A large, randomised, phase III DETRMINATION study investigated the effect of adding autologous stem-cell transplantation (ASCT) to triplet treatment of lenalidomide, bortezomib, and dexamethasone (RVD), followed by lenalidomide maintenance treatment until disease progression in adult patients with newly diagnosed multiple myeloma. RVD plus ASCT was associated with longer progression-free survival (PFS) than RVD alone with a significant 21.3-month benefit in median PFS and a 35% lower risk of disease progression or death. However, no overall survival (OS) benefit was observed. Dr. Paul G. Richardson of the Department of Medical Oncology, Dana–Farber Cancer Institute in Boston, MA, US and colleagues, who published the study results in The New England Journal of Medicine along report during the ASCO 2022 Annual Meeting, concluded that in the absence of a demonstrated OS benefit and in the context of considerations regarding real-world factors such as treatment burden, acute and long-term side effects, patient preference, and quality-of-life, the study findings may be taken into account when making treatment decisions.
The authors wrote in the study background that most appropriate use of induction treatment, ASCT, and maintenance treatment for patients with newly diagnosed multiple myeloma, who are eligible to undergo ASCT, continues to evolve. The IFM 2009 study, in which patients received induction treatment with RVD alone or with high-dose melphalan plus ASCT, followed by lenalidomide maintenance for 1 year, showed superior PFS with the use of ASCT. These findings provided support for the benefit of ASCT in patients with newly diagnosed myeloma. In that study, in which patients had multiple effective treatment options at relapse and in which many received ASCT after RVD alone, no OS benefit of RVD plus ASCT was evident after a median follow-up of more than 7 years.
The phase III DETERMINATION study was originally designed as a parallel study to the IFM 2009, but it was amended to include the use of lenalidomide maintenance treatment until disease progression in both the RVD alone and the RVD plus ASCT arm. In this study, patients with symptomatic myeloma received one cycle of RVD and then were randomly assigned in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilisation, followed by either five additional RVD cycles or high-dose melphalan plus ASCT followed by two additional RVD cycles. Both arms received lenalidomide until disease progression, unacceptable side effects, or both. The study primary endpoint was PFS.
At a median follow-up of 76.0 months, 328 events of disease progression or death occurred among 357 patients in the RVD alone arm and 365 patients in the transplantation arm. The risk was 53% higher in the RVD alone arm than in the transplantation arm (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.23 to 1.91; p < 0.001). Median PFS was 46.2 months and 67.5 months, respectively.
The percentage of patients with a partial response or better was 95.0% in the RVD alone arm and 97.5% in the transplantation arm (p = 0.55) and 42.0% and 46.8% patients had a complete response or better (p = 0.99). Five-year survival was 79.2% and 80.7% with HR for death 1.10 (95% CI 0.73 to 1.65). The study team conducted preplanned subgroup analyses that showed HRs for disease progression or death ranging from 0.96 to 3.40 for the comparison of RVD alone with RVD plus ASCT. However, the study was not powered to evaluate PFS in patient subgroups, and no definitive interactions were identified for any subgroup category.
Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively. In DETERMINATION study, the 5-year cumulative incidence of second primary haematologic malignancies was 1.6% with RVD alone, as compared with 3.5% with RVD plus ASCT and the respective incidences in the IFM 2009 study were 0.6% and 1.4%.
The authors concluded that DETERMINATION study showed the superiority of ASCT-based first-line treatment with respect to PFS among eligible patients with newly diagnosed myeloma, findings that confirm those of the IFM 2009 study. The results also highlight the value of long-term lenalidomide maintenance treatment until disease progression. However, despite a median follow-up of more than 6 years in DETERMINATION study, approximately one quarter of the patients had died, and given the lengthy median OS among patients in this population in general, there was no OS advantage of RVD plus ASCT over RVD alone.
The authors commented that the lack of OS benefit for RVD plus ASCT is probably associated with multiple, highly efficacious options available after first-line treatment that have emerged over the past 10 years. Personalising decision-making regarding treatment is important for patients with multiple myeloma, a heterogeneous population with heterogeneous disease who have differing treatment preferences and needs. Numerous patient-related and myeloma-related factors can affect treatment outcomes.
Further investigations are under way to evaluate outcomes according to cytogenetic risk and specific genetic abnormalities, given preliminary whole-genome sequencing analyses suggesting lower response rates associated with the presence of 17p deletion and TP53 mutations and the known association of 17p deletion with impairment of the tumour suppressor p53, an impairment that confers resistance to chemotherapy. An evaluation of the study findings in Afro-American patients, who composed almost 20% of the study population, and other racial subgroups is under way to understand any differences that may mediate differential outcomes. Evaluations of the study findings according to body mass index are also under way, given the effect of obesity on the pathobiologic features of myeloma and the side-effect profile of intensive treatment.
The study was supported by grants from the US National Heart, Lung, and Blood Institute, the US National Cancer Institute, the US National Institutes of Health, Celgene-Bristol Myers Squibb, Takeda Pharmaceuticals, the Dana-Farber Cancer Institute, and the R.J. Corman Multiple Myeloma Research Fund.
Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med 2022; 387:132-147.