Leflunomide for High-Risk Smoldering Multiple Myeloma

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

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)

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, ongoing

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effects of leflunomide in treating African-American and European-American patients with high-risk smoldering multiple myeloma. Leflunomide is used to decrease the body's immune response and may delay the symptoms of multiple myeloma in patients of African-American and European decent.

Do I have to stop taking my current medications for this trial?

Yes, you need to stop taking prior therapies at least 2 weeks before starting the trial, except for prednisone or equivalent up to 10 mg per day.

What data supports the idea that Leflunomide for High-Risk Smoldering Multiple Myeloma is an effective drug?

The available research shows that Leflunomide, when tested on patients with relapsed or hard-to-treat multiple myeloma, helped stabilize the disease in 9 out of 11 patients. This means that the disease did not get worse for these patients, and two of them maintained this stability for nearly a year or longer. This suggests that Leflunomide might help delay the progression of high-risk smoldering multiple myeloma. Compared to other treatments like thalidomide, which had a 63% improvement rate but required many patients to stop or reduce the dose due to side effects, Leflunomide appears to have a more manageable safety profile. ^{1 2 3 4 5}

What safety data exists for leflunomide?

Leflunomide, also known as Arava, has been evaluated primarily for rheumatoid arthritis. It is considered to have a manageable safety profile, with common adverse effects including diarrhea, elevated liver enzymes, alopecia, and rash. Concerns about hepatotoxicity have been raised, but most adverse events are considered manageable. The safety profile is consistent across clinical trials, postmarketing surveillance, and epidemiological studies. The incidence of side effects tends to diminish with continued treatment, and dose adjustments can be made if necessary. ^{6 7 8 9 10}

Is the drug Leflunomide a promising treatment for High-Risk Smoldering Multiple Myeloma?

Leflunomide is a drug that has shown promise in treating rheumatoid arthritis and has potential in other areas like organ transplantation. It has a rapid onset of action and can improve patient outcomes, making it a promising option to explore for High-Risk Smoldering Multiple Myeloma. ^{6 10 11 12 13}

Research Team

Michael A. Rosenzweig

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

This trial is for African-American and European-American adults with high-risk smoldering multiple myeloma. Participants must have a life expectancy over 24 months, no hepatitis or HIV, not be pregnant or breastfeeding, agree to use contraception, and have specific blood counts and organ function levels. They should not have had previous treatments for this condition or certain other cancers within the last 3 years.

Inclusion Criteria

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

My kidney function, measured by creatinine clearance, is adequate.

My lung function tests show at least half the normal capacity.

Exclusion Criteria

You have at least one small abnormal area (5 millimeters or larger) on your MRI scan.

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

You have had allergic reactions to drugs similar to leflunomide and cholestyramine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, ongoing

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 days after last dose

Long-term follow-up

Participants are followed up yearly to assess long-term outcomes and progression-free survival

Yearly

Treatment Details

Interventions

• Leflunomide

Trial Overview The trial is testing leflunomide's effectiveness in delaying symptoms of high-risk smoldering multiple myeloma in African-American and European-American patients. It involves taking leflunomide to reduce immune response as a potential treatment strategy.

Participant Groups

Group I: Treatment (leflunomide) Experimental Treatment 2 Interventions

Patients receive leflunomide PO QD on days 1-28. 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

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]

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]

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]

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]

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]

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]

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]

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

Lenalidomide in multiple myeloma. [2018]

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

The road to treating smoldering multiple myeloma. [2014]

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

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

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

[Efficacy of leflunomide]. [2018]

7. Canada pubmed.ncbi.nlm.nih.gov

Leflunomide: a manageable safety profile. [2018]

8. England pubmed.ncbi.nlm.nih.gov

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

9. 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]

10. Italy pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. [2019]

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]