CC-92480 + Other Drugs for Multiple Myeloma

Recruiting at 26 trial locations

Overseen By BMS Study Connect Contact Center www.BMSStudyConnect.com

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bristol-Myers Squibb

Must not be taking: Investigational agents

Disqualifiers: CNS involvement, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

160 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the safety, tolerability and preliminary effectiveness of CC-92480 (BMS-986348) in novel therapeutic combinations for the treatment of Relapsed or Refractory Multiple Myeloma (RRMM).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot have used any systemic anti-myeloma drug therapy within 14 days before starting the study treatment.

What data supports the effectiveness of the drug CC-92480 in treating multiple myeloma?

Research shows that CC-92480, a cereblon E3 ubiquitin ligase modulating drug, has potent antimyeloma activity. Mezigdomide, a similar drug, has shown strong tumor-killing effects in multiple myeloma models, even in cases resistant to other treatments. ^{1 2 3 4 5}

Is CC-92480 safe for humans?

The safety of CC-92480 in humans is not directly addressed in the provided research articles. However, it is a cereblon E3 ubiquitin ligase modulator with potent antimyeloma activity, and similar drugs in this class have been used in multiple myeloma treatment. Further clinical trials would be needed to determine its safety in humans. ^{2 3 4 5 6}

What makes the drug CC-92480 unique for treating multiple myeloma?

CC-92480, also known as Mezigdomide, is unique because it is a cereblon E3 ubiquitin ligase modulator that shows strong activity against multiple myeloma, even in cases resistant to other similar drugs like lenalidomide and pomalidomide. This drug works by targeting specific proteins essential for the growth of myeloma cells, making it a promising option for patients with relapsed or refractory multiple myeloma. ^{1 2 3 4 6}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with Multiple Myeloma that has come back or didn't respond to treatment. They must have measurable disease, be in good physical condition (ECOG PS of 0 or 1), and not suitable for other effective treatments. Participants can't join if they've had certain prior therapies, recent stem-cell transplants, CNS involvement by MM, recent SARS-CoV-2 infection, major surgery, radiation therapy, anti-myeloma drugs or investigational agents within specific time frames.

Inclusion Criteria

My multiple myeloma has worsened despite treatment.

My multiple myeloma hasn't responded to, or I can't tolerate, standard treatments.

Agree to follow the CC-92480 Pregnancy Prevention Plan (PPP)

Exclusion Criteria

I have previously been treated with CC-92480, tazemetostat, BMS-986158, or trametinib.

I haven't had major surgery, certain therapies, or a COVID-19 vaccine recently.

I have had a stem-cell transplant from a donor or my own within the last 12 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

Participants receive varying doses of CC-92480 in combination with other treatments to determine the optimal dose

8-12 weeks

Dose Expansion

Participants receive the optimal dose of CC-92480 in combination with other treatments to further assess safety and efficacy

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• BMS-986158
• CC-92480
• Dexamethasone
• Tazemetostat
• Trametinib

Trial Overview The study tests the safety and effectiveness of CC-92480 (BMS-986348) combined with other drugs like BMS-986158, Trametinib, Dexamethasone and Tazemetostat in treating Relapsed/Refractory Multiple Myeloma. It aims to find out how well these combinations work together.

Participant Groups

Group I: Part 2 Arm G: Dose Expansion Experimental Treatment 3 Interventions

Group II: Part 2 Arm E: Dose Expansion Experimental Treatment 3 Interventions

Group III: Part 1 Arm C: Dose Finding Experimental Treatment 3 Interventions

Group IV: Part 1 Arm B: Dose Finding Experimental Treatment 3 Interventions

Group V: Part 1 Arm A: Dose Finding Experimental Treatment 3 Interventions

Group VI: Part 2 Arm D: Dose Expansion Active Control 2 Interventions

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

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]

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]

A sensitive method was developed to measure CC-92480 levels in rat plasma, showing excellent accuracy and reliability, which is crucial for understanding its pharmacokinetics.

CC-92480 demonstrated a high oral bioavailability of over 63%, and its metabolic pathways were identified, indicating potential routes for drug metabolism that could inform future studies on its efficacy in treating myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry. You, W., Pang, J.[2021]

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]

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]

Cereblon (CRBN) is a key target for thalidomide and its derivatives, which are known as immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, highlighting their role in modulating CRBN activity.

Recent structural analyses have shown that IMiDs uniquely control the degradation of specific transcription factors through the CRBN-CRLA ubiquitin ligase pathway, suggesting a targeted mechanism of action that is particularly relevant for treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Thalidomide, cereblon and multiple myeloma]. Ogura, T.[2020]

References

1. 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]

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

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

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

Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry. [2021]

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

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]

6. Japan pubmed.ncbi.nlm.nih.gov

[Thalidomide, cereblon and multiple myeloma]. [2020]