Iberdomide + Daratumumab vs. Bortezomib for Multiple Myeloma

(EXCALIBER-RRMM Trial)

Recruiting at 681 trial locations

Overseen By BMS Clinical Trials Contact Center www.BMSClinicalTrials.com

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Celgene

Disqualifiers: Plasma cell leukemia, Waldenstrom's, POEMS, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 5 years

864 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatment combinations for multiple myeloma, a type of blood cancer, to determine which works better. It compares a new drug, iberdomide, with an existing treatment, bortezomib (also known as Velcade), both used alongside daratumumab and dexamethasone. Researchers aim to discover which combination is more effective and safer for patients whose cancer has returned or is not responding to previous treatments. The trial seeks participants diagnosed with multiple myeloma who have undergone 1 to 2 previous treatments and whose disease has worsened after their last treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to access potentially groundbreaking treatments.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of iberdomide, daratumumab, and dexamethasone is generally easy for patients to handle. Studies have found that this combination works well for patients with multiple myeloma and has a manageable safety profile. Previous research indicated that patients found the treatment both effective and tolerable.

The other treatment being compared, which includes daratumumab, bortezomib, and dexamethasone, is already commonly used for multiple myeloma. Its safety record is well-known, and any side effects are generally known and manageable due to its prior use in treating this condition.

In summary, past studies have shown that both treatment options in this trial are well-tolerated. As with any treatment, side effects might occur, but these are usually manageable with proper care and monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Iberdomide and Daratumumab for treating multiple myeloma because it introduces a new mechanism of action. Unlike current treatments like Bortezomib, which primarily target proteasomes in cancer cells, Iberdomide is an oral drug that modulates the immune system to enhance the body's ability to fight cancer. This novel approach, paired with the established efficacy of Daratumumab, a monoclonal antibody that targets CD38 on myeloma cells, offers a potentially more effective treatment option. Additionally, the convenience of Iberdomide's oral administration could improve patient adherence compared to injectable therapies.

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

This trial will compare two treatment combinations for relapsed or refractory multiple myeloma (RRMM). One group of participants will receive iberdomide, daratumumab, and dexamethasone (IberDd). Studies have shown that IberDd holds promise for treating RRMM, as iberdomide is a new drug that boosts the immune system to attack cancer cells, and patients receiving this combination have lived longer overall. Another group will receive daratumumab, bortezomib, and dexamethasone (DVd). This combination has effectively managed RRMM, with many patients experiencing longer periods without disease progression. Researchers are carefully studying both combinations in this trial to determine which might offer the best results for patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for people with multiple myeloma who've had 1-2 previous treatments but their cancer has gotten worse. They should be fairly active and able to do light work (ECOG score of 0, 1, or 2). It's not for those with certain other blood disorders, brain involvement by myeloma, or anyone previously treated with Iberdomide.

Inclusion Criteria

I have been diagnosed with multiple myeloma and it can be measured.

My myeloma has worsened despite my last treatment.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

Any condition that confounds the ability to interpret data from the study

Other protocol-defined Inclusion/Exclusion criteria apply

My multiple myeloma has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Iberdomide, Daratumumab, and Dexamethasone (IberDd) or Daratumumab, Bortezomib, and Dexamethasone (DVd) until confirmed progressive disease, unacceptable toxicity, or withdrawal of consent

Up to approximately 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment discontinuation for reasons other than confirmed progressive disease or withdrawal of consent

Up to approximately 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Iberdomide

Trial Overview The study compares two drug combos in patients whose multiple myeloma has returned or didn't respond to treatment: one group gets Iberdomide with Dexamethasone and Daratumumab; the other gets Daratumumab, Bortezomib, and Dexamethasone. The goal is to see which works better.

How Is the Trial Designed?

Group I: Daratumumab in combination with Iberdomide and dexamethasone - Dose 3 Experimental Treatment 3 Interventions

Group II: Daratumumab in combination with Iberdomide and dexamethasone - Dose 2 Experimental Treatment 3 Interventions

Group III: Daratumumab in combination with Iberdomide and dexamethasone - Dose 1 Experimental Treatment 3 Interventions

Participants will receive oral iberdomide, subcutaneous daratumumab and oral dexamethasone.

Group IV: Daratumumab in combination with dexamethasone and bortezomib Active Control 3 Interventions

Participants will receive subcutaneous daratumumab, bortezomib and oral dexamethasone

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Celgene

Lead Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

In the phase 3 LEPUS study involving 211 Chinese patients with relapsed or refractory multiple myeloma, the combination of daratumumab, bortezomib, and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) compared to bortezomib and dexamethasone alone (median PFS of 14.8 months vs. 6.3 months).

D-Vd also showed higher overall response rates and better response quality, with 84.7% of patients achieving an overall response compared to 66.7% with Vd, and no new safety concerns were identified, supporting D-Vd as a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS. Fu, W., Li, W., Hu, J., et al.[2023]

The addition of daratumumab to bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) for treating relapsed or refractory multiple myeloma was shown to be effective, but the cost-effectiveness of these combinations is questionable due to high costs.

The incremental cost-effectiveness ratio (ICER) for DVd was $284,180 per quality-adjusted life year (QALY) and for DRd was $1,369,062 per QALY, indicating that significant price reductions for daratumumab would be necessary for these treatments to be considered cost-effective in the US healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma. Zhang, TT., Wang, S., Wan, N., et al.[2019]

In a study of 23 patients with relapsed or refractory multiple myeloma, both low (1.0 mg/m2) and standard (1.3 mg/m2) doses of bortezomib combined with dexamethasone showed similar response rates, with 70% for the low dose and 61.5% for the standard dose, indicating that lower doses can be just as effective.

However, the standard dose of 1.3 mg/m2 was associated with more adverse effects, including serious infections and treatment-related deaths, suggesting that while it may be more effective, it also carries a higher risk of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of bortezomib at different doses in combination with dexamethasone in treatment of relapsed or refractory multiple myeloma: a comparative study]. Bao, L., Lu, XJ., Zhang, XH., et al.[2015]

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 the final analysis of the CASTOR study, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly improved overall survival (OS) in patients with relapsed or refractory multiple myeloma, with a median OS of 49.6 months compared to 38.5 months for bortezomib and dexamethasone alone (Vd).

The study, which followed patients for a median of 72.6 months, found that D-Vd provided OS benefits across various subgroups, including older patients and those with high-risk disease, although it was associated with higher rates of certain adverse events like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. Sonneveld, P., Chanan-Khan, A., Weisel, K., et al.[2023]

In a phase 3 study (CASTOR) with a median follow-up of 19.4 months, the combination of daratumumab, bortezomib, and dexamethasone significantly improved progression-free survival (16.7 months) compared to bortezomib and dexamethasone alone (7.1 months), indicating its efficacy in treating relapsed/refractory multiple myeloma.

Daratumumab plus bortezomib and dexamethasone also showed a higher overall response rate (83.8% vs. 63.2%) and was particularly beneficial for patients with one prior line of therapy, demonstrating a favorable safety profile consistent over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Spencer, A., Lentzsch, S., Weisel, K., et al.[2019]

In a study of 22 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and dexamethasone (BD therapy) resulted in a high response rate, with 77.3% achieving at least a partial response, indicating its efficacy.

Switching to a once-weekly administration of bortezomib after initial twice-weekly treatment significantly reduced severe gastrointestinal side effects while maintaining the therapy's effectiveness, suggesting a safer dosing strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Fukushima, T., Nakamura, T., Iwao, H., et al.[2015]

In a subgroup analysis of the CASTOR trial involving 498 patients, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) in patients with high cytogenetic risk (12.6 months) compared to bortezomib and dexamethasone alone (6.2 months).

D-Vd also demonstrated a higher rate of minimal residual disease (MRD) negativity, indicating deeper responses in treatment effectiveness, while maintaining a safety profile consistent with the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. Weisel, K., Spencer, A., Lentzsch, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04975997

NCT04975997 | Open-label Study Comparing Iberdomide, ... To evaluate clinical efficacy in terms of overall survival (OS) in participants with relapsed or refractory multiple myeloma (RRMM) treated with iberdomide, ...

2. bmsclinicaltrials.com bmsclinicaltrials.com/us/en/clinical-trials/NCT04975997

Trial ID CC-220-MM-002 | NCT04975997 - BMS Clinical Trials This is a multicenter, two-stage, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of iberdomide in combination with ...

3. clinicaltrialsregister.eu clinicaltrialsregister.eu/ctr-search/trial/2020-000431-49/FI

Clinical Trials Register A clinical study that compares a treatment with Iberdomide, Daratumumab and Dexamethasone against a treatment with Daratumumab, Bortezomib ...

4. bmsstudyconnect.com bmsstudyconnect.com/mx/en/clinical-trials/NCT04975997.html

Open-label Study Comparing Iberdomide, Daratumumab and ... This is a multicenter, two-stage, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of iberdomide in ...

5. anzctr.org.au anzctr.org.au/Trial/Registration/TrialReview.aspx?id=19900&isClinicalTrial=True

ANZCTR - Registration To compare the efficacy of iberdomide (also known as BMS-986382), daratumumab, and dexamethasone (IberDd) to that of daratumumab, bortezomib, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02773030

NCT02773030 | A Study to Determine Dose, Safety ... The dose of CC-220 will not be higher than the dose of CC-220 used in combination with dexamethasone in Cohort B that has been determined to be safe.

7. onclive.com onclive.com/view/iberdomide-daratumumab-dexamethasone-is-effective-in-newly-diagnosed-multiple-myeloma

Iberdomide/Daratumumab/Dexamethasone Is Effective in ... Iberdomide plus daratumumab and dexamethasone yielded deep responses and had a manageable safety profile in transplant-ineligible multiple ...

8. cancernetwork.com cancernetwork.com/view/early-data-indicate-iberdomide-combination-yields-a-promising-safety-profile-in-relapsed-refractory-myeloma

Early Data Indicate Iberdomide Combination Yields a ... Iberdomide combined with dexamethasone and either daratumumab (Darzalex), bortezomib (Velcade), or carfilzomib (Kyprolis) showed efficacy and tolerability.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12150652/

EXCALIBER-RRMM: a phase III trial of iberdomide ... EXCALIBER-RRMM is a phase III study evaluating the efficacy and safety of IberDd versus DVd in patients with RRMM. aThe recommended dose for ...

10. targetedonc.com targetedonc.com/view/iberdomide-triplet-regimen-signals-deep-responses-in-multiple-myeloma

Iberdomide Triplet Regimen Signals Deep Responses in ... The iberdomide, daratumumab, and dexamethasone regimen achieved a 93.1% overall response rate in transplant-ineligible multiple myeloma patients ...