Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma

Background:

Smoldering multiple myeloma (SMM) is a precursor condition to MM defined by the clinical parameters of M-protein >=3.0 g/dL or bone marrow plasma cells >=10%, and absence of end organ disease.

Patients with high-risk SMM have a risk of progression to MM of 72-75% in 5 years with median time to progression of <2 years.

The current standard of care for SMM is close follow-up without treatment, until symptomatic MM develops. However, International Myeloma Working Group (IMWG) recommends Preventive clinical trials need to be considered for patients with high risk smoldering myeloma.

Carfilzomib is a proteasome inhibitor and daratumumab is an anti-CD38 monoclonal antibody, both with potent anti-MM effects.

Objectives:

To assess the remission rate of daratumumab, carfilzomib, and dexamethasone (DKd) in patients with high-risk (HR) smoldering multiple myeloma (SMM) by determining the minimal residual disease (MRD) negative complete response (CR) rate by up to 12 cycles of induction therapy using flow cytometry.

Eligibility:

SMM according to the IMWG definition; i.e.:

Serum M-protein >=3 g/dl and/or bone marrow plasma cells >=10 % and <60%

Absence of anemia: Hemoglobin >10 g/dl

Absence of renal failure: serum creatinine <2.0 mg/dL.

Absence of hypercalcemia: Ca <10.5 mg/dl or 2.62 mmol/L

Absence of lytic bone lesions

<=1 focal lesion on MRI

Involved/un-involved light chain ratio <100

High-risk SMM per Mayo Clinic, Spanish PETHEMA, or the Rajkumar, Landgren, Mateos criteria

Age >=18 years

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Adequate laboratory parameters

Design:

Single arm trial of combination therapy (daratumumab, carfilzomib, and dexamethasone) followed by daratumumab maintenance monotherapy (DKd-D) for high-risk SMM.

Participants will receive 8 cycles of DKd induction combination therapy. After 8 cycles, participants who have not attained an MRD negative remission will receive 4 additional cycles of DKd. Each cycle consists of 28-days.

After 4 cycles of induction therapy, transplant eligible participants may choose to undergo stem cell collection for storage.

After induction with DKd, participants will receive daratumumab maintenance therapy for 24 cycles.

Participants will have routine blood work with SPEP and free light chains at the start of each cycle during the induction phase. Laboratory evaluations may be spread out to every 3-6 months during the maintenance and follow-up phases.

Pre-treatment, post-treatment and follow-up bone marrow biopsies will be obtained for confirmation of diagnosis, response and correlative studies.

Participants will also undergo evaluation for MRD at regular interval time points, using multi-parametric flow cytometry, FDG PET-CT, and Diffusion Weighted Whole Body (DW-MRI).

The statistical analysis of the primary endpoint, MRD negativity, will be performed at the end of induction therapy.