Monoclonal Gammopathy of Undetermined SignificancePhase 2NCT04850846
Investigation of Metformin for the Prevention of Progression of Precursor Multiple Myeloma
A Phase 2 study testing Metformin XR in people with Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma, run by Dana-Farber Cancer Institute at 7 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma
- What is being tested?
- Metformin XR
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 7 sitesUnited States
- Study dates
- 27 Apr 2021to 31 Jul 2027
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- -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):
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- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
United States7 sites
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Dana-Farber at Brighton
Brighton, Massachusetts, 02135
Dana-Farber at NHOH
Londonderry, New Hampshire, 35053
Dana-Farber at Merrimack Valley
Methuen, Massachusetts, 01844
Dana-Farber at Milford
Milford, Massachusetts, 01757
DF/ BWCC in Clinical Affiliation with South Shore Hospital
Weymouth, Massachusetts, 02190
About this study
Official title: A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma
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.
The names of the study drug involved in this study is:
- Metformin, extended release
- Placebo ( a pill that has no active ingredients)
Read the detailed description
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.
Participants will have the option to learn their treatment assignment after primary (6-month) outcome assessments are complete, and individuals randomized to metformin will have the opportunity to continue to take metformin for an additional 6-months to allow for the observation of potentially longer-term treatment response. Participants who choose to be unblinded and are taking placebo will discontinue study medication.
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.
- Being tested
- Metformin XR, Placebo
- Keywords
- Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma
- Medical subject headings
- Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin XRDrug
Also called Glucophage XR
Orally by mouth
PlaceboOther
Orally by mouth
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Randomly assigned participants receive a stepped dose escalation until target daily dose of 1500mg Metformin XR is reached (3 x 500mg pills/day). The intervention duration will last an additional 6 months.
Metformin Extension:
Participants will have the option of unblinding at the end of their 6months treatment and those who were randomly assigned to the metformin experimental arm can continue taking metformin if they opt in. The extended intervention duration will last an additional 6 months. (1500mg Metformin XR or highest tolerated dose ) Receives: Drug: Metformin XR |
| Placebo | Experimental | Randomly assigned participants receive a stepped dose escalation until target daily dose of 3 pills/day is reached. The intervention duration will last 6 months. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
(M-)Protein Concentrations Change
Assessed by using the serum-protein electrophoresis
Measured: Baseline to 6-months
Secondary outcomes (9)
Serum Free Light Chains Change by Mass Spectrometry
Measured: Baseline to 6-months
Hemoglobin Concentrations Change
Measured: Baseline to 6-months
Hemoglobin A1c (HbA1c) Concentrations Change
Measured: Baseline to 6-months
Molecular Evolution of CD138+ Cells
Measured: Baseline to 6-months
Molecular Evolution of Immune Cells (CD138- or CD45+)
Measured: Baseline to 6-months
Changes in Plasma Metabolites Measured by Liquid Chromatography-mass Spectrometry
Measured: Baseline to 6-months
Changes in PROMIS Global Health Summary Score v1.2
Measured: Baseline to 6-months
Number of Participants Willing to Continue to Take Metformin Beyond 6 Month Primary Assessment Period
Measured: Baseline- 12 months
Changes in Response for Those Who Choose to Take Metformin for up to 1 Year Per IMWG Response Criteria
Measured: Baseline- 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Apr 2021
- Study start27 Apr 2021
- Primary completion29 Jan 2025
- Study completion31 Jul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Monoclonal Gammopathy of Undetermined SignificanceStudies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Omar Nadeem, MD, Dana-Farber Cancer Institute
- Investigators
- Omar Nadeem, MD, Principal investigator, Dana-Farber Cancer InstituteCatherine R Marinac, PhD, Study director, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04850846
- Sponsor's protocol ID
- 21-008
- Other IDs
- K22CA251648
- Status last verified
- Jan 2026
- First submitted
- 18 Mar 2021
- Last updated
- 9 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: CatherineR\_Marinac@dfci.harvard.edu. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Study at a glance
From the registry record, last updated by the sponsor on 9 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma
- ClinicalTrials.gov ID
- NCT04850846
- Acronym / sponsor ID
- 21-008
- Keywords
- Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 27 Apr 2021 (actual)
- Primary completion
- 29 Jan 2025 (actual)
- Study completion
- 31 Jul 2027 (estimated)
- First posted
- 20 Apr 2021 (actual)
- Results
- Posted 9 Feb 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
The names of the study drug involved in this study is:
- Metformin, extended release
- Placebo ( a pill that has no active ingredients)
Detailed description
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.
Participants will have the option to learn their treatment assignment after primary (6-month) outcome assessments are complete, and individuals randomized to metformin will have the opportunity to continue to take metformin for an additional 6-months to allow for the observation of potentially longer-term treatment response. Participants who choose to be unblinded and are taking placebo will discontinue study medication.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin XRRandomly assigned participants receive a stepped dose escalation until target daily dose of 1500mg Metformin XR is reached (3 x 500mg pills/day). The intervention duration will last an additional 6 months. Metformin Extension: Participants will have the option of unblinding at the end of their 6months treatment and those who were randomly assigned to the metformin experimental arm can continue taking metformin if they opt in. The extended intervention duration will last an additional 6 months. (1500mg Metformin XR or highest tolerated dose ) |
| Placebo | Experimental | Other: PlaceboRandomly assigned participants receive a stepped dose escalation until target daily dose of 3 pills/day is reached. The intervention duration will last 6 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- --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.
- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL) related to MM
Key exclusion criteria (13 listed)
- Presence of high-risk smoldering myeloma, as defined by per IMWG/Mayo 2018 "20-2-20" Criteria (at least 2 of the following)
- Diagnosed or treated for another malignancy within the study period.
- Currently on medications for diabetes treatment
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metformin XRAlso: Glucophage XROrally by mouth | Drug | Metformin |
| PlaceboOrally by mouth | Other | Placebo |
Primary outcome
(M-)Protein Concentrations Change
Time frame: Baseline to 6-months
Assessed by using the serum-protein electrophoresis
9 secondary outcomes
Serum Free Light Chains Change by Mass Spectrometry
Time frame: Baseline to 6-months
Hemoglobin Concentrations Change
Time frame: Baseline to 6-months
Hemoglobin A1c (HbA1c) Concentrations Change
Time frame: Baseline to 6-months
Molecular Evolution of CD138+ Cells
Time frame: Baseline to 6-months
Molecular Evolution of Immune Cells (CD138- or CD45+)
Time frame: Baseline to 6-months
Changes in Plasma Metabolites Measured by Liquid Chromatography-mass Spectrometry
Time frame: Baseline to 6-months
Changes in PROMIS Global Health Summary Score v1.2
Time frame: Baseline to 6-months
Number of Participants Willing to Continue to Take Metformin Beyond 6 Month Primary Assessment Period
Time frame: Baseline- 12 months
Changes in Response for Those Who Choose to Take Metformin for up to 1 Year Per IMWG Response Criteria
Time frame: Baseline- 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: CatherineR_Marinac@dfci.harvard.edu. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Omar Nadeem, MD principal investigator
Dana-Farber Cancer Institute
Catherine R Marinac, PhD study director
Dana-Farber Cancer Institute
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin XR in people with Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma, run by Dana-Farber Cancer Institute at 7 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 9 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Feb 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
(M-)Protein Concentrations Change (time frame: Baseline to 6-months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2026; AzTrials last refreshed its copy on 8 Nov 2026.