Background:
Smoldering multiple myeloma (SMM) is a precursor condition to multiple myeloma (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.
Risk of progression of high risk SMM at 5 years is 72-75% with median time to progression \< 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) states "Preventive clinical trials need to be considered for patients with high risk smoldering myeloma".
Carfilzomib is a new proteasome inhibitor with potent anti-MM effects
Objectives:
To assess the response rate of cyclophosphamide, lenalidomide, and dexamethasone (CRd) in patients with high-risk SMM, focusing on the
Minimal residual disease (MRD(-) Complete Response (CR) rate
Eligibility:
SMM according to the International Myeloma Working Group 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: Calcium (Ca) \< 10.5 mg/dl or 2.65 mmol/L
Absence of lytic bone lesion
Involved/un-involved light chain ratio must be \< 100
Measurable disease
High-risk SMM per Mayo Clinic, Spanish Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA), or the Rajkumar, Landgren, Mateos criteria
Age \>=18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Adequate laboratory parameters as defined in the protocol
Design:
Single arm pilot trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for high risk smoldering multiple myeloma
Patients will receive 8 cycles of induction combination therapy of CRd
Each cycle consists of 28-days
After 4 cycles of therapy, transplant eligible patients may choose to undergo stem cell collection
After 8 cycles of CRd, patients will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year.
Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly during the induction phase. Laboratory evaluations may be spread out to every 3 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
Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT)
This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect a very good partial response (VGPR) from baseline. A replicate cohort of 16 evaluable patients will then be enrolled in order to more precisely define the response rate to the CRd regimen in this population. Accrual will then be extended to a total of 50 evaluable patients in order to estimate the MRD(-) CR rate with reasonable precision. To allow for a number of inevaluable patients and screen failures, the accrual ceiling will be set at 63.
