Advance Multicenter Clinical Trial: MRD-Driven Therapy in Newly Diagnosed Multiple Myeloma Patients

Background and Significance: The use of modern combination therapy in newly diagnosed multiple myeloma (NDMM) patients delivers deep and durable treatment responses in large numbers of patients. Recently, the IFM 2009 and DFCI randomized studies for newly diagnosed patients have shown that MRD negativity 10^-6 translates into similar PFS and OS outcomes when comparing patients treated across treatment arms irrespective of receiving early transplant. Delayed transplant does not shorten OS. In the current ADVANCE study (NCT04268498), patients are randomly assigned to receive 8 cycles of carfilzomib-lenalidomide-dexamethasone with or without daratumumab (i.e. Dara-KRd versus KRd). High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) is only offered to patients who remain MRD positive after 8 cycles with all patients transitioning to maintenance lenalidomide. MRD negativity is the primary end-point. PFS, EFS, sustained MRD negativity, OS, and correlative assays are part of the secondary endpoints. Unique features of this large, randomized study include the full integration of whole-genome sequencing, single cell sequencing, MRD tracking, and its multi-academic center design.

Study Design and Methods: A total of 306 NDMM patients will be randomly assigned to receive 8 cycles (28-day cycles) of either Dara-KRd or KRd (Dara: 1800 mg SC, days 1, 8, 15, and 22 (cycles 1-2), days 1 and 15 (cycles 3-6), day 1 (cycles 7-8); K: 20/56 mg/m2 IV, days 1, 8, and 15; R: 25 mg days 1-21; d: 40/20 mg). HDM-ASCT candidate patients are encouraged to collect peripheral stem cells after 4-6 cycles of therapy and subsequently continue with combination therapy (8 cycles total). After completion of cycle 8, patients will be evaluated for MRD status (Adaptive ClonoSeq). HDM-ASCT is only offered to patients who are MRD positive after cycles 8. For patients who are MRD-negative, per study protocol, will transition to maintenance therapy with lenalidomide 10 mg on days 1-21 of a 28-day cycle for a total of 2 years and thereafter continue per physician standard of care. Per protocol, sustained MRD status will be monitored annually while on maintenance. Patients will remain monitored long-term for PFS, EFS, and OS. Key eligibility includes confirmation of NDMM per IMWG diagnostic criteria with evaluable disease, ECOG performance status 0-2, adequate organ function, <1 cycle of prior MM treatment; related malignancies, prior anti-CD38 treatment, significant comorbidities including severe asthma, COPD, hypertension, diabetes, hepatitis, HIV, and cardiac ejection fraction <40% are excluded. Assuming an MRD negativity rate of 34% (KRd) vs 50% (D-KRd), a total of 306 patients will be randomized 1:1 to each arm (153 per arm). The comparison will have 80% power using a two-sided alpha level of 0.05.

Current Status: The ADVANCE trial (NCT04268498) is currently open to enrollment with over 96% of the planned patients already enrolled. In this multicenter investigator-initiated study, the Sylvester Myeloma Institute at the University of Miami is the Lead Investigator and Study Coordinating site with several other sites across the US also participating (Huntsman Cancer Institute, MD Anderson Cancer Center, Memorial Sloan Kettering, Moffitt Cancer Center, Roswell Park Comprehensive Cancer Center, Stony Brook Hospital,) or close to activation at this time (National Cancer Institute, Walter Reed Medical Center). Early data confirm and expand our findings from the MANHATTAN trial (JAMA Onc, 2021). The study has met statistical futility/safety thresholds monitored and approved by an independent data safety monitoring committee. Detailed information on feasibility will be presented at the meeting.

Conclusions: The large multicenter, randomized ADVANCE study is open for NDMM patients across the US and is near enrollment completion as of July 2024. We expect to present the initial primary objective efficacy and safety results during Spring 2025 and longer-term endpoints, in particular, sustained MRD negativity at subsequent milestones. Using MRD testing after completed combination therapy, patients will only be offered HDM-ASCT if they remain MRD-positive after 8 cycles; otherwise, they collected stem cells will be stored (delayed transplant) and transition to maintenance therapy. The aim of this translational effort is to define the underlying biology of sustained MRD negativity in NDMM patients.

Landgren:Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Kazandjian:NCI/NIH, FDA, MMRF, DoD-PROMETHEUS (Murtha Cancer Center Research Program), Amgen, BMS/Celgene, Janssen,: Research Funding; BMS: Honoraria; Dedham Group: Consultancy; Aptitude Health: Honoraria; MJH Life Sciences: Honoraria; Magnolia: Honoraria; Plexus: Honoraria; Alphasights: Consultancy; Karyopharm Therapeutics: Honoraria, Research Funding, Speakers Bureau; Curio Science: Honoraria; Bridger Consulting Group: Consultancy; Aperture Medical Technologies: Honoraria, Other: served on independent data monitoring committees (IDMC); Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcellx: Honoraria, Other: served on independent data monitoring committees (IDMC); MMRF: Honoraria; MJH Life Sciences: Honoraria.

KRd and DaraKRd are not approved for newly diagnosed myeloma