Minimal Residual Disease (MRD)-Driven Cessation of Maintenance: Free from Drug Therapy in Multiple Myeloma (FREEDMM trial in progress)

Background Indefinite maintenance in MM with continuous lenalidomide carries both significant clinical and financial toxicity. We hypothesize that MRD could be used to predict a subset of patients who can safely stop maintenance therapy and enter into a disease surveillance phase. Study Design and Methods Prospective phase 2 study (NCT 05192122) designed to stop post-ASCT maintenance therapy once sustained MRD negativity is achieved. MM patients are eligible if completed ≥2 years of maintenance therapy post-ASCT, and meet criteria for ≥ PR. Bone marrow (BM) MRD testing is performed twice, one year apart, using NGS. Sustained MRD-negativity is defined at a threshold of 10−6, with negative MRD sustained between the Year 1 and Year 2. Patients with sustained MRD negativity and absence of new bony lesions undergo maintenance cessation. MRD-positive patients are removed from study. In patients who discontinue maintenance, BM testing to re-assess for MRD is repeated yearly for 3 years. In parallel with MRD assessment, peripheral blood samples are collected for MALDI-TOF and circulating multiple myeloma cell (CMMC) enumeration. Cellular indexing of transcriptomes and epitopes (CITE-seq) to simultaneously quantify cell surface protein and transcriptome data is used to characterize differences in the immune microenvironment Preliminary Results 31 patients have been enrolled. Median follow up of our cohort is 414 days. The median age is 69.5 years, and the majority are either Black (n=9; 29%) or Hispanic (n=11; 35%). 18 patients had R-ISS 1 or 2, while 2 patients had 17p deletion. The median number of years of maintenance therapy prior to Year 1 BM is 3.4 years. At Year 1, 11 (68.8 %) of 16 patients were MRD-negative, while 5 (31.3%) patients were MRD-positive. MALDI-TOF results were false negative in 3 MRD-positive patients. PB CMMC samples were concordant with MRD results in all 5 (100%) patients who were tested. There was concordance between MALDI-TOF and CMMC results in 9 (75%) of 12 patients. At year 2, 4 patients continued to be MRD negative, while 1 patient who was previously MRD-negative became MRD positive. At most recent follow-up, 3 (42.9%) of 7 MRD positive patients at Year 1 experienced clinical progression and were removed from the study. All patients with sustained MRD-negativity have undergone maintenance cessation. Pilot CITE-seq captured 10,000-15,000 cells with 33,000-56,000 reads/cell on one MRD-positive BM and paired PB sample. Conclusion This phase 2 trial applies a novel clinical trial design with an adaptive strategy to explore use of MRD testing as a guide to maintenance therapy cessation in MM patients and represents one of the first studies introducing transcriptome analysis of the tumor and immune microenvironment in the maintenance setting. CITE-seq results for remaining patients will be presented at the conference.