Drug Combination for Multiple Myeloma

Overseen By Yohana Sebhat, MPH

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Oncotherapeutics

Must be taking: Lenalidomide

Must not be taking: JAK inhibitors, Strong CYP3A4

Disqualifiers: POEMS syndrome, Plasma cell leukemia, Primary amyloidosis, Uncontrolled infections, Impaired cardiac function, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 54 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment combination for individuals with multiple myeloma (a type of blood cancer) whose disease has worsened despite previous treatments. The trial evaluates the safety and effectiveness of a combination of three drugs: ruxolitinib (a JAK inhibitor), steroids (such as methylprednisolone), and lenalidomide. Participants will be divided into two groups to receive different combinations of these drugs to assess their combined effectiveness. The trial seeks individuals with multiple myeloma who have tried at least two treatments and are experiencing disease progression. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking medical research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting, such as chemotherapy, corticosteroids, immunotherapy, and some other drugs, at least 3 weeks prior. Additionally, you cannot use strong CYP3A4 inhibitors or inducers close to the start of the study.

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

In a previous study, experts found no unexpected safety issues with ruxolitinib. This drug has been safely used for other conditions. Research showed that when combined with methylprednisolone (a type of steroid), it was safe for patients with multiple myeloma. In trials, patients managed the combination of these drugs well.

When lenalidomide was added to ruxolitinib and steroids, studies also showed promising safety results. Patients did not experience unusual side effects, and the combination seemed to work without causing many problems.

These findings suggest the treatment could be well-tolerated. However, as this is an early phase study, researchers continue to collect more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple myeloma because they explore new combinations of drugs that could enhance effectiveness. Unlike standard treatments that often rely on single agents like bortezomib or lenalidomide alone, this approach combines Ruxolitinib, a JAK inhibitor, with Methylprednisolone and Lenalidomide. Ruxolitinib targets specific pathways that may contribute to tumor growth, potentially providing a novel mechanism of action. Moreover, the flexible dosing in the combination with Lenalidomide allows for dose escalation, which could optimize treatment efficacy and minimize side effects, offering a tailored approach to patient care.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Research has shown that combining ruxolitinib and methylprednisolone may help treat multiple myeloma (MM) patients whose disease is worsening. Studies have found that about 30% of patients respond to this combination, and 40% experience some clinical benefit. Specifically, two patients in these studies had a very good partial response, meaning their cancer significantly decreased. In this trial, one treatment arm will receive ruxolitinib and methylprednisolone, while another will receive these drugs with lenalidomide. Adding lenalidomide may enhance ruxolitinib's effectiveness, even when lenalidomide and steroids alone are no longer effective. Overall, these findings suggest a possible new way to manage difficult MM cases. ^{6 7 8 9 10}

Who Is on the Research Team?

James Berenson, MD

Principal Investigator

Oncotherapeutics

Are You a Good Fit for This Trial?

This trial is for multiple myeloma patients with progressive disease, evidenced by specific blood protein levels and bone lesions. Participants need to have certain criteria met, like a monoclonal immunoglobulin spike or plasmacytosis in the bone marrow. It's not clear what excludes someone from this study.

Inclusion Criteria

I have never taken Ruxolitinib.

Subjects must be able to adhere to the study visit schedule and other protocol requirements

Subjects must have a life-expectancy of greater than 3 months

Exclusion Criteria

I am not taking any excluded medications or have any disqualifying health conditions.

I do not have HIV, hepatitis B or C, or active tuberculosis.

Subjects must not have any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent signing the informed consent form

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib and methylprednisolone until disease progression, with lenalidomide added upon progression

54 months

Weekly visits during the first treatment cycle, monthly thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Methylprednisolone
• Ruxolitinib

Trial Overview The study tests the combination of ruxolitinib (a tablet), steroids (methylprednisolone), and lenalidomide on those with worsening multiple myeloma. The effectiveness is measured using BCMA levels as an indicator of disease progression.

How Is the Trial Designed?

Group I: Rux + Steroid + Len Experimental Treatment 3 Interventions

Ruxolitinib Oral Tablet \[Jakafi\] at 5mg, 10mg or 15mg BID, Lenalidomide Oral at 5mg or 10mg QD and Methylprednisolone Oral at 40mg QOD. (Dose varies during dose escalation portion of the study)

Group II: Rux + Steroid Experimental Treatment 2 Interventions

Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, and Methylprednisolone at 40mg QOD until disease progression. Lenalidomide at 10mg QD will be added to the treatment (Ruxolitinib, Methylprednisolone) once disease progression was confirmed.

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

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Who Is Running the Clinical Trial?

Oncotherapeutics

Lead Sponsor

Trials

23

Recruited

940+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

In a study of 1162 multiple myeloma patients, those treated with the combination of thalidomide, melphalan, and prednisone (MPT) showed significantly better overall survival (OS) rates compared to those treated with melphalan and prednisone (MP) alone, with median OS of 4.2 years for MPT versus 2.2 years for MP in the first line of treatment.

The relative risk of death was reduced by 39% in the MPT group compared to the MP group in the first line of therapy, indicating that MPT is a more effective treatment option for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma--a retrospective population based study of 1162 patients. Lund, J., Uttervall, K., Liwing, J., et al.[2013]

In a study of 75 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib and dexamethasone (Kd56) showed a 60% overall response rate and a median progression-free survival (PFS) of 10 months, indicating its efficacy in a real-world clinical setting.

The treatment was well tolerated, with a low rate of adverse events, including no cases of neuropathy and only 10% of patients experiencing cardiovascular events above grade 3, suggesting a favorable safety profile for elderly and heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. Del Giudice, ML., Gozzetti, A., Antonioli, E., et al.[2023]

Ruxolitinib, when combined with lenalidomide and methylprednisolone, shows potential to overcome resistance to lenalidomide in patients with relapsed/refractory multiple myeloma, achieving a clinical benefit rate of 49% and an overall response rate of 36% in a Phase I trial with 49 participants.

The trial demonstrated that ruxolitinib was safe, with no dose-limiting toxicities reported, although some patients experienced grade 3 or 4 adverse events, including anemia and decreased lymphocyte count, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients. Berenson, JR., Kim, C., Bujarski, S., et al.[2022]

In a phase I trial involving 28 patients with relapsed/refractory multiple myeloma, ruxolitinib combined with lenalidomide and methylprednisolone showed a clinical benefit rate of 46% and an overall response rate of 38%, indicating its potential effectiveness in overcoming resistance to lenalidomide.

The trial reported no dose-limiting toxicities, suggesting that ruxolitinib is safe to use in this combination therapy, although some patients experienced grade 3 or 4 adverse events like anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma. Berenson, JR., To, J., Spektor, TM., et al.[2021]

A systematic review of 18 randomized controlled trials involving 2221 patients found that combinations of disease-modifying anti-rheumatic drugs, particularly methotrexate with sulfasalazine and hydroxychloroquine, are effective for treating rheumatoid arthritis with manageable side effects.

The combination of anti-tumor necrosis factor (TNF) therapy with methotrexate is also shown to be effective and well tolerated, with all four trials reviewed reporting favorable outcomes for this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis. Garrood, T., Scott, DL.[2018]

In a study comparing lenalidomide-dexamethasone (len/dex) and melphalan-prednisone-lenalidomide (MPR) in 89 elderly patients with myeloma, both treatments showed similar efficacy in terms of time to progression, progression-free survival, and overall survival, indicating that either regimen can be effective for this patient group.

However, MPR was associated with significantly higher rates of severe hematologic toxicities, such as neutropenia and thrombocytopenia, suggesting that while both treatments are effective, len/dex may be a safer option with fewer severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. Gay, F., Vincent Rajkumar, S., Falco, P., et al.[2018]

In a study of 999 rheumatoid arthritis patients over 52 weeks, methotrexate showed greater improvements in tender and swollen joint counts compared to leflunomide, indicating it may be more effective in the short term.

While both treatments had similar safety profiles, methotrexate was associated with more serious adverse events, including elevated liver enzymes and two drug-related deaths, suggesting that leflunomide may be a safer option for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Emery, P., Breedveld, FC., Lemmel, EM., et al.[2019]

In a phase IIb study involving 25 lenalidomide-refractory multiple myeloma patients, the combination of vorinostat, lenalidomide, and dexamethasone showed an overall response rate of 24% and a clinical benefit rate of 80%, indicating significant activity in this challenging patient population.

The most common severe side effects included neutropenia (48%) and thrombocytopenia (32%), highlighting the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens. Sanchez, L., Vesole, DH., Richter, JR., et al.[2018]

Leflunomide, an FDA-approved drug for rheumatoid arthritis, shows promise in treating cutaneous melanoma by reducing viable melanoma cells and inducing apoptosis, particularly in combination with the BRAF inhibitor vemurafenib.

The combination of leflunomide with the MEK inhibitor selumetinib resulted in a synergistic effect, leading to a greater reduction in tumor size in vivo compared to using either drug alone, suggesting a potential new treatment strategy for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth. Hanson, K., Robinson, SD., Al-Yousuf, K., et al.[2019]

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 lenalidomide, bendamustine, and prednisolone (RBP) showed a high response rate in 88% of the 25 patients with relapsed/refractory multiple myeloma, indicating its efficacy as a treatment option.

While RBP was effective, many patients experienced increased hematological toxicity, necessitating dose reductions in subsequent treatment cycles, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with bendamustine and prednisolone in relapsed/refractory multiple myeloma: results of a phase 2 clinical trial (OSHO-#077). Beck, J., Schwarzer, A., Gläser, D., et al.[2018]

In a study of 54 newly diagnosed elderly multiple myeloma patients, the combination of melphalan, prednisone, and lenalidomide (MPR) resulted in a high response rate, with 81% of patients achieving at least a partial response and 23.8% achieving a complete response.

The treatment showed excellent safety profiles, with manageable hematologic adverse events, and a remarkable 1-year overall survival rate of 100%, indicating that MPR is a promising first-line therapy for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. Palumbo, A., Falco, P., Corradini, P., et al.[2020]

Citations

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A phase 1 study of ruxolitinib, steroids and lenalidomide for ... This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These ...

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A phase I trial of ruxolitinib, lenalidomide, and ... Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RR MM pts. These ...

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A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide ... Together, these results suggest that ruxolitinib may overcome lenalidomide and steroid resistance for RRMM patients that are failing therapy from steroids alone ...

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A Phase 1 Trial of Ruxolitinib, Lenalidomide and ... The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory ...

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Ruxolitinib Is Under Investigation as JAK Inhibition Strategy ... The overall response rate and clinical benefit rate was 30% and 40%, respectively. Within this group, 2 patients achieved a very good partial ...

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Clinical Review - Ruxolitinib (Jakavi) - NCBI - NIH According to the clinical experts consulted by CADTH, no unexpected safety concerns were observed with ruxolitinib. Go to: Introduction. Disease Background.

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Ten years of treatment with ruxolitinib for myelofibrosis This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent ...

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Efficacy and Safety of Ruxolitinib and Steroids for Treating ... Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) ...

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Preclinical and clinical evaluation of the Janus Kinase ... Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma. Br J Haematol. 2023; 200:722–30. https ...

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Efficacy and Safety of Ruxolitinib and Steroids for Treating ... This ongoing Phase 1 trial is the first study demonstrating clinical activity of the two-drug combination of the JAK inhibitor RUX with steroids for MM ...