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 , Mo Clifton Craig , Laubach Jacob , Prescott Julia , Metivier Amada , Davie Christine , Bertoni Meredith , Murphy Elizabeth , Sheehan Brian , Tague Kelsey , Shrestha Hira , Medina Rebekah , Distaso Alexandra , Leblebjian Houry , Richardson Paul G. , Ghobrial Irene M. 
Published: June 2022

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Background: Early therapeutic intervention with lenalidomide has shown to be effective in delaying progression in patients with high-risk smoldering multiple myeloma (HR-SMM) (Lonial J Clin Oncol 2020). Quadruplet regimen of daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has demonstrated significant activity in multiple myeloma, achieving high rates of minimal residual disease (MRD) negativity (Voorhees Blood 2020). Thus, we proposed to examine the activity and safety of D-RVD in patients with HR-SMM. Methods: This is a phase II single center, single-arm, open label study evaluating the combination of D-RVD in HR-SMM. Eligibility included high risk per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, presence of immunoparesis, evolving type of SMM, and high risk FISH. Primary objective is rate of sustained MRD negativity at 2 years. Secondary objectives include PFS, response rates and safety. Treatment duration with modified D-RVD is for total of 2 years (24 cycles). Daratumumab is administered subcutaneously (SQ) per standard dose and schedule, bortezomib given weekly on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24. Lenalidomide is administered on days 1-21 and dexamethasone is administered weekly. All eligible patients will undergo stem cell collection after 6 cycles of therapy. Results: At the time of data cut off, 20 patients have been enrolled with a median follow up of 6 months. The median age is 58 years old (range 40-73). Sixteen out of 20 (80%) patients met high risk criteria per Mayo 2018 model with median plasmacytosis of 20%, median M protein value of 2.6 g/dl and median FLC ratio of 28.2. Seven patients had high-risk FISH: 5 with 1q duplication, 2 with t(4;14). Most common toxicities of any grade included neutropenia (65%), WBC decreased (55%) insomnia (50%), constipation (45%) and hypophosphatemia (45%). Most common grade 3 toxicities included neutropenia (15%), ALT increased (5%), thrombocytopenia (5%), hyperglycemia (5%), hypertension (5%), diarrhea (5%), syncope (5%). No patients discontinued therapy due to toxicity. The overall response rate is 90% with 40% PR, 25% VGPR and 25% CR. All patients have achieved at least a MR and 50% achieved VGPR or greater with responses deepening over time. No patients have progressed on treatment. MRD was evaluable in 16 patients and 8 patients have undergone MRD testing, with MRD negativity rate of 50% (4/8) and 25% (2/8) at thresholds of 10-5 and 10-6, respectively. Stem cells were successfully collected in all patients with mean stem cell yield of 5.78 x 106 CD34+/kg cells. Conclusions: D-RVD is well tolerated in patients with HR-SMM demonstrating significant early activity. Responses continue to deepen over time with patients achieving MRD negative disease. Clinical trial information: NCT04775550.