Impact of residual clonal plasma cells in S-phase at the time of autologous stem cell transplantation on clinical outcomes

Autologous stem cell transplantation (ASCT) is a key therapeutic strategy for many patients diagnosed with multiple myeloma (MM), yet early relapses post-transplant remains a major clinical challenge. The plasma cell proliferation (PCPRO) test, which quantifies the proportion of clonal plasma cells in the bone marrow in S-phase (S-phase%) offers a scalable alternative to measuring their proliferation rate compared to the older plasma cell labeling index (PCLI) assay. The impact of the S-phase% in residual clonal plasma cells at the time of ASCT is not clear. We retrospectively analyzed MM patients undergoing an ASCT within one year of diagnosis at Mayo Clinic between January 2013-August 2024. The S-phase% was determined by multiparametric flow cytometry. Patients were grouped into S-phase <2%, ≥2%, or non-assessable, reflecting low numbers of clonal plasma cells at time of ASCT. Among 1,136 patients, 372 had an S-phase <2%, 142 had an S-phase of ≥2% and 622 had non-assessable S-phase. Patients with S-phase ≥2% had higher rates of high-risk cytogenetics, ISS stage III, and elevated creatinine. Median progression-free survival (PFS) and overall survival (OS) from time of ASCT were 26 months and 57 months for patients with S-phase ≥2%, compared to 47 months and not reached for those with S-phase <2%. (P < 0.0001 for both PFS and OS). Patients with non-assessable S-phase, had the most favorable outcomes. In conclusion, our results show that S-phase% at the time of ASCT is a significant prognostic marker in MM. Notably, patients with S-phase ≥5%, and especially ≥10%, had extremely poor outcomes (median PFS of 13 and 3.5 months, respectively), identifying a functionally high-risk group that may derive little or no benefit from standard ASCT. This poor prognostic factor should lead to consideration of alternative strategies including enrollment in clinical trials evaluating novel immunotherapies such as CAR T-cells or T-cell engagers as part of first-line therapy.