Study Title: Phase III Study of Daratumumab/rHuPh20 plus Lenalidomide or Lenalidomide as Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Multiple Myeloma Using Minimal Residual Disease to Direct Therapy Duration (DRAMMATIC Study, S1803)
Clinicaltrials.Gov Identifier: NCT04071457
Sponsor: Southwest Oncology Group (SWOG) in collaboration with the National Cancer Institute
Accrual Goal: 1,100 participants
Participating Centers: All SWOG sites and National Clinical Trials Network (NCTN) organizations: Eastern Cooperative Oncology Group (ECOG), Alliance for Clinical Trials in Oncology, Blood and Marrow Clinical Trials Network (BMTCTN), NRG Oncology, and Canadian Cancer Trials Group
Study Design: S1803 is a randomized phase III clinical trial designed to examine the efficacy of daratumumab/rhuph20 (the subcutaneously administered form of the drug) and lenalidomide or lenalidomide alone as a maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT) in adult patients (age ≥ 18–75 years) with multiple myeloma (MM).
Patients with MM who are within 12 months of ASCT and without progression from diagnosis are eligible. Patients may enroll any time after induction (registration step 1) prior to or after ASCT, but prior to registration step 2 and with ASCT being within 18 months of initial registration. Patients will undergo first randomization within 180 days of ASCT to lenalidomide or daratumumab/rhuph20 and lenalidomide for two years. Minimal residual disease (MRD) will be assessed using next-generation sequencing (NGS) at baseline and then annually. After two years of maintenance, MRD is assessed in patients with very good partial response or better to guide the treatment. Patients who are MRD negative (< 10−5) will undergo second randomization (registration step 3) to either continue maintenance on their assigned arm or discontinue maintenance. Patients who are MRD positive (≥ 10−5) will continue the assigned maintenance for seven years or until disease progression or unacceptable toxicity.
The primary objective of the trial is to compare the overall survival (OS) between primary treatment arms (daratumumab/rhuph20 and lenalidomide vs. lenalidomide). Secondary objectives include comparisons of progression-free survival (PFS), overall response rates, and MRD negativity rates between the treatment arms. The objectives of second randomization are to compare the OS of MRD-negative patients who continue in each arm versus those who discontinue. All randomized patients who have initiated treatment will be considered evaluable for toxicity analysis. Finally, the additional objective would include the 24-month MRD analysis as early as 24 months after all patients have been accrued.
Rationale: The outcomes of patients with MM have changed significantly in the past two decades with the development of proteasome inhibitors, immunomodulators, and monoclonal antibodies.1 High-dose therapy followed by ASCT remains the standard treatment for eligible patients even in the context of modern therapy2 and has been associated with improvements in depth of response, PFS, and OS in some studies.3 Further improvement in survival has been made possible with the use of post-ASCT maintenance therapy. Lenalidomide is the standard of care for maintenance therapy in most patients and gained its regulatory approval based on the Cancer and Leukemia Group B (CALGB) C100104 — a phase III randomized trial of lenalidomide versus placebo — and showed a longer time to disease progression in the lenalidomide group (median time to progression, 46 months vs. 26 months in lenalidomide vs. placebo; p<0.001).4 The use of lenalidomide maintenance led to the improvement in PFS from 24 months to 42 months compared to the placebo arm in another phase III randomized trial led by the French group.5 Neither of these trials showed an OS benefit with lenalidomide; however, a meta-analysis that included these studies did show OS as well as PFS benefits, underscoring its role in post-ASCT maintenance.6 Although the impact of maintenance is well established, the impact of lenalidomide maintenance in high-risk MM is not clear as results were not consistent across studies.2,7 Adding another potent agent to the lenalidomide backbone could form a reasonable strategy to improve upon the outcomes in most patients with MM. Another question that is not answered in this setting is regarding the optimal duration of maintenance therapy. In this context, using sensitive tools to predict long-term outcomes will perhaps help identify patients who could potentially benefit from the treatment-free interval. We are increasingly recognizing the inability of the traditional response criteria to predict long-term outcomes in MM8,9 and the strong prognostic utility of MRD using either NGS or next-generation flow for both newly diagnosed and relapsed MM.9,10
The rationale for S1803 is to answer two questions: 1) Can we improve upon lenalidomide maintenance? 2) Can we determine an optimal duration of maintenance? Addition of the CD-38 monoclonal antibody daratumumab to lenalidomide has shown higher MRD negativity rates in newly diagnosed patients11 as well as those with relapsed MM12 with acceptable safety profiles. Based on these observations, combining daratumumab with lenalidomide provides a strong rationale to evaluate this combination as post-ASCT maintenance (first randomization). Then, given the strong prognostic ability of MRD, using it to decide the duration of continuous versus fixed duration in patients who are MRD negative (second randomization) forms the basis for the second question.
Comment: MM is a heterogenous disease with varying outcomes.13 In addition to achieving a deep response, maintaining a deep response remains an important goal in MM. While we can achieve a higher proportion of patients with deep responses following modern induction followed by ASCT, exploring a novel maintenance strategy to possibly maintain the deep response remains a reasonable strategy. Furthermore, using MRD as a guide to help identify patients who will likely benefit from continuous versus fixed duration of maintenance serves another major goal of providing the treatment-free interval, and quality of life, which is an equally important goal. S1803 will provide significant information on both these questions, using daratumumab on a lenalidomide platform with MRD monitoring. This is also the first and largest national trial to use the MRD-directed strategy to guide therapeutic decisions.
Dr. Dhakal receives honoraria from Celgene/BMS, is on the advisory board for Takeda, Amgen, Janssen, GSK, Natera, and Arcellx, and receives research support from Takeda, Amgen, Janssen, Carsgen, Cartesian, Fate, and Arcellx. Dr. Usmani has received research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from Amgen, BMS, Celgene, EdoPharma, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio; and speaker fees from Amgen, BMS, Janssen, and Sanofi.