Metformin XR for Preventing Multiple Myeloma

Recruiting at 6 trial locations

Overseen By Omar Nadeem, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Diabetes medications, Investigational agents

Disqualifiers: High-risk smoldering myeloma, Other malignancy, Pregnancy, Renal or liver failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

60 Participants Needed

Trial Summary

What is 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. The names of the study drug involved in this study is: * Metformin, extended release * Placebo ( a pill that has no active ingredients)

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently on medications for diabetes treatment.

What data supports the effectiveness of the drug Metformin XR for preventing multiple myeloma?

A study found that the use of metformin in US veterans with diabetes was associated with a reduced progression from a condition called monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma, suggesting potential effectiveness in prevention. ^{1 2 3 4 5}

Is Metformin XR safe for humans?

The research does not provide specific safety information about Metformin XR for preventing multiple myeloma, but Metformin (also known as Glucophage, Glucophage XR, Glumetza, Riomet, Riomet ER, Fortamet) is generally considered safe for humans and is commonly used to treat diabetes. ^{2 4 6 7 8}

How is the drug Metformin XR unique in preventing multiple myeloma?

Metformin XR is unique in the context of multiple myeloma because it is traditionally used to manage blood sugar levels in diabetes, and its use in preventing multiple myeloma represents a novel approach that differs from the standard treatments like immunotherapy and combination drug regimens typically used for this condition. ^{9 10 11 12 13}

Research Team

Omar Nadeem, MD

Principal Investigator

Dana-Farber Cancer Institute

Catherine R Marinac, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults over 18 with higher-risk MGUS or low-risk SMM, who can consent to the study. They must have good organ function and not meet criteria for active multiple myeloma. Pregnant women, those on diabetes meds, heavy drinkers, or anyone with conditions affecting drug absorption or increasing risk of lactic acidosis cannot join.

Inclusion Criteria

Your AST and ALT levels must be less than 1.5 times the normal limit at the institution where you are being treated.

Ability to understand and the willingness to sign a written informed consent document

I am 18 years old or older.

Exclusion Criteria

Any other condition that, in the investigator's judgment, would contraindicate the use of metformin or otherwise interfere with participation in the trial

I am taking medication for diabetes.

I don't have conditions that increase the risk of lactic acidosis and I drink less than 3 alcoholic drinks a day.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Metformin or Placebo for 6 months with dose escalation

6 months

Regular visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants who received Metformin can continue for an additional 6 months

6 months

Treatment Details

Interventions

• Metformin XR
• Placebo

Trial Overview The study is testing if Metformin XR can prevent progression from precursor stages (MGUS/SMM) to full-blown Multiple Myeloma compared to a placebo. Participants will be randomly assigned to receive either Metformin XR or a placebo pill without any active ingredients.

Participant Groups

Group I: Placebo Experimental Treatment 1 Intervention

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.

Group II: Metformin Experimental Treatment 1 Intervention

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 )

Metformin XR is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Glucophage for:

• Type 2 Diabetes Mellitus

Approved in European Union as Glucophage for:

• Type 2 Diabetes Mellitus

Approved in Canada as Glumetza for:

• Type 2 Diabetes Mellitus

Approved in Japan as Riomet for:

• Type 2 Diabetes Mellitus

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The introduction of novel agents for treating relapsed and/or refractory multiple myeloma (RRMM) has significantly improved response rates, rising from about 30% with single agents to up to 90% with combination therapies.

Newer treatments, including pomalidomide, panobinostat, carfilzomib, ixazomib, and monoclonal antibodies like daratumumab and elotuzumab, have enhanced overall response rates, even in heavily pretreated patients, while also improving the tolerability of treatment regimens and health-related quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients? Sonneveld, P., De Wit, E., Moreau, P.[2022]

In a real-world study of 47 patients with relapsed/refractory multiple myeloma treated with daratumumab, bortezomib, and dexamethasone (DVd), the overall response rate was 78%, indicating that this combination is an effective treatment option.

The treatment was found to be safe, with mostly mild adverse events and no cases leading to permanent drug interruptions, and the median progression-free survival was 10 months, suggesting good durability of response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of daratumumab, bortezomib and dexamethasone in relapsed/refractory multiple myeloma in Slovakia. Harvanová, Ľ., Štulajterová, V., Guman, T., et al.[2021]

In a study of 138 Korean patients with relapsed/refractory multiple myeloma, carfilzomib combined with lenalidomide and dexamethasone (KRd) was associated with a higher risk of specific adverse events, including dyspnea, muscle spasms, and thrombocytopenia, particularly during the early treatment cycles.

Despite the increased risk of these side effects, most adverse events were of low severity (grade 1-2), suggesting that while carfilzomib has notable side effects, it can still be used effectively and safely in real-world treatment settings for RRMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib's Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records. Jang, HY., Lee, HK., Kim, CJ., et al.[2023]

In a study of 80 newly diagnosed multiple myeloma patients, ixazomib combined with dexamethasone showed a higher complete remission rate compared to lenalidomide with dexamethasone, indicating it may be a more effective treatment option.

Both treatment combinations resulted in similar progression-free survival and overall survival rates, but ixazomib was associated with a higher incidence of mild peripheral neuropathy, suggesting it is generally safe but may have some side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and safety of ixazomib and lenalidomide combined with dexamethasone in the treatment of multiple myeloma. Zheng, Z., Lin, K.[2021]

Triplet regimens including lenalidomide and dexamethasone show effectiveness for high-risk smoldering multiple myeloma, but more long-term follow-up is necessary to confirm these results.

For newly diagnosed multiple myeloma patients, carfilzomib- and daratumumab-based combinations are promising as safe and effective induction treatments, while maintenance therapy with ixazomib significantly prolongs progression-free survival compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018. Terpos, E., Ntanasis-Stathopoulos, I.[2020]

Monoclonal antibodies (mAbs) are a promising new treatment for multiple myeloma (MM), with two already approved: daratumumab for newly diagnosed and relapsed patients, and elotuzumab for relapsed cases.

mAbs work by targeting specific antigens on MM cells to induce cell death, enhance immune response, or deliver cytotoxic drugs, and ongoing clinical trials are exploring their effectiveness in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma. Bonello, F., Mina, R., Boccadoro, M., et al.[2020]

Lenalidomide, when combined with dexamethasone, is a safe and effective treatment for newly diagnosed multiple myeloma patients who cannot undergo autologous stem cell transplantation, providing rapid disease control.

Long-term use of lenalidomide has led to significant improvements in progression-free survival for patients ineligible for stem cell transplantation and has resulted in deep, durable remissions for those with relapsed or refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the use of lenalidomide for the treatment of multiple myeloma. Zagouri, F., Terpos, E., Kastritis, E., et al.[2018]

The combination therapy of daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd) was well tolerated in a study of 22 patients with newly diagnosed multiple myeloma, with a high overall response rate of 95%.

Most treatment-emergent adverse events were mild, with the most common being diarrhea and lymphopenia, and infusion-related reactions were primarily mild, indicating a favorable safety profile for D-KRd therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma. Jakubowiak, A., Usmani, SZ., Krishnan, A., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients? [2022]

2. England pubmed.ncbi.nlm.nih.gov

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Pre-existing diabetes mellitus in patients with multiple myeloma. [2012]

5. Slovakia pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of daratumumab, bortezomib and dexamethasone in relapsed/refractory multiple myeloma in Slovakia. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Carfilzomib's Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and safety of ixazomib and lenalidomide combined with dexamethasone in the treatment of multiple myeloma. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Investigating the Vascular Toxicity Outcomes of the Irreversible Proteasome Inhibitor Carfilzomib. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Novel investigational drugs active as single agents in multiple myeloma. [2017]

12. England pubmed.ncbi.nlm.nih.gov

An update on the use of lenalidomide for the treatment of multiple myeloma. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma. [2022]