Quadruple Therapy for Multiple Myeloma

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Mayo Clinic

Must not be taking: CYP3A4/5 inhibitors

Disqualifiers: HIV, Hepatitis C, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 11

49 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of iberdomide and how well it works in combination with daratumumab, bortezomib, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving iberdomide in combination with daratumumab, bortezomib, and dexamethasone may kill more cancer cells in patients with newly diagnosed multiple myeloma.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that any additional agents not listed must be approved by the principal investigator, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination used in the Quadruple Therapy for Multiple Myeloma?

Research shows that iberdomide, when combined with dexamethasone, has shown promising results in treating multiple myeloma, especially in patients who have already tried other treatments. Additionally, bortezomib combined with dexamethasone has been effective for patients with relapsed or hard-to-treat multiple myeloma. ^{1 2 3 4 5}

What safety data exists for the quadruple therapy involving Bortezomib, Daratumumab, Dexamethasone, and Iberdomide in humans?

Studies have shown that Bortezomib combined with Dexamethasone is generally safe for treating multiple myeloma, though it may cause some side effects like gastrointestinal issues. Iberdomide with Dexamethasone has also been evaluated for safety in heavily pretreated multiple myeloma patients, indicating it is generally safe but may have side effects. ^{1 2 3 6 7}

What makes the quadruple therapy for multiple myeloma unique?

This quadruple therapy combines four drugs—Bortezomib, Daratumumab, Dexamethasone, and Iberdomide—to target multiple myeloma in different ways, potentially offering a more comprehensive approach than existing treatments. Bortezomib is a proteasome inhibitor, Daratumumab is an antibody that targets cancer cells, Dexamethasone is a steroid that reduces inflammation, and Iberdomide is a new drug that modulates the immune system, making this combination novel and potentially more effective. ^{8 9 10 11 12}

Research Team

Prashant Kapoor, MD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

Adults with newly diagnosed multiple myeloma who haven't been treated or have had only one treatment cycle. They must have measurable disease, be in good physical condition, and have proper organ function. Pregnant or breastfeeding individuals can't join, nor can those unwilling to use contraception or those with certain medical conditions that could interfere with the trial.

Inclusion Criteria

I agree not to donate blood during the study.

Negative hepatitis B test

Willingness to provide mandatory bone marrow specimens for correlative research

Exclusion Criteria

I have no allergies to study drugs, haven't had major surgery, plasmapheresis, or investigational treatments recently.

I haven't had live vaccines recently and have no cancer history except MM, with some exceptions.

I am HIV positive or have active hepatitis B or C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive iberdomide, bortezomib, dexamethasone, and daratumumab in a 28-day cycle for 12 cycles

48 weeks

4 visits per cycle (in-person)

Maintenance

Patients receive iberdomide monotherapy in a 28-day cycle for up to 36 cycles

24 months

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 6 months

Treatment Details

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Iberdomide

Trial Overview The IDEAL study is testing a combination of drugs: Iberdomide (an immunotherapy), Daratumumab (a monoclonal antibody), Bortezomib (blocks enzymes for cell growth), and Dexamethasone (chemotherapy). The goal is to find the best dose of Iberdomide and see how well these drugs work together against multiple myeloma.

Participant Groups

Group I: Treatment (iberdomide, bortezomib, dexamethasone, daratumumab) Experimental Treatment 4 Interventions

INDUCTION PHASE: Patients receive iberdomide PO QD on days 1-21, bortezomib SC on days, 1, 8, 15, and 22, and dexamethasone PO on days 1, 8, 15, 22. Patients also receive daratumumab SC on days 1, 8, 15, 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. CYCLES 13-36 CYCLES: Patients receive iberdomide PO QD on days 1-21. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 a study of 16 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and dexamethasone resulted in a high clinical response rate of 87.5%, with 6 patients achieving near complete response.

The treatment was associated with manageable side effects, primarily gastrointestinal issues and thrombocytopenia, which were alleviated with supportive care, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma]. Yuan, ZG., Hou, J., Zhou, F., et al.[2015]

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]

In two phase 2 studies involving 256 patients with relapsed or refractory multiple myeloma, adding dexamethasone to bortezomib improved treatment responses, with 18% of patients in the SUMMIT study and 33% in the CREST study showing better outcomes.

The combination therapy did not significantly increase the type or number of adverse events, indicating that dexamethasone can enhance efficacy without adding prohibitive toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Jagannath, S., Richardson, PG., Barlogie, B., et al.[2022]

In a study of 669 patients with relapsed multiple myeloma, bortezomib demonstrated significantly higher response rates and longer survival compared to high-dose dexamethasone, with complete response rates of 6% versus less than 1%.

Patients treated with bortezomib had a median time to progression of 6.22 months compared to 3.49 months for those on dexamethasone, indicating bortezomib's greater efficacy in delaying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. Richardson, PG., Sonneveld, P., Schuster, MW., et al.[2022]

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 study of 24 multiple myeloma patients treated with bortezomib and dexamethasone, 79.2% showed a positive response, with a notably higher complete remission rate in light-chain type patients (57.1%) compared to non-light-chain type patients (5.9%).

The treatment was found to be safe for patients with renal impairment, as their renal function improved during chemotherapy, and the adverse events were manageable, with most patients tolerating the side effects well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of bortezomib combined dexamethasone in 24 patients with multiple myeloma]. Li, J., Zhao, Y., Luo, SK., et al.[2015]

Bortezomib is recommended for use in both newly diagnosed and relapsed/refractory multiple myeloma patients, whether they are eligible for autologous stem cell transplantation or not, based on a systematic review of evidence.

The guidelines also emphasize the importance of monitoring and managing potential toxicities associated with bortezomib treatment, such as the risk of herpes zoster reactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. Kouroukis, CT., Baldassarre, FG., Haynes, AE., et al.[2015]

In a study comparing two induction therapies for newly diagnosed multiple myeloma, the quadruplet regimen (D-VTd) showed significantly better response rates after treatment, with 90.5% achieving complete remission (CR) or stringent complete remission (sCR) compared to 68.6% in the triplet regimen (VRd).

The quadruplet regimen (D-VTd) also resulted in a higher rate of very good partial response (VGPR or better) at 93%, compared to 67.6% in the triplet regimen (VRd), although VRd was associated with a higher incidence of skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. Byun, JM., Park, SS., Yoon, SS., et al.[2023]

In a study of 78 patients with relapsed or refractory multiple myeloma, the combination of bortezomib, bendamustine, and prednisone showed a 69% response rate, indicating significant efficacy in treating this condition.

Patients without severe prior hematological toxicities had a median progression-free survival (PFS) of 11 months and overall survival (OS) of 50 months, while those with severe toxicities had much poorer outcomes, highlighting the importance of patient health status in treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. Pönisch, W., Bourgeois, M., Moll, B., et al.[2021]

In a study of 96 relapsed/refractory multiple myeloma patients treated with the CyBorP/D regimen, 69% achieved at least a partial response, indicating strong efficacy of this treatment approach.

The regimen was generally well-tolerated, with mild and manageable toxicities, although some patients experienced new or worsening peripheral neuropathy; importantly, no second primary malignancies were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide and Bortezomib With Prednisone or Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma. Reece, DE., Trieu, Y., Masih-Khan, E., et al.[2018]

Bortezomib is the first proteasome inhibitor approved for treating multiple myeloma (MM), showing significant survival benefits as a mono-therapy and in combination with other drugs.

The neurotoxicity associated with bortezomib has been reduced through subcutaneous administration and weekly dosing, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib for the treatment of multiple myeloma. Grosicki, S., Barchnicka, A., Jurczyszyn, A., et al.[2015]

References

1. 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]

2. China pubmed.ncbi.nlm.nih.gov

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma]. [2015]

3. China 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]. [2015]

4. Italy pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. [2022]

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

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. [2022]

6. Greece 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. [2015]

7. China pubmed.ncbi.nlm.nih.gov

[Efficacy of bortezomib combined dexamethasone in 24 patients with multiple myeloma]. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. [2015]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. [2021]

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

Cyclophosphamide and Bortezomib With Prednisone or Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Bortezomib for the treatment of multiple myeloma. [2015]