Advance Multicenter Clinical Trial: MRD-Driven Therapy in Newly Diagnosed Multiple Myeloma Patients
Authors: Landgren Ola , Maura Francesco , Kazandjian Dickran 
Published: December 2023

Background and Significance: The use of modern combination therapy in newly diagnosed multiple myeloma 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 progression-free survival (PFS) and overall survival (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, event-free survival (EFS), sustained MRD negativity, OS and correlative assays are part of the secondary endpoints. Unique features of this large 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 308 newly diagnosed multiple myeloma patients will be randomized between Dara-KRd or KRd. Enrolled patients are encouraged to collect peripheral stem cells after 4-6 cycles of therapy. For patients who collect stem cells, afterwards they will continue with combination therapy (total of 8 cycles). 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, they transition to maintenance therapy with lenalidomide 10 mg daily days 1-21 on 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 the International Working Group Criteria (IMWG) diagnostic criteria with evaluable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, adequate organ function, &lt;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 &lt;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 withover 57% of the planned patients have already been 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 already either enrolling or close to activation at this time. Early data confirm and expand our findings from the MANHATTAN trial (JAMA Onc, 2021). Detailed information on feasibility will be presented at the meeting.
Conclusions: The large multicenter, randomized ADVANCE study is open for newly diagnosed multiple myeloma patients across the US. Using MRD testing after completed combination therapy, patients will only be offered HDM-ASCT if they remain MRD-positive after 8 cycles; else, they will keep the collected stem cells (delayed transplant) and move forward with maintenance therapy. The aim of this translational effort is to define the underlying biology of sustained MRD negativity in multiple myeloma patients.