Metformin XR for Preventing Multiple Myeloma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether metformin, commonly used to manage diabetes, can prevent certain blood conditions from progressing to multiple myeloma, a type of blood cancer. Participants will take either extended-release metformin (Metformin XR) or a placebo (a pill with no active ingredients) to determine metformin's effectiveness in prevention. The trial seeks participants diagnosed with conditions that could develop into multiple myeloma, such as higher-risk MGUS or low-risk smoldering myeloma. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that metformin, a common diabetes medication, is generally well-tolerated by most people, with many individuals using it without major problems. Studies indicate that for people with diabetes, taking metformin is linked to a lower risk of developing multiple myeloma, a type of blood cancer. This suggests it might be safe for those at risk of this condition.

While detailed safety data on using metformin specifically to prevent multiple myeloma is lacking, the FDA has already approved it for diabetes treatment. This approval means it has been tested for safety and is considered safe for many people. Common side effects include stomach issues like nausea or diarrhea, but these are usually mild. Overall, metformin appears to be a safe option based on its long history of use in treating diabetes. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple myeloma?

Metformin XR is unique because it offers a new approach to preventing multiple myeloma, a type of blood cancer. While most treatments for multiple myeloma focus on directly targeting cancer cells with chemotherapy or immunotherapy, Metformin XR works by potentially influencing the body's metabolism and cellular energy balance. Researchers are excited because this could provide a more preventive strategy, reducing the risk of developing the disease in the first place rather than treating it after it occurs. Additionally, Metformin is already widely used for diabetes, so its safety profile is well known, offering a promising new use for an existing drug.

What evidence suggests that metformin XR might be an effective treatment for preventing multiple myeloma?

Research has shown that metformin, a drug commonly used to treat diabetes, might help prevent certain blood conditions from developing into multiple myeloma, a type of bone marrow cancer. In this trial, participants will be randomly assigned to receive either Metformin XR or a placebo. One study found that US veterans with diabetes who took metformin had a lower chance of their condition, called monoclonal gammopathy of undetermined significance (MGUS), progressing to multiple myeloma. Another study found that using metformin for four years or more was linked to a reduced risk of MGUS advancing to cancer. Metformin may help by causing weight loss, which reduces obesity—a known risk factor for this cancer. Additionally, lab tests suggest that metformin might directly combat cancer cells in myeloma. ^{1 2 4 5 6}

Who Is on the Research Team?

Omar Nadeem, MD

Principal Investigator

Dana-Farber Cancer Institute

Catherine R Marinac, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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

Your bilirubin levels are within the normal range for the testing lab, unless you have Gilbert's Disease, in which case your direct bilirubin levels should be within the normal range.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04850846

Investigation of Metformin for the Prevention of Progression ... 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 ...

2. withpower.com withpower.com/trial/phase-3-monoclonal-gammopathy-of-undetermined-significance-3-2021-b20ed

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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5371023/

Impact of metformin on the progression of MGUS ... Metformin is associated with weight loss, which could also modify the risk of MGUS to MM progression as obesity in a known risk factor for MM [10]. Metformin ...

4. europepmc.org europepmc.org/article/med/26034780

Association between metformin use and progression of ... For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple ...

5. mdpi.com mdpi.com/2218-273X/13/2/250

Action Mechanism of Metformin and Its Application in ... In vitro and in vivo experiments demonstrated a direct anti-tumor effect of metformin on myeloma [92,191,194,201,202,235,237,274]. Metformin inhibits the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9953052/

Action Mechanism of Metformin and Its Application in ... Metformin inhibited the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. The molecular mechanism involved the dual repression of ...