Novel Drug Combinations for Multiple Myeloma

Recruiting at 27 trial locations

Overseen By First line of the email MUST contain NCT # and Site #.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

Disqualifiers: CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

111 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to establish a safe and tolerable dose of BMS-986393 in combinations with alnuctamab, mezigdomide, and iberdomide in participants with relapsed and/or refractory multiple myeloma (RRMM).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combinations involving Alnuctamab and other agents for treating multiple myeloma?

Research shows that Mezigdomide and Iberdomide, both part of the drug combinations, have demonstrated strong anti-cancer effects in multiple myeloma, even in cases resistant to other treatments. These drugs work by targeting specific proteins involved in cancer cell growth, making them promising options for patients with relapsed or hard-to-treat multiple myeloma. ^{1 2 3 4 5}

Is the novel drug combination for multiple myeloma safe for humans?

Iberdomide and Mezigdomide, both novel drugs being studied for multiple myeloma, have shown potential in preclinical models. However, specific safety data from human trials is not detailed in the provided research articles. ^{1 2 6 7 8}

What makes the drug combination of Alnuctamab, BMS-986393, Iberdomide, and Mezigdomide unique for treating multiple myeloma?

This drug combination is unique because it includes novel cereblon E3 ligase modulators (CELMoDs) like Iberdomide and Mezigdomide, which have enhanced tumor-killing and immune-boosting effects compared to traditional treatments. These drugs are designed to work even in cases where other treatments, like lenalidomide, have failed, offering a new option for patients with relapsed or refractory multiple myeloma. ^{1 2 3 4 8}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for people with multiple myeloma that has come back or didn't respond to treatment. They must have had at least one but not more than three prior treatments and be in good physical condition. People can't join if their cancer has spread to the brain or they have other health issues that could affect the study results.

Inclusion Criteria

I have multiple myeloma that has come back or didn't respond to treatment, and I've had 1-3 prior treatments.

I am fully active or can carry out light work.

My multiple myeloma can be measured.

Exclusion Criteria

My multiple myeloma has affected or previously affected my brain or spinal cord.

You have a health condition that could make it hard to understand the study results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BMS-986393 in combination with either alnuctamab, mezigdomide, or iberdomide to establish a safe and tolerable dose

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alnuctamab
• BMS-986393
• Iberdomide
• Mezigdomide

Trial Overview The trial is testing BMS-986393 combined with alnuctamab, mezigdomide, and iberdomide to find a safe dose for patients whose multiple myeloma has relapsed or isn't responding to treatment.

Participant Groups

Group I: Arm C: BMS-986393 + Iberdomide Experimental Treatment 2 Interventions

Group II: Arm B: BMS-986393 + Mezigdomide Experimental Treatment 2 Interventions

Group III: Arm A: BMS-986393 + Alnuctamab Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

Lead Sponsor

Trials

19

Recruited

3,100+

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]

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]

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]

Cereblon-targeting immunomodulatory agents like lenalidomide and pomalidomide are crucial in treating Multiple Myeloma due to their ability to enhance anti-tumor effects and work well with other therapies.

Next-generation cereblon E3 ligase modulators, such as iberdomide and CC-92480, are being developed to improve treatment outcomes, highlighting the importance of understanding drug mechanisms and patient-specific factors in creating effective combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Thakurta, A., Pierceall, WE., Amatangelo, MD., 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]

Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide have significantly improved outcomes for patients with multiple myeloma, being effective in various treatment settings including newly diagnosed and relapsed cases.

The mechanism of action for IMiDs involves binding to cereblon, which regulates the ubiquitination of important transcription factors, enhancing their therapeutic effects while also raising concerns about potential risks for secondary malignancies and thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience. Holstein, SA., McCarthy, PL.[2018]

Immunomodulatory drugs (IMiDs) have significantly improved the prognosis for multiple myeloma (MM) patients by targeting the cereblon (CRBN) protein, leading to the degradation of survival proteins in MM cells.

The review highlights the potential of next-generation CRBN E3 ligase modulators (CELMoDs) and proteolysis targeting chimeras (PROTACs) as innovative strategies for treating MM and other cancers by expanding the range of targetable proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma. Barankiewicz, J., Salomon-Perzyński, A., Misiewicz-Krzemińska, I., et al.[2022]

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

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

4. 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]

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

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. [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]

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

Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma. [2022]