Elotuzumab + Mezigdomide + Dexamethasone for Multiple Myeloma

Overseen By The Ohio State Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Abdullah Khan

Must not be taking: CYP3A modulators, Proton-pump inhibitors

Disqualifiers: Waldenstrom macroglobulinemia, AL amyloidosis, others

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

Compensation: Varies

Number of Visits: 17

Duration: Up to 2 years

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects, and best dose of CC-92480 in combination with elotuzumab and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment or has not responded to previous treatment (refractory). Multiple myeloma (MM) remains the second most common hematologic malignancy in the United States. A number of therapies have been approved for patients with MM, including CD38- and B-cell maturating antigen (BCMA)-targeted therapies (antibody and plasma cell treatments that help the body's immune system to kill cancer cells); however, patients will often relapse and become refractory to these therapies. Because of this, it is important to identify effective treatment options for patients progressing on anti-CD38 therapy and BCMA-directed therapies. Elotuzumab is a humanized IgG1 monoclonal antibody, which is a type of protein that can bind to other target cells to prevent them from working the way they should or cause them to act differently. Elotuzumab works by targeting a protein called SLAMF7, which is present on myeloma cells, and makes it easier for the immune system to target the cancer. CC-92480 works by binding to a protein called CRBN that triggers the breakdown of proteins: Ikaros and Aiolos, leading to cell death in multiple myeloma cells. Dexamethasone is a synthetic adrenocortical steroid, or steroid normally naturally made by the adrenal gland in the brain which has been produced in a laboratory, that helps to regulate the amount of different chemicals and water that are being processed by the kidneys. It is also used in patients with myeloma to help treat their disease. The combination of CC-92480 with elotuzumab and dexamethasone may be a safe and effective treatment when given to patients with relapsed or recurrent MM.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use strong CYP3A modulators or proton-pump inhibitors within 2 weeks before starting the trial drugs.

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

Research shows that Mezigdomide, a new type of drug, has strong effects against multiple myeloma, even in cases where other treatments have failed. Additionally, similar drugs like iberdomide have shown positive results when combined with dexamethasone, suggesting potential effectiveness for this combination. ^{1 2 3 4 5}

Is the combination of Elotuzumab, Mezigdomide, and Dexamethasone safe for humans?

Research on Mezigdomide and Dexamethasone in multiple myeloma patients shows that these drugs have been studied for safety, but specific safety data for the combination with Elotuzumab is not detailed in the available research. ^{1 2 6 7 8}

What makes the drug combination of Elotuzumab, Mezigdomide, and Dexamethasone unique for treating multiple myeloma?

This drug combination is unique because it includes Mezigdomide, a new type of drug that targets a protein called cereblon, which helps kill cancer cells even in cases resistant to other treatments. Elotuzumab, another component, works by activating the body's natural killer cells to attack the cancer, offering a novel approach compared to standard therapies. ^{1 3 9 10 11}

Research Team

Abdullah M. Khan, MBBS, MSc

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

Adults with relapsed or refractory multiple myeloma who've had at least two prior treatments including lenalidomide, a proteasome inhibitor, anti-CD38 antibody, and BCMA-targeted therapy. They must have proper heart function, be able to swallow pills, and have adequate blood counts and liver/kidney function. Women of childbearing potential and men must agree to use contraception.

Inclusion Criteria

Breastfeeding is not permitted

Your ECG test shows a QT interval of less than or equal to 470 milliseconds.

Patients must provide informed consent

Exclusion Criteria

I do not have high-risk heart conditions.

I am taking corticosteroids for reasons other than basic bodily functions.

I am not using alternative medicines that could affect the study's drug results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive elotuzumab, CC-92480, and dexamethasone in 28-day cycles

Up to 2 years

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 12 weeks

Treatment Details

Interventions

• CC-92480
• Dexamethasone
• Elotuzumab

Trial Overview The trial is testing the combination of CC-92480 with elotuzumab and dexamethasone for safety, side effects, and optimal dosage in patients whose multiple myeloma has returned or resisted treatment. These drugs work together to target cancer cells more effectively.

Participant Groups

Group I: Treatment (elotuzumab, CC-92480, dexamethasone) Experimental Treatment 10 Interventions

Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.

Who Is Running the Clinical Trial?

Abdullah Khan

Lead Sponsor

Trials

2

Recruited

30+

Findings from Research

In a phase 1-2 study involving 178 patients with relapsed and refractory multiple myeloma, the combination of mezigdomide and dexamethasone demonstrated an overall response rate of 41%, indicating promising efficacy for this treatment in heavily pretreated patients.

The most common side effects were neutropenia and infections, which were mostly reversible, suggesting that while the treatment has myelotoxic effects, it does not present unexpected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma. Richardson, PG., Trudel, S., Popat, R., et al.[2023]

Iberdomide combined with dexamethasone demonstrated meaningful clinical activity in heavily pretreated patients with relapsed or refractory multiple myeloma, achieving an overall response rate of 32% in the dose-escalation cohort and 26% in the dose-expansion cohort, indicating its potential effectiveness even in difficult-to-treat cases.

The treatment was generally safe, with a recommended phase 2 dose established at 1.6 mg, although some patients experienced serious adverse events, including neutropenia and infections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lonial, S., Popat, R., Hulin, C., et al.[2022]

In a phase 1/2 trial involving 65 patients with newly diagnosed multiple myeloma, the combination of oral ixazomib, lenalidomide, and dexamethasone was found to be generally well tolerated, with a maximum tolerated dose of ixazomib established at 2.97 mg/m².

The treatment resulted in a very good partial response or better in 58% of patients, indicating significant efficacy and supporting further phase 3 trials for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Kumar, SK., Berdeja, JG., Niesvizky, R., et al.[2019]

Thalidomide and similar drugs are important treatments for multiple myeloma, as they target cereblon, a protein that plays a crucial role in protein degradation.

By binding to cereblon, these drugs change how the ubiquitin ligase complex works, leading to the destruction of Ikaros and Aiolos, which are key transcription factors needed for the growth of multiple myeloma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. Licht, JD., Shortt, J., Johnstone, R.[2021]

In a study involving 43 East Asian patients with relapsed/refractory multiple myeloma, the oral proteasome inhibitor ixazomib was found to be rapidly absorbed and had a recommended phase 2/3 dose of 4.0 mg, with no dose-limiting toxicities reported.

The combination of ixazomib with lenalidomide and dexamethasone showed promising efficacy, with 65% of response-evaluable patients achieving at least a partial response, indicating that this treatment regimen is both active and well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study. Gupta, N., Goh, YT., Min, CK., et al.[2019]

The study identified argonaute 2 (AGO2) as a key cereblon binding partner that is regulated by the immunomodulatory drug lenalidomide, which affects multiple myeloma (MM) cell survival.

Silencing AGO2 in MM cells led to significant cell death, suggesting that targeting AGO2 could be a promising strategy to overcome resistance to IMiDs like lenalidomide in treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. Xu, Q., Hou, YX., Langlais, P., et al.[2020]

Thalidomide and its derivatives, lenalidomide and pomalidomide, are FDA-approved immunomodulatory drugs that play a crucial role in treating multiple myeloma, confirmed by large phase 3 trials.

The review highlights the recently understood mechanism of action of these drugs, which involves binding to cereblon, and discusses potential resistance mechanisms that may limit their effectiveness in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cereblon binding molecules in multiple myeloma. Kortüm, KM., Zhu, YX., Shi, CX., et al.[2020]

Avadomide, when combined with obinutuzumab, demonstrated manageable toxicity in patients with relapsed or refractory non-Hodgkin lymphoma, with a recommended phase 2 dose established at 3.0 mg.

Although the study did not meet the prespecified threshold for activity, the preliminary antitumor effects suggest that this combination could be a promising chemotherapy-free treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study. Michot, JM., Bouabdallah, R., Vitolo, U., et al.[2020]

In the phase III ELOQUENT-2 trial involving adults with relapsed multiple myeloma, elotuzumab combined with lenalidomide and dexamethasone significantly improved progression-free survival and overall response rates compared to the standard treatment alone.

The addition of elotuzumab did not negatively affect health-related quality of life and had a manageable safety profile, with the most common serious side effects being blood-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Lamb, YN.[2019]

In a study of 117 patients with relapsed or refractory multiple myeloma, those treated with elotuzumab plus pomalidomide and dexamethasone experienced a median progression-free survival of 10.3 months, compared to 4.7 months for those receiving pomalidomide and dexamethasone alone, indicating a significant improvement in treatment efficacy.

The overall response rate was also higher in the elotuzumab group at 53% versus 26% in the control group, with fewer severe adverse events like neutropenia and anemia, suggesting that elotuzumab may enhance treatment outcomes while maintaining a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. Dimopoulos, MA., Dytfeld, D., Grosicki, S., et al.[2019]

Elotuzumab is a humanized monoclonal antibody that targets a specific protein on plasma cells, showing significant clinical activity in treating multiple myeloma, particularly when used in combination with other drugs like lenalidomide and dexamethasone.

The mechanism of action for elotuzumab involves enhancing the immune response through natural killer (NK) cells, which helps to destroy myeloma cells, making it an effective treatment option for patients with relapsed myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on elotuzumab for the treatment of relapsed/refractory multiple myeloma: patients' selection and perspective. Trudel, S., Moreau, P., Touzeau, C.[2020]

References

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

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. [2022]

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

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. [2019]

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

From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study. [2019]

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

Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Cereblon binding molecules in multiple myeloma. [2020]

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

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study. [2020]

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

Elotuzumab: A Review in Relapsed and/or Refractory Multiple Myeloma. [2019]

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

Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. [2019]

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

Update on elotuzumab for the treatment of relapsed/refractory multiple myeloma: patients' selection and perspective. [2020]