RVd ± ASCT and R Maintenance to Progression for NDMM: Results from the DETERMINATION Trial

The treatment landscape in patients with newly diagnosed multiple myeloma (NDMM) eligible for earlier transplant continues to evolve with the use of triplet/quadruplet induction, autologous stem-cell transplantation (ASCT), and lenalidomide (R)-based maintenance therapy. An earlier trial by Attal and colleagues (the IFM 2009 Study) showed progression-free survival (PFS) benefit but no overall survival (OS) benefit with R maintenance for 1 year and lenalidomide, bortezomib, and dexamethasone (RVd) plus ASCT versus RVd alone.¹ At the 2022 American Society of Clinical Oncology conference, Richardson presented primary data from the DETERMINATION trial.² The DETERMINATION trial was originally a parallel study to the IFM 2009 Study; however, the protocol was amended and R maintenance was continued until disease progression.

DETERMINATION consisted of 2 arms: arm A patients (n = 357) received 3 RVd cycles, stem-cell mobilization, 5 more RVd cycles, followed by R maintenance; arm B patients (n = 365) received 3 RVd cycles, intravenous melphalan 200 mg/m² + ASCT, 2 more RVd cycles, followed by R maintenance. Both arms received maintenance R until disease progression or intolerance. The primary end point was PFS. Other end points included event-free survival (EFS), response rates, duration of response (DOR), time to progression (TTP), OS, quality of life, and safety.²

Patients in the 2 arms were well-balanced, and there was representation from many high-risk groups, including 14% (arm A) and 13% (arm B) with International Staging System stage III MM. A total of 291 patients in group A 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.²

A favorable PFS was seen for RVd with early transplant: median PFS of 67.5 months, compared with 46.2 months with RVd alone. For both arms, this is the best PFS reported to date; however, a clear benefit is seen with RVd and early transplant. Nearly all hazard ratios favored RVd with early transplant in preplanned subgroup analyses of PFS. TTP and EFS also favored early transplant: 5-year TTP was 58.4% with RVd and early transplant, compared with 41.6% with RVd alone; and median EFS was 47.3 months, compared with 32.0 months, respectively. Between both arms, the overall response rate was similar and not statistically significantly; however, DOR favored early transplant. A preliminary analysis of minimal residual disease (MRD) in 108 patients with RVd alone and 90 patients with RVd plus ASCT yielded an MRD-negativity rate of 39.8% with RVd alone, compared with 54.4% with early transplant. In patients who achieved MRD-negative status, the 5-year PFS was similar in both arms, 59.2% with RVd alone, compared with 53.5% with RVd plus ASCT. No difference in OS was seen between the 2 arms; however, further follow-up is needed. In addition, only 28% of patients in the RVd-alone arm received ASCT as salvage therapy following the end of study treatment.²

All grade ≥3 and hematologic grade ≥3 treatment-related adverse events during treatment were significantly higher with RVd plus ASCT (P <.001). Rates of secondary malignancies were similar between the 2 groups, 10.4% (RVd alone) versus 10.7% (RVd plus ASCT). Difference in mean change from baseline in the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire) global health status scores were similar across the 2 arms throughout treatment except at RVd cycle 5 following ASCT. Whole-genome sequencing, additional quality of life, and correlative analyses are ongoing.²

These results show that RVd plus ASCT offers significantly superior PFS compared with RVd alone, the longest seen to date with RVd-based treatment approaches. No OS difference was seen, however, after median follow-up of >6 years, underscoring the need for a personalized treatment approach with both options available to patients.

References

1. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320.
2. 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: American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL.