B-PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma
Authors: Nadeem Omar , Redd Robert A. , Prescott Julia , Metivier Amada , Tague Kelsey , Romines Veronica , Bertoni Meredith , Savell Alexandra , Medina Rebekah , Distaso Alexandra , Leblebjian Houry , Mo Clifton C. , Laubach Jacob P. , Sperling Adam S. , Richardson Paul G. , Ghobrial Irene M. 
Published: November 2021

Abstract
Background: Early therapeutic intervention with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma (HR-SMM) has shown to be effective by delaying time to progression to overt myeloma (Lonial J Clin Oncol 2020 Apr 10;38(11):1126-1137). Triplet and quadruplet combination therapies utilizing a proteasome inhibitor, immunomodulatory agent and a CD38 monoclonal antibody are used extensively in patients with multiple myeloma due to far greater efficacy compared to lenalidomide and dexamethasone alone. These combinations have been studied in HR-SMM, demonstrating encouraging activity, including ixazomib, lenalidomide and dexamethasone and elotuzumab, lenalidomide and dexamethasone. There are also current ongoing studies with curative intent utilizing more potent therapy in HR-SMM, including carfilzomib, lenalidomide and dexamethasone with autologous stem cell transplantation (Mateos EHA 2019, abstract S871) and daratumumab, carfilzomib, lenalidomide and dexamethasone (NCT03289299).
Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) combination is highly effective and well-tolerated in newly diagnosed multiple myeloma at achieving high response rates as well as minimal residual disease (MRD) negativity based on results from the phase II GRIFFIN trial (Voorhees Blood 2020 Aug 20;136(8):936-945). Thus, we propose to examine the activity and safety of D-RVD in patients with HR-SMM.
Study Design and Methods: This is a phase II single center, single-arm, open label study evaluating the combination of D-RVD in HR-SMM. Primary objective of this study is to determine the proportion of HR-SMM patients who are MRD negative at 2 years after receiving D-RVD. Secondary objectives include MRD negativity rate at 6 months, 12 months, 24 months and 36 months, progression-free survival, response rates and safety. Exploratory objectives include assessment of mass spectrometry quantification of M protein, examination of molecular evolution of tumor cells and to determine role of immune cells in progression of SMM.
Patients must meet criteria for HR-SMM based on bone marrow clonal plasma cells ≥10% and any one or more of the following: Serum M protein ≥3.0 gm/dL, immunoparesis with reduction of two uninvolved immunoglobulin isotypes, serum involved/uninvolved free light chain ratio ≥8 (but less than 100), progressive increase in M protein level (evolving type of SMM), bone marrow clonal plasma cells 50-60%, abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes, high risk FISH defined as any one or several of the following: t(4;14), t(14;16), t(14;20), del 17p or 1q gain, MRI with diffuse abnormalities or 1 focal lesion (≥5mm), PET-CT with one focal lesion (≥5mm) with increased uptake without underlying osteolytic bone destruction.
Patients that meet high risk definition by the new Mayo/IMWG 2018 "20-2-20" criteria are also eligible if they have 2 out of the following 3 criteria: Bone marrow plasmacytosis ≥20% , ≥2g/dl M protein, ≥20 involved: uninvolved serum free light chain ratio.
Treatment duration with D-RVD is for 2 years (24 cycles). Daratumumab is administered at a dose of 1800mg subcutaneously (SQ) weekly for cycles 1-2, biweekly for cycles 3-6 and monthly until completion of cycle 24. Bortezomib is given at a dose of 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24. Lenalidomide is administered on days 1-21 at a dose of 25mg for cycles 1-6 and 15mg for cycles 7-24. Dexamethasone is administered weekly at 20mg cycles 1-6 and biweekly during cycles 7-24. All eligible patients will undergo stem cell collection after cycle 6 of therapy.
A single-stage design will be employed with 30 eligible patients entered. If 12 or more of the 30 eligible patients are MRD negative at 2 years (observed rate of &gt;=40%), we will conclude that this treatment warrants further study. The probability of concluding that the treatment is effective if the true rate is 25% is 0.051 and is 0.90 if the true rate is 50%.
Figure 1 Figure 1.

Disclosures
Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Sperling: Adaptive: Consultancy. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.