Maintenance Therapy Cessation for Sustained MRD Negative Multiple Myeloma Patients

Introduction Maintenance therapy with lenalidomide (len) and other drugs is a cornerstone therapeutic strategy for sustaining deep durable remissions in multiple myeloma (MM). However, indefinite treatment, as currently recommended, may lead to financial, emotional, and physical toxicity. Current guidelines lack data on optimal duration of maintenance in MM patients (pts) who have achieved sustained negative minimal residual disease (MRD) status. Here, we present the first pre-planned interim results from a phase II study evaluating maintenance cessation in patients with sustained MRD negative status for at least 3 years at the time of enrollment on study.

Methods The current two-stage designed study of fifty MM pts, having already demonstrated >3 years of durable MRD negative responses, will be evaluated for MRD negative sustainability after ceasing maintenance therapy. Enrolled pts stop maintenance therapy and undergo active surveillance for three years, including serum protein testing every 3 months, bone marrow MRD testing by multiparametric flow cytometry (single 10-color tube with limit of detection of at least 6x10⁶ (6 cells in 1 million) every 6 months, and annual PET-CTs. Primary endpoint includes sustained MRD negative rate after 1 year. Secondary endpoints include sustained MRD negative rate 3 years of cessation, re-treatment responses, microbiome and immune studies, health-related quality of life outcomes (HRQoL), and progression-free survival (PFS). The first stage includes 15 pts, and if 8 or more remain MRD negative at the end of 1 year, study enrollment continues to stage two (n=35).

Results At data cutoff, on July 31, 2022, twenty-three pts (15 - stage 1; 8 - stage 2) have been enrolled on study. Median follow-up was 14.8 months (95% LL-UL: 11.1 - 25.1) after study enrollment, included 17(74%) male and 6(26%) female; 19(83%) ISS-stage 1, 2(9%) ISS-stage 2, and 2(9%) ISS-stage 3; and 4(17.3%) pts with high-risk cytogenetics [1 - t(4,14) and t(14,16); 1 - t(4,14) and +1q21gain; 2 - +1q21gain]. All pts enrolled onto study were receiving lenalidomide maintenance at the time. For stage 1, 13/15 (87%) remained MRD negative at 12 months of stopping maintenance therapy, and study accrual is ongoing with enrollment of 8 additional pts onto second stage. Overall, MRD negative sustained rates at 6 months and 12 months are 17/18 (94%) (95% CI: 73%-99%) and 14/16 (88%) (95% CI: 62%-98%), respectively. Progression free survival at 12 months was 94% (95% CI: 83%-100%). Two pts converted from MRD negative to MRD positive disease states while meeting clinical progression criteria with new FDG avid bone lesions. These pts have transitioned to new regimens: Pt 13 initiated carfilzomib, pomalidomide, and dexamethasone with VGPR; Pt 2 with a plan to initiate daratumamab-based therapy locally. Pt 10 converted to MRD positivity without clinical progression and opted to restart maintenance therapy with repeat MRD testing pending. Among the three MRD converters, one pt demonstrated standard risk cytogenetics and two pts had unknown risk cytogenetics. Additional HRQoL outcome data will be presented at the time of the meeting.

Conclusions Initial first stage results of stopping maintenance in sustained MRD negative patients (>3 years) warrants further investigation and study continuation. This study and similar ones, such as MRD2STOP (NCT04108624), set a benchmark for future trials investigating maintenance cessation. One such trial includes SWOG 1803, which randomizes maintenance continuation vs. discontinuation in two-year MRD negative sustained patients. While maintenance therapy demonstrates clear benefit for MM patients, feasibility of treatment-free periods remain an unanswered critical question in the field.

Korde:Amgen, Janssen: Research Funding; Clinical Care Options, OncLive, Intellisphere: Consultancy. Diamond:Medscape: Honoraria; Janssen: Honoraria. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Janssen Pharmaceuticals: Research Funding. Landau:Karyopharm: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Juno: Consultancy; Caelum Biosciences: Consultancy; Legend Biotech USA Inc: Consultancy; Takeda Pharmaceuticals: Consultancy, Other: grants/pending grants; Janssen: Consultancy; Alexion: Other: grants/pending grants; Janssen Scientific Affairs, LLC: Other: grants/pending grants; Memorial Sloan Kettering Cancer Center: Current Employment; Prothena: Honoraria. Hultcrantz:Intellisphere LLC: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Curio Science LLC: Consultancy; Amgen, Daichii Sankyo, Cosette, GSK: Research Funding. Mailankody:Janssen Oncology: Consultancy, Research Funding; BioAscend: Consultancy; Optum Oncology: Consultancy; Allogene Therapeutics: Research Funding; Takeda Oncology: Research Funding; Juno Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Fate Therapeutics: Research Funding; Plexus Communication: Honoraria; OncLive: Honoraria; Physician Education Resource: Honoraria; Evicore: Consultancy; Legend Biotech: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment. Shah:MJH Lifesciences: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; Sanofi: Consultancy; MashUpMD: Honoraria; ACCC: Honoraria; Janssen: Consultancy, Research Funding. Usmani:Amgen, BMS, Janssen, Sanofi: Speakers Bureau; Abbvie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen,Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio: Consultancy; Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda: Research Funding. Landgren:Janssen: Honoraria, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials, Research Funding; Merck & Co., Inc.: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Leukemia & Lymphoma Society: Research Funding; Tow Foundation: Research Funding; Pfizer Inc: Consultancy; Aptitude Health: Honoraria; MMRF: Honoraria; Riney Foundation: Research Funding; NCI/NIH: Research Funding; Theradex: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Rising Tide Foundation: Research Funding; Amgen: Honoraria, Research Funding. Lesokhin:BMS, Janssen, Amgen, Boehringer, Genmab: Consultancy; BMS, Janssen: Research Funding.