Preemptive Daratumumab Therapy for Minimal Residual Disease Reappearance or Biochemical Relapse in Multiple Myeloma: Rationale and Design of the Polish Myeloma Consortium Predator Study

Background: The patterns of relapse in multiple myeloma (MM) are heterogeneous and include frequent biochemical (paraprotein) relapses in the absence of clinical symptoms. Patients with such relapses can remain free of therapy for certain periods, but they eventually develop clinical relapse. It has been shown that diagnosis of biochemical relapse precedes the start of next line of chemotherapy by 10 months (Garcia-Sanz et al., Haematologica 2015). The current recommendation of the International Myeloma Working Group (IMWG) is, however, not to treat MM relapse until the criteria of clinical relapse (CRAB symptoms) or significant paraprotein relapse (SPR) are met. The question of how to approach asymptomatic MM progression becomes even more important in the era of new sensitive tools that allow detection of small changes in tumor burden, such as minimal residual disease (MRD). Assessment of MRD by flow cytometry or next-generation sequencing was recently included in the updated IMWG response criteria. Interestingly, two small studies indicated that MRD reappearance in previously MRD-negative patients precedes biochemical relapse by four months, and clinical relapse by nine months (Ferrero et al., Leukemia 2015; Oliva et al., Oncotarget 2016). It may therefore be hypothesized that an early start of therapy at biochemical relapse not meeting the SPR criteria or at MRD reappearance is a reasonable strategy to delay clinical progression, provided that the risk of cumulative treatment toxicity is low. In this regard, recent approvals of novel potent and well tolerated anti-MM drugs including daratumumab, the first in class antiCD38 monoclonal antibody, may allow such preemptive therapy to become possible. Objective: Randomized, open-label, multi-center PREDATOR study (Registration number EudraCT 2017-003253-41, Research Funding Source: Janssen Pharmaceuticals) of Polish Myeloma Consortium (PMC) is designed to investigate whether preemptive therapy with daratumumab is able to delay clinical relapse in patients with biochemical relapse of MM or MRD reappearance. Study design: The PREDATOR study is composed of two phase 2 randomized multi-center substudies: PREDATOR-BR and PREDATOR-MRD. The former will investigate treatment with daratumumab in the setting of biochemical relapse while the latter will test the drug efficacy in patients with MRD reappearance. The primary endpoint of both substudies is event-free survival (EFS), defined as the time from the randomization date to the date of clinical relapse, SPR or death from any cause. Secondary endpoints include response to daratumumab, MRD negativity rate, safety, quality of life and overall survival. Sample size calculations were based on an assumed true hazard ratio of daratumumab treated vs. control patients of 0.5 and power of 80%. In patients randomized to the investigational arms, the treatment with daratumumab will be administered during the induction phase of 24 weeks followed by a maintenance phase of 52 weeks, while patients randomized to observational arms will not be treated. PREDATOR-BR will enroll 92 patients, who achieved at least partial response (PR) to the last line of therapy and experienced asymptomatic biochemical progression not meeting SPR criteria, during an accrual interval of 24 months. Patients will be randomized 1:1 to daratumumab or observation. PREDATOR-MRD will include 182 subjects during an accrual interval of 24 months. The major inclusion criteria of PREDATOR-MRD are: achievement of complete remission (CR) or very good partial remission (VGPR) with MRD negativity to the last line of therapy, and confirmation of MRD-negative status by flow cytometry with sensitivity of at least 10^-5, not earlier than 3 months before enrollment to the study. It is predicted that during the subsequent observation phase of 18 months, with MRD tested by flow cytometry at 4-month intervals, MRD will reappear in 118 patients who will be then randomized 1:1 to treatment with daratumumab or observation. Conclusion: PREDATOR study will provide new insights into the approach to asymptomatic relapse of MM and MRD reappearance that currently do not meet indications to initiate therapy.