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MLN9708

Carl O Landgren, M.D.

Background:

- Smoldering multiple myeloma (SMM) is a condition that can lead to multiple myeloma, a type of blood cancer. In many high-risk cases, SMM can develop into multiple myeloma in less than 2 years. The current standard of care for SMM is follow-up without treatment until multiple myeloma develops. However, some drugs are being studied to see if they can slow down or prevent the disease from progressing. One such drug is MLN9708. It has shown some results against multiple myeloma. Researchers want to combine MLN9708 with dexamethasone to see how it works against high-risk SMM.

Objectives:

- To see if MLN9708 with dexamethasone is a safe and effective treatment for high-risk smoldering multiple myeloma.

Eligibility:

- Individuals at least 18 years of age who have high-risk smoldering multiple myeloma.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and a bone marrow biopsy may also be performed.
* Participants will take MLN9708 and dexamethasone on a regular schedule for 28 days. They will take each drug four times at regular intervals during each cycle of treatment.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will have 12 cycles of treatment. After four cycles, patients will be recommended to have their own stem cells collected and stored. This will allow the potential application of a highdose melpahalan/autologous stem cell transplant in the event there is a need in the future (not part of this study).
* After 12 cycles, participants will keep taking MLN9708 as long as the disease does not progress and the side effects are not too severe.

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.

MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma

MLN9708 and Dexamethasone in High Risk Smoldering Multiple Myeloma: A Clinical and Correlative Pilot Study

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for induction combination therapy