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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for multiple myeloma, a type of blood cancer. Researchers aim to determine the safety and optimal dose of the drugs elotuzumab, mezigdomide (also known as CC-92480, a cereblon modulator), and dexamethasone to assess their effectiveness in treating cancer when previous treatments have failed. The trial targets individuals whose multiple myeloma has returned or not responded to other treatments. Those who have undergone at least two previous treatments for multiple myeloma and continue to experience issues might be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the combination of elotuzumab, mezigdomide, and dexamethasone is under study to assess its safety and effectiveness in treating multiple myeloma, a type of blood cancer. Elotuzumab, used with other drugs for this condition, is usually well-tolerated but can cause side effects like tiredness and fever.

Mezigdomide, a newer drug under testing, might cause fewer side effects with carefully adjusted doses. Early research has shown promising effects in boosting the immune system in lab studies.

Dexamethasone, a steroid often used in treating multiple myeloma, can cause side effects like mood changes or stomach upset but is generally considered safe at the doses used for this condition.

While these findings are encouraging, researchers continue to test the combination of these three drugs to ensure safety. This involves determining the best doses and monitoring for any unexpected side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of elotuzumab, mezigdomide (CC-92480), and dexamethasone for treating multiple myeloma because it introduces a potentially game-changing mechanism. Unlike standard treatments that mainly target cancer cells directly, this regimen enhances the immune system's ability to recognize and attack these cells. Elotuzumab, an antibody, works by activating natural killer cells, while mezigdomide is a novel cereblon modulator that boosts the immune response and enhances the killing effect. This combination approach not only aims to tackle the cancer more effectively but may also help in overcoming resistance seen in standard therapies.

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

Research shows that a combination of three treatments—elotuzumab, CC-92480, and dexamethasone—may help treat relapsed or refractory multiple myeloma, a type of blood cancer. Participants in this trial will receive this combination therapy. Elotuzumab helps the immune system find and attack myeloma cells by targeting a specific protein. CC-92480 causes certain proteins in myeloma cells to break down, leading to cell death. Dexamethasone, a steroid, supports the treatment process. Studies have found that using these treatments together can be more effective than using them separately, especially for patients who haven't had success with other treatments. Overall, early research suggests this combination could be a promising option for patients seeking new treatment strategies. ^{1 2 3 6 7}

Who Is on the Research Team?

Abdullah M. Khan, MBBS, MSc

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05981209

Study Details | NCT05981209 | Elotuzumab, CC-92480 ... 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 ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1013/499010/Mezigdomide-MEZI-Plus-Dexamethasone-DEX-and

Mezigdomide (MEZI) Plus Dexamethasone (DEX) and ... In preclinical studies, MEZI showed synergy with anti-myeloma drugs including DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123076164

Mezigdomide (MEZI) Plus Dexamethasone (DEX) and ... Here we report the preliminary efficacy and safety of MEZI, DARA, and DEX (MeziDd) over 3 dosing schedules, as well as MEZI, ELO and DEX (MeziEd), in pts with ...

4. myeloma.org myeloma.org/videos/mezigdomide-mezi-plus-dexamethasone-dex-daratumumab-dara-or-elotuzumab-elo-patients-pts

MEZI Combo Therapy for Relapsed Myeloma Dr. Paul G. Richardson reports on the use of various mezigdomide combinations in the treatment of relapsed/refractory multiple myeloma.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12102281/

Real world outcomes with elotuzumab-based therapies for ... In this retrospective analysis, we aim to evaluate the real-world efficacy and the clinical outcomes of RRMM patients treated with Elo+ImiD+Dex ...

6. myeloma.org myeloma.org/empliciti-elotuzumab

Empliciti (Elotuzumab) Empliciti® (elotuzumab) is treats multiple myeloma in combination with other drugs. Read about possible side effects, dosing schedule and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10969776/

Mezigdomide—A Novel Cereblon E3 Ligase Modulator ... Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its ...