Triple Drug Therapy for Multiple Myeloma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Other anti-myeloma therapies

Disqualifiers: Tuberculosis, Hepatitis, HIV, 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

Compensation: Varies

Number of Visits: 58

Duration: Up to 1 year

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well leflunomide, pomalidomide, and dexamethasone work for the treatment of multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with pomalidomide, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving leflunomide with pomalidomide and dexamethasone may work better in treating multiple myeloma compared to pomalidomide and dexamethasone alone.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use other anti-myeloma therapies besides leflunomide, pomalidomide, and dexamethasone. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination of Dexamethasone, Leflunomide, and Pomalidomide for treating multiple myeloma?

Research shows that the combination of pomalidomide and low-dose dexamethasone is effective for patients with relapsed and refractory multiple myeloma, improving survival and response rates compared to high-dose dexamethasone alone. This suggests that pomalidomide and dexamethasone are effective components in treating this condition. ^{1 2 3 4 5}

Is the triple drug therapy for multiple myeloma safe for humans?

The combination of pomalidomide and low-dose dexamethasone has been shown to have a manageable safety profile in patients with relapsed and refractory multiple myeloma. Common side effects include neutropenia (low white blood cell count), infections, anemia (low red blood cell count), and thrombocytopenia (low platelet count), but these were generally manageable. ^{1 2 5 6 7}

What makes the triple drug therapy for multiple myeloma unique?

This triple drug therapy combines Dexamethasone, Leflunomide, and Pomalidomide, offering a novel approach by using Leflunomide's unique ability to inhibit immune cell proliferation, which is not commonly used in multiple myeloma treatments. This combination may provide a new mechanism of action compared to standard therapies. ^{8 9 10 11 12}

Research Team

Michael A. Rosenzweig

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with multiple myeloma that has returned or isn't responding to treatment. They must have had at least one prior therapy, be in relatively good health (ECOG <=2), and not planning a transplant soon. Participants need measurable levels of cancer markers in their blood/urine and adequate organ function. Women of childbearing age must test negative for pregnancy and agree to birth control.

Inclusion Criteria

I have been diagnosed with multiple myeloma and it can be measured.

Assent, when appropriate, will be obtained per institutional guidelines

Agreement to allow the use of archival tissue from diagnostic tumor biopsies

Exclusion Criteria

I have been diagnosed with rheumatoid arthritis.

You have tested positive for hepatitis A, B, or C.

I am not using other myeloma treatments besides leflunomide, pomalidomide, and dexamethasone.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide, pomalidomide, and dexamethasone in 28-day cycles

Up to 1 year

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Follow-up at 30 days post-treatment, then every 3 months

Treatment Details

Interventions

• Dexamethasone
• Leflunomide
• Pomalidomide

Trial Overview The study tests the combination of leflunomide, pomalidomide, and dexamethasone against multiple myeloma. Leflunomide may block enzymes needed by cancer cells; pomalidomide could alter the immune system's response to tumor cells; dexamethasone aims to stop cancer cell growth.

Participant Groups

Group I: Treatment (leflunomide, pomalidomide, dexamethasone) Experimental Treatment 3 Interventions

Patients receive leflunomide PO on days 1-28, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

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

Pomalidomide, combined with low-dose dexamethasone, has been shown to be effective in treating adult patients with relapsed and refractory multiple myeloma, significantly improving progression-free survival and overall response rates compared to high-dose dexamethasone.

The treatment demonstrated a manageable safety profile and was effective across various patient subgroups, including those who were refractory to previous therapies, indicating its potential as a valuable salvage therapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide: a review of its use in patients with recurrent multiple myeloma. Scott, LJ.[2022]

Pomalidomide, when combined with low-dose dexamethasone, significantly improves progression-free survival and overall survival in adults with relapsed and refractory multiple myeloma, based on results from multinational phase II and III studies involving patients who had undergone at least two prior treatments.

The treatment has a manageable safety profile, with the most common serious side effects being neutropenia, infections, anemia, and thrombocytopenia, making it a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma. Hoy, SM.[2018]

A subgroup analysis from two phase III clinical trials demonstrated that combining lenalidomide with dexamethasone is more effective than using dexamethasone alone for patients with relapsed or refractory multiple myeloma who had prior treatment with thalidomide.

This finding suggests that the lenalidomide and dexamethasone combination could be a more beneficial treatment option for these patients, potentially improving their outcomes in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematology: Lenalidomide plus dexamethasone is effective in multiple myeloma. Meijer, E., Sonneveld, P.[2021]

In a study of 20 patients with relapsed/refractory multiple myeloma, the combination of thalidomide, cyclophosphamide, and dexamethasone led to significant treatment responses, with 13 patients achieving partial remission after 6 cycles.

This treatment regimen shows promise as an effective option for patients who have not responded to previous therapies, indicating its potential role in managing difficult cases of multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of cyclophosphamide, thalidomide and dexamethasone combination therapy in relapsed/refractory multiple myeloma]. Gao, W., An, N., Chen, SL.[2014]

In a phase 3 trial involving 455 patients with refractory or relapsed multiple myeloma, pomalidomide combined with low-dose dexamethasone significantly improved progression-free survival and overall survival compared to high-dose dexamethasone.

The treatment was effective across all patient subgroups, regardless of their previous treatments, and showed no cross-resistance with prior therapies, making it a strong candidate for standard care in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. San Miguel, JF., Weisel, KC., Song, KW., et al.[2022]

Pomalidomide is a new immunomodulatory drug (IMiD) that has shown more potent anti-myeloma activity compared to existing IMiDs like thalidomide and lenalidomide, with a similar safety profile.

In clinical trials, pomalidomide combined with low-dose dexamethasone has demonstrated effectiveness in myeloma patients who are resistant to other treatments, leading to its accelerated approval by the FDA and EMA as a new strategy for relapsed and refractory myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide for the treatment of relapsed-refractory multiple myeloma: a review of biological and clinical data. Offidani, M., Corvatta, L., Caraffa, P., et al.[2014]

Thalidomide, along with corticosteroids, is effective in treating multiple myeloma and myelofibrosis due to its strong anti-inflammatory and immunomodulatory properties, and it is FDA-approved for specific conditions.

Lenalidomide and pomalidomide, as second-generation drugs derived from thalidomide, aim to reduce toxicity while maintaining efficacy in treating myeloma and myelofibrosis, with lenalidomide being FDA-approved for certain myelodysplastic syndromes and relapsed myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pomalidomide therapy for multiple myeloma and myelofibrosis: an update. Lacy, MQ., Tefferi, A.[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 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]

Leflunomide (LF) effectively delays corneal allograft rejection in rats, showing similar efficacy to cyclosporin A (CSA), with significant improvements in graft survival times compared to untreated controls.

The combination of LF and CSA provides a statistically significant enhancement in prolonging allograft survival compared to either treatment alone, indicating a potential synergistic effect in preventing organ rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide therapy following penetrating keratoplasty in the rat. Coupland, SE., Klebe, S., Karow, AC., et al.[2019]

In a study of 16 patients with steroid-dependent and steroid-resistant minimal change disease, leflunomide combined with prednisone therapy led to a high remission rate, with 93.8% of patients achieving complete remission, including those who were previously steroid-resistant.

Leflunomide therapy significantly reduced the required dose of prednisone to maintain remission and decreased the relapse rate from 100% to 31.3%, demonstrating its efficacy and potential to improve treatment outcomes for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of leflunomide in treatment of steroid-dependent and steroid-resistant adult onset minimal change disease. Zhou, J., Zhang, Y., Liu, G., et al.[2018]

Leflunomide is an immunomodulating drug that works by inhibiting dihydro-orotate dehydrogenase (DHO-DH), which blocks the proliferation of T- and B cells, affecting antibody production as well.

Clinical studies have shown that leflunomide has both symptomatic and structural benefits for patients with active rheumatoid arthritis, but further research is needed to confirm its safety and efficacy when used with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for the treatment of rheumatoid arthritis. Miceli-Richard, C., Dougados, M.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Pomalidomide: a review of its use in patients with recurrent multiple myeloma. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Pomalidomide: A Review in Relapsed and Refractory Multiple Myeloma. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Hematology: Lenalidomide plus dexamethasone is effective in multiple myeloma. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[The effect of cyclophosphamide, thalidomide and dexamethasone combination therapy in relapsed/refractory multiple myeloma]. [2014]

5. Italy pubmed.ncbi.nlm.nih.gov

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Pomalidomide for the treatment of relapsed-refractory multiple myeloma: a review of biological and clinical data. [2014]

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

Pomalidomide therapy for multiple myeloma and myelofibrosis: an update. [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. [2018]

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

Experiences with leflunomide in solid organ transplantation. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Leflunomide therapy following penetrating keratoplasty in the rat. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of leflunomide in treatment of steroid-dependent and steroid-resistant adult onset minimal change disease. [2018]

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

Leflunomide for the treatment of rheumatoid arthritis. [2019]