The addition of ASCT to triplet induction with lenalidomide, bortezomib, and dexamethasone (RVd) and lenalidomide maintenance resulted in significant PFS benefit versus RVd alone.
The treatment landscape in patients with newly diagnosed multiple myeloma eligible for transplant continues to evolve with the use of triplet/quadruplet induction, autologous stem-cell transplant (ASCT), and lenalidomide (R)-based maintenance therapy. The phase 3 IFM 2009 trial showed progression-free survival (PFS), but no overall survival (OS), benefit with R maintenance for 1 year with R, bortezomib, and dexamethasone (RVd) + ASCT induction versus RVd induction alone. DETERMINATION is a phase 3 trial that investigated the addition of ASCT to RVd induction treatment but allowed R maintenance to continue until disease progression. There were 2 arms; arm A consisted of RVd alone for a total of 8 cycles, the harvesting of stem cells, and R maintenance. Arm B consisted of the same RVd construct but with stem-cell collection, high-dose melphalan with ASCT support, RVd consolidation, then R maintenance. Both arms received maintenance R until disease progression or intolerance. The primary end point was PFS. Other end points included response rates, duration of response, time to progression (TTP), OS, quality of life, and safety.
A total of 357 and 365 patients were randomized to arms A and B, respectively. Patient demographics were well balanced and there was representation from many risk groups. In group A, 291 patients received R maintenance for a median duration of 36 months, and 289 patients in group B received R maintenance for a median duration of 41 months. Median PFS for RVd with early transplant was 67.5 months versus 46.2 months with RVd alone (P <.0001). Although there is a clear benefit with RVd and early transplant, this is the best PFS to date for both arms. Broadly, PFS benefit with early transplant was consistent across subgroups; however, there were differences in some specific patient subsets including cytogenetics, race, International Staging System (ISS) stage III, and body mass index. Interestingly, ISS stage III and high-risk cytogenetics groups showed less of a PFS benefit with early transplant, a concept that needs more understanding. TTP and event-free survival (EFS) also favored early transplant with a 5-year TTP of 58.4% with RVd and transplant versus 41.6% with RVd alone (P <.001) and a median EFS of 47.3 months versus 32.0 months. Between both arms, the overall response rates were similar and not statistically significantly different; however, duration of response favored early transplant (38.9 months vs 56.4 months, P = .003). In a preliminary analysis of minimal residual disease (MRD) including 108 patients with RVd alone and 90 patients with RVd + ASCT, the rate of MRD negativity was 39.8% with RVd alone versus 54.4% with early transplant. In patients who achieved MRD status, the 5-year PFS was similar in both arms, 59.2% with RVd alone versus 53.5% with RVd + ASCT. There was no difference in overall survival between the 2 arms; however, further follow-up is needed. Additionally, only 28% of patients in the RVd-alone arm received ASCT as salvage therapy following the end of study treatment. All grade ≥3 and hematologic grade ≥3 treatment-related adverse events during treatment were significantly higher with RVd + ASCT. Rates of secondary malignancies were similar between the 2 groups: 10% of patients with early transplant versus 11% with RVd alone.
RVd + ASCT demonstrated significantly superior PFS benefit compared to RVd alone, and both arms demonstrated the longest PFS to date. There was no OS benefit seen with early transplant; however, further follow-up is warranted. The DETERMINATION trial demonstrated the clinical benefit of R maintenance until progression and reaffirms ASCT as standard of care.
Reference
- Richardson PG, Jacobus SJ, Weller E, et al. Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): the phase 3 DETERMINATION trial. Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7; Chicago, IL. Abstract LBA4.