A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Protocol # :
Monoclonal Gammopathy of Undetermined Significance
Smoldering Multiple Myeloma
Disease Sites
Unknown Sites
Multiple Myeloma
Principal Investigator
Nadeem, Omar
Site Research Nurses
Brule, Maurice, N.
Davie, Christine, M.
Fleming, Norah, Michelle
Freeman, Stefani, Danielle
Gentile, Alissa
Ginter, Lindsey
Hixon, Nicole, R.
Houghton, Nicole
Kosinski, Michelle
Loeser, Wendy
Miles, Brandy
Piper, Audrey, L.
Quinn, Caroline
Ricciardi, Caroline

Trial Description

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

The names of the study drug involved in this study is:

- Metformin, extended release

- Placebo ( a pill that has no active ingredients)

Eligibility Requirements

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

- 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

- 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