Mezigdomide After CAR T-cell Therapy for Multiple Myeloma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4/5 inhibitors, Proton pump inhibitors

Disqualifiers: Active CNS involvement, COVID-19, others

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

Compensation: Varies

Number of Visits: 31

Duration: 48 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the safety, side effects, best dose and effectiveness of mezigdomide (CC-92480) when given after idecabtagene vicleucel (Abecma chimeric antigen receptor \[CAR\] T-cell therapy) in patients with multiple myeloma that has come back after a period of improvement (relapsed). 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. Giving mezigdomide after Abecma CAR T cell therapy may extending the amount of time that the CAR T cells persist in the body in patients with relapsed multiple myeloma.

Will I have to stop taking my current medications?

The trial requires that participants do not use other therapies besides mezigdomide and avoid certain medications like CYP3A4/5 inhibitors, inducers, and proton pump inhibitors. If you are on these medications, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug Mezigdomide for multiple myeloma?

Research shows that Mezigdomide, a new type of drug that targets a protein called cereblon, has strong anti-cancer effects in lab models of multiple myeloma, even in cases where other similar drugs like lenalidomide and pomalidomide have failed. This suggests it could be effective for patients whose cancer has returned or not responded to previous treatments. ^{1 2 3 4 5}

Is Mezigdomide safe for humans?

Mezigdomide, also known as CC-92480, is a new type of drug being studied for multiple myeloma, a type of blood cancer. While the research focuses on its effectiveness, it is important to note that it is still in clinical trials, which means its safety is being carefully monitored and evaluated. ^{1 2 3 4 5}

How is the drug Mezigdomide unique for treating multiple myeloma after CAR T-cell therapy?

Mezigdomide is unique because it is a novel cereblon E3 ubiquitin ligase modulator, which means it works by targeting specific proteins for degradation, showing strong anti-cancer activity even in cases resistant to other similar drugs like lenalidomide and pomalidomide. ^{1 2 3 4 6}

Research Team

Murali Janakiram

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with relapsed multiple myeloma who've had at least four prior treatments, including specific agents like immunomodulatory drugs and proteasome inhibitors. They must have shown a stable disease response to CAR T-cell therapy (idecabtagene vicleucel), be in good health otherwise, and not pregnant or breastfeeding. Participants need normal organ function tests and can't be on certain other medications or have uncontrolled infections.

Inclusion Criteria

Assent, when appropriate, will be obtained per institutional guidelines

Agreement by females of childbearing potential and males to follow the guidelines of the mezigdomide (CC-92480) pregnancy prevention plan

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

If you have HIV, your CD4+ T cell count is less than 200.

Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive mezigdomide orally on days 1-21 or days 1-14 of each cycle, repeating every 28 days for up to 12 cycles

48 weeks

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Follow-up at 30 days, every 3 months within 1 year, then every 6 months

Treatment Details

Interventions

• Mezigdomide

Trial Overview The trial is testing the safety and effectiveness of Mezigdomide given after CAR T-cell therapy in patients with relapsed multiple myeloma. It will determine the best dose while monitoring how long the CAR T cells stay active post-treatment. The study includes various assessments like CT scans, PET scans, bone marrow aspirations, and biospecimen collection.

Participant Groups

Group I: Treatment (mezigdomide) Experimental Treatment 5 Interventions

Starting between 30 and 90 days after infusion of idecabtagene vicleucel, patients receive mezigdomide PO on days 1-21 or days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT during screening. Patients also undergo bone marrow aspiration and blood sample collection throughout the study.

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

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]

Novel cereblon E3 ligase modulators (CELMoDs) show promise for treating relapsed or refractory multiple myeloma (RRMM), particularly in patients resistant to lenalidomide, by enhancing degradation efficiency and kinetics.

CC-92480 is the first CELMoD to enter clinical development, specifically designed for rapid protein degradation, which may improve treatment outcomes for patients with RRMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. Hansen, JD., Correa, M., Nagy, MA., 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]

CC-220 (compound 6) is a new cereblon modulator that binds more tightly to the cereblon protein than existing drugs lenalidomide and pomalidomide, leading to more effective degradation of the transcription factors Ikaros and Aiolos.

The enhanced binding affinity of CC-220 results in greater cellular degradation of these targets, suggesting it may offer improved therapeutic potential for conditions like systemic lupus erythematosus and relapsed/refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. Matyskiela, ME., Zhang, W., Man, HW., et al.[2021]

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]

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

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Cereblon binding molecules in multiple myeloma. [2020]

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

A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. [2021]

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]