Smouldering Myeloma Clinical Trial
Official title:
Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in High- Risk Smoldering Multiple Myeloma: A Randomized Phase II Study.
Randomized (2:1) multi-center open-label phase II trial. Patients with high-risk SMM will be enrolled on the study and treated with KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9) or Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).
Background of the study: A recent study has shown that intervention with the use of novel agents in smoldering myeloma (SMM) resulted in prolonged PFS and OS without significant toxicity. A more recent pilot study in high-risk smoldering myeloma using carfilzomib, lenalidomide in combination with dexamethasone resulted in 100% CR rate and 10 out of 12 patients reached MRD negativity. These studies formed the rationale to compare the efficacy and safety of carfilzomib, lenalidomide and dexamethasone vs. lenalidomide, dexamethasone, both followed by 24 months of lenalidomide maintenance in high-risk SMM. This study is designed to compare 2 treatment modalities to find the optimal treatment in efficacy and safety for highrisk SMM, to define new risk stratifiers for outcome to treatment in SMM and to better understand the biology of SMM. Objective of the study: The primary objective of the study is : To assess the progression-free survival rate of KRd versus Rd in patients with high-risk SMM Secondary objectives: - To assess MRD status after 4 and 9 cycles induction treatment - To assess the correlation between PFS and MRD - To determine progression-free survival-2 (PFS2 ) - To determine duration of response (DOR) - To determine overall survival (OS) - To assess correlation of MRD status with PFS2, DOR and OS To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone). - To evaluate disease heterogeneity in relation to clinical outcomes (molecular profiling on bone marrow samples) Study design: Randomized multi-center open-label phase 2 trial. Study population: Patients with high-risk SMM, age 18 years or older Intervention (if applicable): Patients will be treated with KRd combination 9 cycles a 28 days (carfilzomib , lenalidomide , dexamethasone) or Rd combination (lenalidomide , dexamethasone ); followed by extended lenalidomide dosing (for 24 cycles a 28 days). Primary study parameters/outcome of the study: - Progression-free survival rate, defined as time from study entry to progression or death, whichever comes first; Secundary study parameters/outcome of the study (if applicable): - MRD status after induction cycle 4 and 9, - Progression-free survival-2 (PFS2), defined at time from randomization to progression after second-line treatment or death, whichever comes first; - Duration of response (DOR), defined as time from response to progression or death, whichever comes first; - Overall survival (OS), defined as time from study entry to death from any cause. Patients still alive at the date last contact will be censored; - Correlation of MRD status with PFS, PFS2, DOR and OS; - Toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone). Nature and extent of the burden and risks associated with participation, benefit and group relatedness (if applicable): Given the high rates of progression specific to the high risk SMM populations and low toxicity profile of combination therapy, risk of exposure does not seem to outweigh the clinical benefit that patients may derive from therapy. More importantly, much of patient morbidity in MM is associated with pain from irreversible skeletal related events. This study aims to treat or cure the disease before irreversible bone damage occurs or before aggressive clinical MM occurs. Discomfort from venipuncture, bone marrow biopsy, and CT scan is minimal and of limited risk ;
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