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.
High Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT) remains an important treatment option for transplant eligible patients. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction treatment can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time.
The role of consolidation treatment for newly diagnosed, transplant-eligible patients with multiple myeloma has not been conclusively established and needed prospective evaluation. The present prospective clinical trial was conducted to study the relevance of consolidation therapy using Bortezomib, Lenalidomide, and Dexamethasone (VRD) followed by Lenalidomide maintenance, compared with Lenalidomide maintenance alone, in transplant-eligible newly diagnosed multiple myeloma patients.
The EMN02/HOVON95 trial is an open-label, Phase III study, performed by the European Myeloma Network (EMN) in which 1197 previously untreated transplant-eligible patients with symptomatic Stages I-III Multiple Myeloma were randomly assigned initially to four cycles of Bortezomib, Melphalan, and Prednisone (VMP) or High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT). Within 2 months after ASCT or last VMP treatment, 878 eligible patients underwent a second randomization to either two 28-day cycles of VRD consolidation treatment, which consisted of Bortezomib 1.3 mg/m2 either IV or SC once daily on days 1, 4, 8, and 11, combined with Lenalidomide 25 mg orally once daily, days 1-21 and Dexamethasone 20 mg orally once daily, on days 1, 2, 4, 5, 8, 9, 11, and 12 (N=451 – Arm B) or no consolidation (N=427 – Arm A). Patients then received Lenalidomide maintenance 10 mg orally once daily on days 1-21 of a 28-day cycle, starting 1-2 months after ASCT or consolidation, and treatment was continued until disease progression or toxicity. The Primary end point was Progression Free Survival (PFS) defined as time from second randomization to disease progression or death. Secondary end points included Partial Response or higher, Overall Survival (OS) from second randomization until death from any cause, and toxicity. Predefined high-risk prognostic subgroups for PFS were cytogenetic abnormalities defined by FISH and included deletion (17p) in 20% or more of enriched plasma cells, t(4;14) in 10% or more of enriched plasma cells, t(14;16) in 10% or more of enriched plasma cells; and amplification 1q. This was in addition to the standard clinical variables such as Hemoglobin level, Serum Creatinine and LDH. Disease assessment was performed before and after consolidation and every 2 months until progression. Bone marrow Minimal Residual Disease (MRD) assessment was performed by multicolor flow cytometry in bone marrow with a detection of 10−4 to 10−5.
At a median follow-up of 74.8 months after the second randomization, the median PFS was significantly prolonged in the VRD consolidation group, compared those who did not receive consolidation treatment (59.3 versus 42.9 months, HR=0.81; P=0.016). This PFS benefit was observed across most predefined subgroups, including Stage, standard-risk cytogenetics, and prior treatment groups. VRD consolidation was however not beneficial in patients with del(17p). Stage III disease and addition of chromosome 1q by FISH at diagnosis were significant adverse prognostic factors for PFS from second randomization. The median duration of maintenance treatment with Lenalidomide was 33 months. Complete Response (CR) or more after consolidation versus no consolidation, and before start of maintenance treatment was 34% versus 18%, respectively (P<0.001). Complete Response or more on protocol including maintenance treatment was 59% with consolidation and 46% without consolidation (P<0.001). Minimal Residual Disease analysis in a subgroup of 226 VRD-consolidated patients with CR or stringent CR or Very Good Partial Response before start of maintenance treatment demonstrated a 74% MRD-negativity rate. Toxicities related to VRD consolidation were acceptable and manageable.
It was concluded from this study that consolidation followed by maintenance treatment after either Bortezomib, Melphalan and Prednisone or High-Dose Melphalan and Autologous Stem Cell Transplantation, significantly improves Progression Free Survival and Overall Response Rate in transplant-eligible and Lenalidomide-naïve newly diagnosed patients with Multiple Myeloma, compared to maintenance treatment alone.
Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. Sonneveld P, Dimopoulos MA, Beksac M, et al. J Clin Oncol. 2021;39:3613-3622.