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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of mezigdomide when taken after CAR T-cell therapy in individuals with recurrent multiple myeloma. The researchers aim to determine if mezigdomide can prolong the activity of CAR T-cells in the body. Mezigdomide works by breaking down specific proteins in cancer cells, potentially aiding in their destruction. Individuals with multiple myeloma who have undergone CAR T-cell therapy and experienced a recurrence may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that mezigdomide has been safe in earlier studies. In one study, when combined with dexamethasone, mezigdomide was well-tolerated by patients who had already undergone multiple treatments for multiple myeloma, a type of blood cancer. Another study tested mezigdomide alone and found it safe, encouraging further research due to promising results.

Patients experienced some side effects, but they were generally manageable, meaning they could be controlled or treated. While specific side effects aren't listed, the overall safety appears promising enough for further study. This suggests that mezigdomide might be a safe option for those considering joining a trial after other treatments like CAR T-cell therapy. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Mezigdomide is unique because it offers a new approach for treating multiple myeloma, especially for patients who have already undergone CAR T-cell therapy. Unlike traditional treatments that often target the cancer cells directly, mezigdomide enhances the immune system by modulating specific proteins that can boost the body's ability to fight cancer. This novel mechanism of action sets it apart from the typical chemotherapy or proteasome inhibitors currently used. Researchers are excited about mezigdomide because it has the potential to work in synergy with previous therapies, potentially improving outcomes for patients who have limited options after CAR T-cell therapy.

What evidence suggests that mezigdomide might be an effective treatment for relapsed multiple myeloma?

Research shows that mezigdomide holds promise for treating multiple myeloma, a type of blood cancer. Studies have found that combining mezigdomide with dexamethasone works well for patients who have already tried many other treatments. This suggests it might be effective even when other options have failed. Mezigdomide attaches to a protein called CRBN, causing cancer cells to break down and die, which could help eliminate multiple myeloma cells. This trial tests whether mezigdomide can help CAR T cells, a type of immune cell, remain active in the body for a longer time. ^{1 5 6 7 8}

Who Is on the Research Team?

Murali Janakiram

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41163399/?utm_source=FeedFetcher&utm_medium=rss&utm_campaign=None&utm_content=1HoKZG5k4YSGTrpmxwd9h4jUYVua2toCx3K_3oQCgrtW4k5g1d&fc=None&ff=20251030091143&v=2.18.0.post22+67771e2

Mezigdomide for multiple myeloma: a focus on phase 2 ... Expert opinion: Mezigdomide, which is not currently approved for the treatment of MM, has higher cereblon binding affinity and greater potency ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303194

Mezigdomide plus Dexamethasone in Relapsed and ... The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06048250

Study Details | NCT06048250 | Mezigdomide (CC-92480) ... This phase I trial studies the safety, side effects, best dose and effectiveness of mezigdomide (CC-92480) when given after idecabtagene vicleucel (Abecma ...

4. tandfonline.com tandfonline.com/doi/full/10.1080/14728214.2025.2575570?src=

Mezigdomide for multiple myeloma: a focus on phase 2 ... Mezigdomide, which is not currently approved for the treatment of MM, has higher cereblon binding affinity and greater potency for substrate ...

5. sparkcures.com sparkcures.com/treatment/307/mezigdomide

Mezigdomide Myeloma Trials Results: As of May 9, 2024, 104 pts were enrolled in Cohorts A, C, and D; 28 pts received MeziVd (Cohort A) and 27 pts received MeziKd (Cohort C) in the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03374085?term=NCT03374085&rank=1

A Safety, PK and Efficacy Study of CC-92480 Monotherapy ... This is an open-label, multi-center, international, Phase 1/2 study to assess the safety, PK and efficacy of CC-92480 monotherapy and in combination with ...

7. onclive.com onclive.com/view/preliminary-efficacy-safety-data-drive-further-exploration-of-mezigdomide-based-combinations-in-r-r-myeloma

Preliminary Efficacy, Safety Data Drive Further Exploration ... David S. Siegel, MD, PhD, discusses early safety and efficacy data that support further development of mezigdomide-based combinations in multiple myeloma.

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265023014416

MM-360 Mezigdomide (MEZI) Plus Dexamethasone (DEX) ... MEZI+DEX demonstrated manageable safety and encouraging efficacy in heavily pretreated RRMM. MEZI is being evaluated with standard therapies in MM in an ...