SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.
In patients with newly diagnosed Myeloma who are eligible for transplant, the optimal use of triplet/quadruplet induction regimens, Autologous Stem Cell Transplantation (ASCT), and REVLIMID® (Lenalidomide)-based maintenance, continues to evolve. In the IFM 2009 French trial, REVLIMID® maintenance treatment was admininstered for one year and after a median follow-up of 89.8 months, the median Progression Free Survival (PFS) was 47.2 months with RVd plus ASCT and 35 months with RVd alone, but there was no Overall Survival (OS) benefit.
DETERMINATION ((Delayed vs Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy) trial is a randomized Phase III trial, conducted to determine whether Autologous Stem Cell Transplantation (ASCT) enhances the efficacy of first line triplet induction therapy or whether it should be kept in reserve for select group of patients. In this study, 722 patients with symptomatic newly diagnosed Myeloma were enrolled. All patients received 3 cycles of RVd followed by stem cell mobilization (for possible ASCT if disease progressed). Patients were then randomly assigned to receive 5 additional cycles of RVd (RVd-alone arm, N=357) or Melphalan at 200 mg/m2, followed by ASCT and 2 additional cycles of RVd (RVd+ASCT arm, N=365). Each RVd cycle consisted of REVLIMID® 25 mg orally on days 1-14, VELCADE® (Bortezomib) 1.3 mg/m2 IV or SC on days 1, 4, 8, 11, and Dexamethasone given orally on days 1, 2, 4, 5, 8, 9, 11, 12, given as 21 day cycles. Dexamethasone was dosed at 20 mg/day for first 3 cycles and 10 mg/day for remaining cycles. Both treatment groups then received REVLIMID® maintenance at 10-15 mg orally daily, until disease progression or drug related toxicities. Both treatment groups were well balanced. The median age of enrolled patients was 56 years, approximately 14% of patients had ISS Stage III Multiple Myeloma and 18% had high-risk cytogenetics such as t(4;14), t(14;16), del17p. Approximately 19% of trial participants were African American, which is the highest representation of this subset of patients in any Phase III Myeloma trial. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Response Rates, Duration of Response (DOR), time to progression, Overall Survival (OS), Quality of Life, and Safety.
At a median follow up of 76 months, the median PFS was 46.2 months in the RVd alone group versus 67.6 months in the RVd plus ASCT group (HR=1.53; P<0.0001). The estimated 5-year PFS rates were 41.5% and 55.6% respectively. The 5 year Overall Survival was similar and not statistically different and was 79.2% and 80.7% respectively. The authors attributed the lack of Overall Survival in the RVd plus ASCT group to the availability of many highly effective treatment options now available after first-line therapy including salvage ASCT, next-generation immunomodulatory drugs, Proteasome Inhibitors, and monoclonal antibodies.
When evaluated by cytogenetic risk, for the standard risk group, the median PFS was 82.3 months in the RVd plus ASCT group versus 53.2 months in the RVd alone group, whereas for patients with high risk cytogenetics, the median PFS was 55.5 versus 17.1 months, respectively. Further, patients with t(4;14) derived more PFS benefit from RVd plus ASCT than those with del(17p). The PFS benefit with RVd plus ASCT was inferior among the African American enrollees and individuals with a Body Mass Index greater than 25 kg/m2.
Even though the Response Rates and quality of responses were similar between the two treatment groups, the Duration of Response was longer in the RVd plus ASCT group at 56.4 months, compared to 39.9 months in the RVd alone group.
More patients in the RVd plus ASCT group achieved MRD (Minimal Residual Disease) negativity compared to RVD alone (54.4% versus 39.8%), despite similar Complete Response Rates in both treatment groups. These MRD negative patients had favorable 5-year PFS, regardless of their treatment assignment. However, RVd plus ASCT improved PFS by 67% among the MRD positive patients.
Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without ASCT than with, at 78% versus 94% respectively. Secondary malignancies occurred in 10% of the RVd-alone group and 11% of the RVd plus ASCT group. Following RVd plus ASCT, 10 patients developed Myelodysplastic syndrome and/or Acute Myeloid Leukemia, compared with none in the RVd-alone group, and this was statistically significant (P=0.002).
The authors concluded that a combination of REVLIMID®, VELCADE® and Dexamethasone (RVd) plus ASCT as initial therapy followed by REVLIMID® maintenance until progression, demonstrated a significant improvement in PFS compared to RVd alone, followed by REVLIMID® maintenance, in patients with newly diagnosed Multiple Myeloma. There was no Overall Survival advantage observed to date. The researchers added that given the lack of benefit in OS and potential toxicities associated with ASCT, these data provide support for personalized treatment approaches, and helps patients make informed decision to delay transplant. Additionally, the significantly longer PFS for both treatment groups in the DETERMINATION study compared to the IFM 2009 (preplanned comparison), suggests that there is a clear benefit to continuous REVLIMID® maintenance until disease progression.
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. Richardson PG, Jacobus SJ, Weller E, et al. J Clin Oncol. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4
