Daratumumab, Lenalidomide, and Dexamethasone for High-Risk Smoldering Multiple Myeloma

STUDY TITLE: Daratumumab to Enhance Therapeutic Effectiveness of Revlimid in Smoldering Myeloma (DETER-SMM)

CLINICAL TRIALS.GOV IDENTIFIER: NCT03937635

PARTICIPATING CENTERS: All Eastern Cooperative Oncology Group–ACRIN Cancer Research Group (ECOG-ACRIN) sites and National Clinical Trials Network (NCTN) organizations: Alliance for Clinical Trials in Oncology, Southwest Oncology Group (SWOG), NRG Oncology, and Canadian Cancer Trials Group

SPONSOR: ECOG-ACRIN in collaboration with National Cancer Institute

ACCRUAL GOAL: 288 participants

STUDY DESIGN: DETER-SMM is a randomized phase III clinical trial designed to examine the efficacy of daratumumab, lenalidomide, and dexamethasone (DRd) compared with lenalidomide and dexamethasone (Rd) in high-risk smoldering multiple myeloma (SMM). Patients must be diagnosed with asymptomatic high-risk SMM within the previous 12 months. “High risk” is defined by the presence of two or more of the following factors:

• Abnormal serum–free light-chain (FLC) ratio of involved-uninvolved that is greater than 20 but less than 100 if the involved FLC is greater than or equal to 10 mg/dL by serum-FLC assay

• Serum M-protein level greater than or equal to 2 g/dL

• Presence of t(4;14) or del 17p, del 13q, or 1q gained by conventional cytogenetics or fluorescence in situ hybridization studies

• Greater than 20 percent plasma cells on biopsy or aspirate.

Patients must not have any features of active MM with or without end-organ damage, as defined by the International Myeloma Working Group (IMWG).¹  Patients will be randomized to either DRd (experimental arm) or Rd (control arm) to receive treatment up to two years in the absence of disease progression or unacceptable toxicity. The primary end points of the study are overall survival and the Functional Assessment of Cancer Therapy-General (FACT-G) score. The secondary end points include progression-free survival, best response by IMWG criteria,²  safety profile, stem cell mobilization failure, early stem cell mobilization feasibility, FACT-G score levels, and trends throughout the course of the study treatment.

RATIONALE: SMM is defined by 10 to 60 percent clonal plasma cells in the bone marrow biopsy, typically an M-protein measuring less than 3 g/dL, and absence of any myeloma-defining events.¹  From a disease evolution standpoint, the malignant plasma cells in SMM are biologically similar to those of active MM in terms of cytogenetic abnormalities. However, some patients may progress to active MM sooner than others, predicated by immune surveillance exhaustion, immune paresis, and increasing disease burden. Several groups have defined this group as being at “high risk” of progression to active MM, with the most recent IMWG effort³  defining this risk based on M spike value (either < or ≥ 2 g/dL), bone marrow plasmacytosis (either < or ≥ 20%), and serum FLC ratios (either < or ≥ 20). There are two randomized phase III trials (QUIREDEX and ECOG E3A06) that have demonstrated that early intervention with lenalidomide (+/- dexamethasone) in high-risk SMM delays risk of progression to active MM and end-organ damage when compared with observation.^4,5  DETER-SMM is a follow-up phase III trial to the ECOG E3A06 trial, with the goal of further improving outcomes in patients with high-risk SMM.

COMMENT: Many in the field continue to debate about the timing and optimal treatment approach for high-risk SMM. Studies examine approaches to delay progression to active MM using single agents or in combination with dexamethasone,^4-7  as well as approaches similar to those used for active MM, incorporating three to four drug induction/consolidation regimens with and without high-dose melphalan/autologous stem cell transplantation^8-10  with curative intent. Building on results from early intervention studies of QUIREDEX and ECOG E3A06, DETER-SMM is a randomized phase III trial comparing the triplet regimen DRd to the doublet regimen Rd with a fixed duration of treatment for the management of high-risk SMM, using the 2020 IMWG risk stratification definition with a primary end point of overall survival and functional assessment score.

Currently, there is no clear consensus regarding the optimal management of patients with high-risk SMM. Given the evolving definition of MM and the heterogeneity of definitions for high-risk SMM in clinical trials, cross-trial comparisons and the development of evidence-based guidelines have been challenging. Clinical trial enrollment remains the recommended approach for these patients. Dynamic models, based on markers repeatedly assessed during monitoring, may help better predict risk progression to MM and help ensure selection of patients who are truly at high risk of progression, for clinical trial enrollment. Results of DETER-SMM and other clinical trials are eagerly awaited and may provide clarity and shape future treatment approaches for patients with high-risk SMM.