Investigation of Metformin for the Prevention of Progression of Precursor Multiple Myeloma

Inclusion Criteria:

-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) or IgA MGUS.

Note: individuals with an abnormal FLC ratio that are classified as light-chain only are eligible. Light-chain only patients are defined as complete loss of immunoglobulin heavy-chain, accompanied by abnormal FLC ratio with an increased level of the appropriate involved light-chain (increased kappa FLC in patient with ratio \>1.65, and increased lambda FLC in patients with ratio \<0.26).

* 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 (note if one or more criteria has not been evaluated (e.g., no MRI), the criteria for active MM or WM for that feature is considered unmet):
* 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
  * For participants who wish to enroll in the open label extended treatment (crossover arm), participants can be unblinded and learn of their drug group AFTER completing primary endpoint collection. Patient must be randomized to metformin in order to continue taking metformin for 6 additional months.

Exclusion Criteria:

* Presence of high-risk smoldering myeloma, as defined by 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