT did poorly, the presence of chronic GVHD conferred a survival benefit, and the presence of two prior auto SCT’s conferred a survival detriment. Though this could represent the previously described survival advantage of mild cGVHD [6], it may indicate survival bias toward a subset of patients who survived long enough to develop cGVHD. Our study’s finding that two prior auto SCT’s is associated with worsened OS and PFS likely reflects the trend that patients who are heavily pre-treated, in general, have more aggressive or advanced disease and are at higher risk of mortality.

This study should be interpreted in the context of several strengths and limitations. The cohort was quite racially/ethnically homogenous with most participants identifying as White. Future studies should aim to include a more diverse and ethnically representative cohort. Furthermore, small numbers among some patient characteristic subgroups limited the power of statistical analyses. Notwithstanding these limitations, the long median follow-up of this study allowed for examination of the extended outcomes and the ability to rely on the higher accuracy of observed, rather than estimated, OS and PFS. Additionally, the cohort size of 85 provides a relatively large series among these patients [29].

In conclusion, allogeneic transplant poses a therapeutic dilemma for myeloma clinicians. Particularly as salvage therapy, allo SCT has poor outcomes. It is curative for a small subset of patients, however, the patient, treatment, and disease characteristics that predispose those in this subgroup to favorable long-term outcomes remain ill-defined. Unfortunately, the curative potential of allo SCT is tempered by poor OS, poor PFS, and a high TRM that exceeded the “cure” rate among the rest of the observed patients. The benefit of allo SCT may be tremendously high—a potential cure—but the risk is even higher. With an expanding array of anti-CD38, BiTE, and other novel therapeutics, we would expect better overall outcomes and tolerability of these agents compared to allo SCT and, if available, would prefer them to allo SCT.

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