MLN9708 and Dexamethasone in High Risk Smoldering Multiple Myeloma: A Clinical and Correlative Pilot Study
- 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
-The primary objective of the study is to assess the response rate of MLN9708/low-dose
dexamethasone in patients with high-risk SMM.
- 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)
- 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
- 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
-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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Carl O Landgren, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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