MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma

Background:

• SMM is a precursor condition to MM defined by the clinical parameters of M-protein greater than or equal to 3.0 g/dL or bone marrow plasma cells greater than or equal to 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 less than 2 years.
• The current standard of care for SMM is close follow-up without treatment until symptomatic MM develops. However, IMWG states Preventive clinical trials need to be considered for patients with high risk smoldering myeloma .
• MLN9708 is a new oral proteasome inhibitor with potent anti-MM effects

Objectives:

Primary Endpoint:

-The primary objective of the study is to assess the response rate of MLN9708/low-dose

dexamethasone in patients with high-risk SMM.

Secondary Endpoints:

• To determine progression free survival (PFS)
• To determine duration of response (DOR)
• To evaluate toxicity of combination therapy (MLN9708 and low-dose dexamethasone).
• To evaluate biological activity of MLN9708 and correlate to clinical outcomes (gene expression profiling and proteasome activity and ubiquination assays, and effects on downstream signaling targets using pre- and post-MLN9708 exposure bone marrow samples)

Eligibility:

• SMM according to the International Myeloma Working Group definition i.e.:
• Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells greater than or equal to 10 %,
• Absence of anemia: Hemoglobin greater than10 g/dl
• Absence of renal failure: calculated creatinine clearance (according to MDRD) greater than 80 ml/min (or alternatively based on standard creatinine level criteria of 2 mg/dl)
• Absence of hypercalcemia: Ca < 10.5 mg/dl or less than or equal to 2.5 mmol/L
• Absence of lytic bone lesion
• Measurable disease within the past 4 weeks defined by any one of the following:
• Serum monoclonal protein greater than or equal to 1.0 g/dl
• Urine monoclonal protein >200 mg/24 hour
• Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio (reference 0.26-1.65)
• High-risk SMM per Mayo Clinic or Spanish PETHEMA criteria
• Age greater than18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Ability to give informed consent
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count greater than1.0 K/uL
• platelets greater than75 K/uL (Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrolment.)
• hemoglobin greater than 8 g/dL(transfusions are permissible)
• total bilirubin less than1.5 X institutional upper limit of normal
• AST(SGOT)/ALT(SGPT) less than 3.0 X institutional upper limit of normal

Design:

-Single arm pilot trial of combination therapy (MLN9708 and dexamethasone) for high risk smoldering multiple myeloma

• Patients will receive 12 cycles (28 days each) of induction combination therapy of MLN9708 and low-dose dexamethasone. After 12 cycles of MLN9708/low-dose dexamethasone, patients will receive MLN9708 maintenance until progression or unacceptable toxicity.
• Patients will have routine blood work with SPEP and free light chains monthly
• Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies
• Patients will also undergo evaluation for minimal residual disease at complete remission/completion of 12 cycles of therapy, using multi-parametric flow cytometry and FDG PET-CT
• This single arm pilot study will enroll 12 evaluable patients and determine M-spike levels on each patient immediately pre-treatment as well as after completing 12 cycles of treatment. The study aim is to find 9 or more patients (out of 12) with a partial response (PR) or better; which would provide strong evidence that the true probability of an overall response is consistent with 80% or more.