What's the purpose of this trial?
The purpose of this research is to understand whether the drug metformin could be used in the future to help prevent patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) from developing multiple myeloma.
This trial is currently open and accepting patients.
What will happen during the trial?
This is a Phase 2, double-blind, randomized placebo-controlled trial in patients with higher-risk monoclonal gammopathy of undetermined significance (MGUS) and low-risk smoldering multiple myeloma (SMM) to test the efficacy of metformin in reducing clinical indicators of disease progression in MGUS and SMM patients.
Metformin is considered "investigational", which means it has not been approved for the study of cancer prevention by the United States Food and Drug Administration. It has been approved for other uses including for blood sugar control in some people with Type II diabetes.
Multiple myeloma is a cancer of the plasma cells, which is an important part of the immune system. Patients with active multiple myeloma generally require treatment. There are currently no approved therapies for MGUS and SMM patients.
Metformin is a medication that is commonly used in the treatment of diabetes. Metformin works by decreasing glucose production in the liver, decreasing glucose absorption, and improving insulin sensitivity. This study is interested in studying this medication because several recent studies indicate that the drug may help prevent progression in patients with MGUS or SMM. This study is looking to learn more about whether metformin will benefit patients with MGUS or SMM who may not have diabetes.
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
After enrollment participants will be randomized assigned to receive either the Placebo or Metformin pills and to take them for 6 months depending on participant tolerance to the drug.
It is expected that about 80 people will take part in this research study.
The National Cancer Institute of the National Institutes of Health is supporting this trial.
You may be able to join this trial if you:
The following criteria is a partial list of reasons why patients may be
eligible to participate in this clinical trial. Further evaluation with a medical professional is
- Diagnosed with higher-risk MGUS or low-risk SMM defined below:
- Higher-Risk MGUS: bone marrow plasma cell concentration <10%# AND either serum M-protein level ≥1.5 g/dL to <3 g/dL or abnormal free light-chain (FLC) ratio (<0.26 or>1.65)
- Low-Risk Smoldering Myeloma: bone marrow plasma cells ≥10%# with the absence of additional high-risk features, which are further defined in the exclusion criteria
- A new bone marrow biopsy is preferred for plasma cell determination at screening; however, determination of eligibility can be made from most recent bone marrow biopsy performed as long as it was within 2 years of enrollment.
- Absence of evidence of CRAB criteria* or new criteria of active MM or active WM which including the following:
- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL) related to MM
- Renal insufficiency (attributable to MM)
- Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
- Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
- Bone marrow plasma cells ≥60%
- Serum involved/uninvolved FLC ratio ≥100, provided the absolute level of the involved free light chain is at least 100 mg/L and repeated twice (light chain smoldering myeloma as described in section 2.4 is not an exclusion criteria).
- MRI with two or more focal lesion that is at least 5 mm or greater in size
- Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
- At least 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- The following laboratory values obtained prior to the first dose of study drug/placebo:
- AST and ALT < 1.5 x institutional ULN
- Serum bilirubin < institutional ULN (in patients with Gilbert's Disease, direct bilirubin < institutional ULN)
- Calculated creatinine clearance ≥ 45 mL/min
- Estimation of renal function will be assessed using the CrCl calculated based on the Cockcroft-Gault formula:
- CrCl (mL/min) = (140-age) (weight [kg]/72 (serum creatinine [mg/dL]; for females the formula is multiplied by 0.85
- Random glucose < 160 mg/dL or fasting glucose < 126 mg/dL (other values require workup to rule out undiagnosed diabetes that may require treatment)
- Ability to understand and the willingness to sign a written informed consent document
- Presence of high-risk smoldering myeloma, as defined by having light-chain restricted bone marrow plasma cells >10% in addition to any one or more of the following:
- Serum M protein ≥3.0g/dL
- IgA SMM
- Immunoparesis with reduction of two uninvolved immunoglobulin isotypes
- Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)
- Free Light Chain Smoldering Myeloma patients as defined in section 2.4 are not excluded
- Progressive increase in M protein level (Evolving type of SMM)
- Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6-month period
- Bone marrow clonal plasma cells 50-60%
- Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes
- t (4;14), t(14;16),t(14;20), del 17p or 1q gain
- Increased circulating plasma cells
- MRI with diffuse abnormalities or 1 focal lesion
- PET-CT with one focal lesion with increased uptake without underlying osteolytic bone destruction
- OR High-risk per IMWG/Mayo 2018 "20-2-20" Criteria (at least 2 of the following)
- Bone marrow plasmacytosis ≥20%
- ≥2g/dl M protein
- ≥20 involved: uninvolved serum free light chain ratio
- Diagnosed or treated for another malignancy within the study period.
- Currently on medications for diabetes treatment
- Patients with hyperglycemia (random glucose < 160 mg/dL or fasting glucose < 126 mg/dl) but who are not on any drug treatment are eligible
- Participants who are receiving any other investigational agents.
- Women who are pregnant or who are unable or unwilling to use contraception during the study period are excluded from this study because it is a class B agent which is known to cross the placenta rapidly and is unbound in serum.
- Any condition associated with increased risk of metformin-associated lactic acidosis (prior renal failure or liver failure, history of acidosis of any type) or habitual intake of 3 or more alcoholic beverages per day.
- Known intolerance to metformin
- Known malabsorption syndrome or diagnosis with a medical condition that may alter gastrointestinal absorption of medications including but not limited to inflammatory bowel disease impacting the small intestine or recent history of bariatric surgery.
- Any other condition that, in the investigator's judgment, would contraindicate the use of metformin or otherwise interfere with participation in the trial
Additional Trial Information
Enrollment: 80 patients (estimated)