Leflunomide for High-Risk Smoldering Multiple Myeloma

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Rheumatoid arthritis, HIV, Liver disease, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 cycles (28 days each)

Trial Summary

What is the purpose of this trial?

This pilot trial studies how well leflunomide works for the treatment of patients with high-risk smoldering plasma cell myeloma, for the delay of disease progression. Anti-inflammatory drugs, such as leflunomide lower the body's immune response and are used with other drugs in the treatment of some types of cancer. The information learned from this study will help researchers to learn more about the anti-myeloma activity of leflunomide, and whether it may delay the onset of symptomatic multiple myeloma in patients with high-risk smoldering multiple myeloma.

Will I have to stop taking my current medications?

The trial requires that you stop any prior therapy at least 2 weeks before starting the treatment, except for low-dose prednisone (up to 10 mg per day). If you're on other medications, you may need to stop them, but the protocol does not specify all details.

What data supports the effectiveness of the drug Leflunomide for high-risk smoldering multiple myeloma?

Leflunomide, a drug commonly used for rheumatoid arthritis, has shown potential in stabilizing multiple myeloma in early studies, with most patients maintaining stable disease and some experiencing stability for nearly a year. This suggests it might help delay the progression of smoldering multiple myeloma. ^{1 2 3 4 5}

Is leflunomide safe for humans?

Leflunomide has been shown to be generally safe in humans, with common side effects including diarrhea, nausea, skin rash, and elevated liver enzymes. While it has a manageable safety profile, there are concerns about liver toxicity, so monitoring is important. ^{6 7 8 9 10}

What makes the drug leflunomide unique for treating high-risk smoldering multiple myeloma?

Leflunomide is unique because it is primarily known as an immunomodulatory drug used for rheumatoid arthritis, working by inhibiting pyrimidine synthesis, which is essential for cell growth. Its use in high-risk smoldering multiple myeloma is novel, as it is not a standard treatment for this condition, potentially offering a new approach by targeting the disease's cellular mechanisms. ^{6 7 11 12 13}

Research Team

Michael A Rosenzweig

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with high-risk smoldering multiple myeloma who haven't been treated with leflunomide before. Participants must not be pregnant, have a life expectancy over 3 months, and an ECOG performance status of 0-2 (which means they are fully active or at least capable of self-care). They should not have serious liver disease, HIV, recent acute infections, or other cancers within the last 3 years.

Inclusion Criteria

Women who could become pregnant must have a negative pregnancy test.

You do not have hepatitis A, B, or C infection.

A female of childbearing potential is defined as a sexually mature woman who:

Exclusion Criteria

You have a liver disease before joining the study.

You have taken leflunomide before.

Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or radiation therapy during the study treatment period

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide orally once daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 36 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 28 days until an alternative myeloma therapy has commenced or until disease progression, and then up to 6 months.

Up to 6 months

Treatment Details

Interventions

• Leflunomide

Trial Overview The study tests how well leflunomide works in delaying disease progression in patients with high-risk smoldering multiple myeloma. Leflunomide is an anti-inflammatory drug that may lower immune response to help treat cancer. The trial also assesses the quality-of-life impact on participants.

Participant Groups

Group I: Treatment (leflunomide) Experimental Treatment 2 Interventions

Patients receive leflunomide PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Leflunomide is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United States as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United Kingdom as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 1 study involving 11 patients with relapsed/refractory multiple myeloma, leflunomide was well-tolerated, with manageable side effects and no dose-limiting toxicities at lower doses (20 and 40 mg).

The treatment resulted in stable disease for 9 out of 11 patients, with some maintaining stability for nearly a year, suggesting leflunomide's potential as a therapeutic option for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study. Rosenzweig, M., Palmer, J., Tsai, NC., et al.[2021]

The study presents results from a single-arm phase II trial involving elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering myeloma, indicating a focus on treatment efficacy.

The research investigates how the genetics of plasma cell clones and the immune microenvironment may serve as biomarkers to predict treatment response, highlighting the potential for personalized medicine in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are we ready to look beyond plasma cells in assessing high-risk smoldering myeloma? Maclachlan, KH., Lesokhin, AM.[2023]

Lenalidomide has shown significant clinical activity in treating multiple myeloma, improving response rates to induction therapy to 85-95% in previously untreated patients, compared to older regimens that had response rates of only 45-55%.

Unlike thalidomide, lenalidomide aims to enhance efficacy while reducing side effects, making it a promising option for patients with newly diagnosed or relapsed multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in multiple myeloma. Thomas, SK., Richards, TA., Weber, DM.[2018]

In a phase 2 trial involving 76 patients with smoldering multiple myeloma, the combination of thalidomide and pamidronate showed that 63% of patients improved, with 25% achieving a partial response, although many required dose reductions or discontinuation of thalidomide.

Low levels of beta-2-microglobulin were linked to better overall and event-free survival, suggesting that this biomarker could help predict patient outcomes and support the need for further studies on preemptive therapy in smoldering multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Barlogie, B., van Rhee, F., Shaughnessy, JD., et al.[2022]

Smoldering multiple myeloma (SMM) has a higher risk of progression to symptomatic myeloma (10% per year) compared to monoclonal gammopathy of undetermined significance (MGUS) (1% per year), but many patients with SMM can remain asymptomatic for years.

Recent randomized trials have shown that early treatment of high-risk SMM can provide clinical benefits, indicating a shift in management strategies as our understanding of the disease improves.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The road to treating smoldering multiple myeloma. Korde, N., Mailankody, S., Landgren, O.[2014]

Leflunomide is an effective treatment for active rheumatoid arthritis (RA), showing comparable efficacy and safety to methotrexate and sulfasalazine in phase III clinical trials.

While leflunomide is generally safe, it can cause side effects like diarrhea and liver enzyme elevations, and it has a much longer half-life than other RA medications, raising concerns about potential hepatotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. Hirohata, S.[2018]

In a study of 32 sarcoidosis patients, leflunomide was found to be effective, with a complete or partial response in 12 out of 17 patients treated with leflunomide alone and 13 out of 15 patients receiving it alongside methotrexate.

Leflunomide was well tolerated, with only three patients experiencing nausea, and no serious adverse reactions reported, suggesting it may be a safer alternative to methotrexate for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. Baughman, RP., Lower, EE.[2019]

Leflunomide has a well-documented safety profile for treating rheumatoid arthritis, showing no increased risk of adverse events compared to other similar medications, based on clinical trials and postmarketing studies.

Common side effects include diarrhea, elevated liver enzymes, alopecia, and rash, but 95% of experts believe these are manageable, and the incidence of side effects tends to decrease with continued treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide: a manageable safety profile. van Riel, PL., Smolen, JS., Emery, P., et al.[2018]

Leflunomide, an oral disease-modifying antirheumatic drug, has a generally good safety profile, but it can induce lupus erythematosus, as demonstrated in a case study of a 58-year-old woman with primary Sjögren's syndrome.

The relationship between leflunomide and induced lupus was confirmed by the patient's skin rash resolving after stopping the drug and recurring upon reintroduction, suggesting that leflunomide may affect the immune system's Th1/Th2 balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lupus erythematosus with leflunomide: induction or reactivation? Gensburger, D., Kawashima, M., Marotte, H., et al.[2018]

The combination of leflunomide with biological agents has been evaluated for its efficacy in treating rheumatoid arthritis, suggesting potential benefits in managing the disease.

Safety profiles of this combination therapy were also assessed, indicating that it may be a viable option for patients with rheumatoid arthritis, although specific safety outcomes were not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of the combination of leflunomide (Arava) and biological agents in treatment of rheumatoid arthritis]. Novak, S.[2018]

A 64-year-old woman developed a lichenoid drug reaction after two months of treatment with leflunomide for rheumatoid arthritis, indicating a potential adverse effect of this immunomodulator.

The reaction improved significantly after stopping the medication and using colestyramine and topical corticosteroids, suggesting that leflunomide can cause serious skin reactions, although such side effects are generally rare and benign.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. Canonne-Courivaud, D., Carpentier, O., Dejobert, Y., et al.[2018]

Early diagnosis and referral of rheumatoid arthritis can greatly enhance patient outcomes, highlighting the importance of timely intervention.

Arava (leflunomide) is a new disease-modifying antirheumatic drug (DMARD) in the UK that acts quickly to slow down disease progression and improve patients' functional abilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide: a new DMARD for rheumatoid arthritis. Emery, P.[2019]

Leflunomide shows significant immunosuppressive effects in liver and kidney transplant recipients, allowing for reductions in conventional immunosuppressive drugs like cyclosporine and prednisone without evidence of acute rejection.

The drug was well tolerated in patients with lower serum creatinine levels, but those with higher levels experienced more side effects, highlighting the importance of monitoring serum drug levels for safe and effective dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experiences with leflunomide in solid organ transplantation. Williams, JW., Mital, D., Chong, A., et al.[2022]

References

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

Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study. [2021]

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

Are we ready to look beyond plasma cells in assessing high-risk smoldering myeloma? [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Lenalidomide in multiple myeloma. [2018]

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

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. [2022]

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

The road to treating smoldering multiple myeloma. [2014]

6. Japan pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. [2018]

7. Italy pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. [2019]

8. Canada pubmed.ncbi.nlm.nih.gov

Leflunomide: a manageable safety profile. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Lupus erythematosus with leflunomide: induction or reactivation? [2018]

10. Croatia pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of the combination of leflunomide (Arava) and biological agents in treatment of rheumatoid arthritis]. [2018]

11. France pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. [2018]

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

Leflunomide: a new DMARD for rheumatoid arthritis. [2019]

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

Experiences with leflunomide in solid organ transplantation. [2022]