Ruxolitinib + Steroids + Lenalidomide for Multiple Myeloma

Recruiting at 6 trial locations

Overseen By Afra Yehwalashet

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Oncotherapeutics

Must be taking: Ruxolitinib, Steroids, Lenalidomide

Must not be taking: Strong CYP3A4 inhibitors, others

Disqualifiers: POEMS syndrome, Plasma cell leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 54 months

134 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the safety and effectiveness of combining ruxolitinib (a JAK inhibitor), steroids, and lenalidomide (Revlimid, an immunomodulatory drug) to treat multiple myeloma in patients whose disease progresses despite other treatments. Researchers are testing various combinations and doses of these drugs to identify the best approach. Individuals with multiple myeloma that hasn't responded to at least two prior treatments, including an IMID and a proteasome inhibitor, may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting. Specifically, you must not have had chemotherapy, corticosteroids, immunotherapy, or certain other treatments within a few weeks before the trial. Check with the trial team for details on your specific medications.

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

Research has shown that both ruxolitinib and lenalidomide have been tested in other contexts and generally have manageable safety profiles. Studies on ruxolitinib indicate it can cause some bleeding, with about 11.5% of patients experiencing this issue, a rate similar to other treatments. It has been used safely for conditions like myelofibrosis, where it helps improve symptoms and overall survival.

Lenalidomide, often used with other drugs, has been shown to improve survival rates in patients with multiple myeloma. In one study, 23% of patients experienced a decreased appetite, but only 3% had significant weight loss, suggesting that side effects are generally mild.

Methylprednisolone, a type of steroid, is commonly used in multiple myeloma and is considered safe and effective. It helps manage symptoms, although specific safety details are less comprehensive.

As this is a phase 1 trial, the main goal is to ensure safety and determine the right dosages. While existing data suggest these treatments are generally well-tolerated, the trial will specifically assess their safety when used together. ^{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 bring a fresh approach to tackling the disease. Most treatments for this condition, like bortezomib and lenalidomide alone, focus on targeting the cancer cells directly. However, this trial combines Ruxolitinib, an innovative JAK1/2 inhibitor, with steroids and lenalidomide, offering a unique multi-pronged attack. Ruxolitinib targets the JAK-STAT pathway, potentially reducing inflammation and suppressing cancer cell growth. This combination could enhance the effectiveness of existing therapies, offering new hope for patients whose disease has progressed despite standard treatments.

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

Research has shown that using ruxolitinib with lenalidomide and steroids may help treat multiple myeloma, particularly in patients unresponsive to other treatments. In this trial, participants will receive different treatment combinations to evaluate their effectiveness. Studies have found that the combination of ruxolitinib, lenalidomide, and steroids can be effective even when lenalidomide and steroids alone are not. Specifically, one study reported that 30% of patients responded to the treatment, and 40% experienced some benefit. Early research suggests that ruxolitinib works by blocking signals in cells that promote cancer growth. This combination is under study to determine if it can offer a new option for patients with worsening multiple myeloma. ^{6 7 8 9 10}

Who Is on the Research Team?

James R Berenson, MD

Principal Investigator

Oncotherapeutics

Are You a Good Fit for This Trial?

This trial is for Multiple Myeloma patients who've had the disease progress despite previous treatments and can't have a transplant. They should be able to perform daily activities with ease (ECOG ≤ 2), not be pregnant, sign consent forms, follow the study schedule, live more than 3 months, join REVLIMID REMS™ program, take aspirin if safe, and have measurable MM with certain lab results.

Inclusion Criteria

I have been treated with lenalidomide before.

I can take aspirin daily and my platelet count is above 30 x 10E9/L.

I have multiple myeloma with signs that can be measured.

Exclusion Criteria

I am positive for HIV, hepatitis B or C, or have active or latent tuberculosis.

I have received specific treatments within certain timeframes.

I developed a peeling rash from taking thalidomide or similar medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ruxolitinib, Steroids, and Lenalidomide until disease progression

54 months

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 (Jakafi), steroids (Methylprednisolone), and Lenalidomide in those whose Multiple Myeloma has worsened. It's an early-stage trial to check how safe this mix is and how well it works against MM when other treatments haven't helped.

How Is the Trial Designed?

Group I: Rux and Steroid until progression, then add Len Experimental Treatment 3 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.

Group II: Rux Len and Steroid 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 III: High-dose Ruxolitinib Experimental Treatment 2 Interventions

Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 20mg BID and Methylprednisolone at 40mg QOD until disease progression.

Group IV: Expanded Eligibility Criteria Experimental Treatment 3 Interventions

Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, Lenalidomide at 10mg QD, and Methylprednisolone at 40mg QOD until disease progression.

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 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]

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 study involving 2,965 patients with rheumatoid arthritis who did not respond adequately to disease-modifying antirheumatic drugs (DMARDs), mavrilimumab 150 mg combined with methotrexate (MTX) was found to be the most effective treatment, significantly improving ACR20 response rates compared to placebo.

Both mavrilimumab and tofacitinib treatments did not show a significant increase in serious adverse events, indicating that these interventions are safe options for patients with inadequate responses to DMARDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and mavrilimumab in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Sung, YK., Lee, YH.[2021]

Namilumab, a monoclonal antibody targeting GM-CSF, showed significant efficacy in reducing disease activity in rheumatoid arthritis patients who did not respond adequately to methotrexate or TNF inhibitors, with a notable improvement in the Disease Activity Score (DAS28-CRP) at week 12.

The treatment was well-tolerated, with no serious infections reported, although one serious adverse event (myocardial infarction) occurred in the highest dose group; overall, the safety profile was acceptable over the 12-week study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial. Taylor, PC., Saurigny, D., Vencovsky, J., et al.[2020]

In a study involving 369 patients with rheumatoid arthritis, switching from adalimumab to sarilumab monotherapy led to significant improvements in disease activity, with 47.1% of switch patients showing meaningful changes in their Disease Activity Score by week 12 of the open-label extension.

The safety profile of sarilumab remained consistent with previous reports, showing no unexpected safety issues, and patients who continued on sarilumab experienced sustained benefits in disease management over the 48-week period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of switching from adalimumab to sarilumab in patients with rheumatoid arthritis in the ongoing MONARCH open-label extension. Burmester, GR., Strand, V., Rubbert-Roth, A., et al.[2020]

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]

In a study of 40 patients with juvenile rheumatoid arthritis, the combination of leflunomide and methotrexate showed significantly greater clinical improvement compared to methotrexate alone, with improvement rates of 39.6% at 12 weeks and 71.9% at 26 weeks for the combination therapy.

The combination therapy was found to be safe and well tolerated, with no significant difference in side effects between the two groups, indicating that leflunomide can be effectively added to methotrexate without increasing the risk of adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of patients with juvenile rheumatoid arthritis with combination of leflunomide and methotrexate]. Gao, JS., Wu, H., Tian, J.[2018]

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]

Lenalidomide has shown significant efficacy in improving survival rates for patients with relapsed and refractory myeloma, especially when used alongside other treatments like bortezomib and thalidomide.

While lenalidomide is effective, it is associated with common side effects such as fatigue and thrombocytopenia, and its combination with other agents can increase the risk of blood clots, highlighting the importance of managing these adverse events for continued treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide for the treatment of relapsed and refractory multiple myeloma. van de Donk, NW., Görgün, G., Groen, RW., et al.[2021]

Janus kinase inhibitors (JAKi) combined with methotrexate (MTX) were more effective than JAKi alone in achieving American College of Rheumatology (ACR) response criteria in patients with active rheumatoid arthritis, based on a pooled analysis of three randomized controlled trials involving 2,290 patients.

While the combination therapy showed better efficacy in terms of ACR responses and achieving low disease activity and remission, it also presented a higher risk of treatment-emergent adverse events compared to JAKi monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of JAK inhibitors as monotherapy and in combination with methotrexate in patients with active rheumatoid arthritis: A systematic review and meta-analysis. Liu, L., Yan, YD., Shi, FH., et al.[2023]

Lenalidomide combined with dexamethasone has been shown to be effective for treating relapsed/refractory multiple myeloma, and it has received approval from both the FDA and EMA for patients who have undergone at least one prior therapy.

The most common serious side effects include cytopenias and infections, but an expert panel has provided management strategies to minimize these risks, ensuring that patients can receive the full benefits of the treatment without unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Palumbo, A., Dimopoulos, M., San Miguel, J., et al.[2018]

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]

Lenalidomide maintenance therapy significantly prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation, as shown in pivotal phase 3 trials like IFM 2005-02 and CALGB 100104.

While lenalidomide is associated with some increased risks, such as grade 3/4 adverse events and a higher chance of second primary cancers, the overall survival benefits outweigh these risks, making it a valuable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Newly Diagnosed Multiple Myeloma as Maintenance Therapy After ASCT. Syed, YY.[2018]

Citations

1. cancernetwork.com cancernetwork.com/view/ruxolitinib-is-under-investigation-as-jak-inhibition-strategy-for-multiple-myeloma

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 ...

2. oncotarget.com oncotarget.com/news/pr/evaluation-of-ruxolitinib-a-janus-kinase-inhibitor-in-multiple-myeloma/

Evaluation of Ruxolitinib, a Janus Kinase Inhibitor, in ... Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10852065/

Preclinical and clinical evaluation of the Janus Kinase ... Ruxolitinib is able to block M2 polarization in macrophages (top left) and is able to inhibit the expression of immune checkpoint proteins ...

4. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(24)02465-0/fulltext

A Review of Real-World Experience With Ruxolitinib for ... Real-world evidence supports the effectiveness of ruxolitinib in improving splenomegaly and MF symptoms while significantly increasing overall survival.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8900057/

Real-World Outcomes of Ruxolitinib Treatment for ... Ruxolitinib has been demonstrated to have clinical efficacy in patients with PV with regards to hematocrit control, splenomegaly, and symptom management. The ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5774211/

Final analysis of survival outcomes in the phase 3 FIRST ... Key Points. Rd continuous significantly extended OS compared with MPT and resulted in comparable OS to that with Rd18 in patients with multiple myeloma.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0959804924017647

Characteristics and outcomes in patients with lenalidomide ... Newer drugs for multiple myeloma (MM) have improved patient outcomes; however, nearly all patients will relapse and require subsequent therapy [1], [2].

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3256976/

Safety and Efficacy of Lenalidomide in Relapsed or ... Combination lenalidomide and dexamethasone (Len+Dex) has been shown to increase response rates and prolong survival compared with dexamethasone alone.

9. myeloma.org myeloma.org/revlimid-lenalidomide

Revlimid (Lenalidomide) In the phase III FIRST clinical trial, 23% of the newly diagnosed patients experienced a decreased appetite. Of those, only 3% had weight loss or malnutrition.

10. clinicaltrials.gov clinicaltrials.gov/study/NCT00689936

NCT00689936 | Study to Determine Efficacy and Safety of ... The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose dexamethasone to that of the combination of melphalan, prednisone ...