Drug Combinations for Multiple Myeloma

Recruiting at 393 trial locations

Overseen By Dana Sparks

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Southwest Oncology Group

Disqualifiers: Prior systemic therapy, Grade 4 neuropathy, Uncontrolled hypertension, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase III trial compares three-drug induction regimens followed by double-or single-drug maintenance therapy for the treatment of newly diagnosed multiple myeloma in patients who are not receiving a stem cell transplant and are considered frail or intermediate-fit based on age, comorbidities, and functional status. Treatment for multiple myeloma includes initial treatment (induction) which is the first treatment a patient receives for cancer followed by ongoing treatment (maintenance) which is given after initial treatment to help keep the cancer from coming back. There are three combinations of four different drugs being studied. Bortezomib is one of the drugs that may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide works by helping bone marrow to produce normal blood cells and killing cancer cells. Anti-inflammatory drugs, such as dexamethasone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Daratumumab and hyaluronidase-fihj is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Patients receive 1 of 3 combinations of these drugs for treatment to determine which combination of study drugs works better to shrink and control multiple myeloma.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have received prior systemic therapy for multiple myeloma, except for certain exceptions like a short course of corticosteroids or one cycle of a non-daratumumab regimen. It's best to discuss your current medications with the trial team.

What data supports the idea that Drug Combinations for Multiple Myeloma is an effective treatment?

The available research shows that combining daratumumab with other drugs like lenalidomide and dexamethasone or bortezomib and dexamethasone is effective for treating multiple myeloma. In one study, 80% of patients responded positively to these combinations, and the survival rates were high, with 84% overall survival and 77% progression-free survival. Another study found that adding daratumumab to lenalidomide and dexamethasone significantly improved patient outcomes compared to using lenalidomide and dexamethasone alone. These results suggest that these drug combinations are more effective than some traditional treatments. ^{1 2 3 4 5}

What safety data exists for drug combinations in multiple myeloma treatment?

The safety data for drug combinations involving daratumumab, lenalidomide, bortezomib, and dexamethasone in multiple myeloma treatment shows that these combinations are generally effective and safe. Common hematologic adverse events include neutropenia, thrombocytopenia, and anemia, while non-hematologic adverse events include peripheral sensory neuropathy and infections. In clinical trials, daratumumab combined with lenalidomide and dexamethasone or bortezomib and dexamethasone showed improved progression-free survival. Frequently reported adverse reactions include infusion reactions, diarrhea, nausea, fatigue, and upper respiratory tract infections. Neutropenia and thrombocytopenia are noted in the drug label warnings. ^{1 2 3 6 7}

Is the drug combination of Bortezomib, Daratumumab, Dexamethasone, and Lenalidomide promising for treating multiple myeloma?

Yes, this drug combination is promising for treating multiple myeloma. Studies show that adding Daratumumab to treatments with Bortezomib and Dexamethasone or Lenalidomide improves patient outcomes. It increases the time patients live without the disease getting worse and has a high response rate. This combination is effective for both newly diagnosed and relapsed patients. ^{1 8 9 10 11}

Research Team

Sikander Ailawadhi

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with newly diagnosed multiple myeloma who are not suitable for stem cell transplant due to age or health issues. They must have measurable disease, adequate organ function, and no severe neuropathy or other cancers that could affect the study. Pregnant individuals can't participate, and those of reproductive potential must use contraception.

Inclusion Criteria

I have been diagnosed with multiple myeloma according to IMWG criteria within the last 28 days.

My diabetes is under control as shown by recent tests.

You need to have certain lab test results within 28 days before joining the study.

Exclusion Criteria

Participants must not have uncontrolled blood pressure within 14 days prior to registration

I do not have severe nerve damage in my hands or feet.

Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive induction therapy with different drug combinations for up to 9 cycles

9 months

4 visits per cycle (in-person)

Maintenance

Patients receive maintenance therapy with lenalidomide or a combination of lenalidomide and daratumumab and hyaluronidase-fihj

Ongoing, every 28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 3 months for 1 year, every 6 months for 2 years, then annually

Treatment Details

Interventions

• Bortezomib (Proteasome Inhibitor)
• Daratumumab and Hyaluronidase-fihj (Monoclonal Antibodies)
• Dexamethasone (Corticosteroid)
• Lenalidomide (Immunomodulatory Agent)

Trial Overview The trial compares three drug combinations as initial treatment followed by maintenance therapy in frail or intermediate-fit patients with multiple myeloma. It tests Bortezomib, Lenalidomide, Dexamethasone, and Daratumumab/Hyaluronidase-fihj to find which regimen best controls the cancer.

Participant Groups

Group I: Arm III (DRd-DR): Experimental Treatment 5 Interventions

INDUCTION CYCLES 1-9: Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7-9, lenalidomide PO on days 1-21 of each cycle, and dexamethasone PO on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE CYCLES 10+: Patients receive daratumumab and hyaluronidase-fihj SC on day 1 of each cycle and lenalidomide PO on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (DRd-R) Experimental Treatment 5 Interventions

INDUCTION CYCLES 1-9: Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7-9, lenalidomide PO on days 1-21 of each cycle, and dexamethasone PO on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE CYCLES 10+: Patients receive lenalidomide PO on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (VRd-Lite) Active Control 5 Interventions

INDUCTION CYCLES 1-9: Patients receive bortezomib SC on days 1, 8, 15, and 22 of each cycle, lenalidomide PO on days 1-21 of each cycle, and dexamethasone PO on days 1, 8, 15, and 22 of each cycle. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE CYCLES 10+: Patients receive lenalidomide PO on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Bortezomib is already approved in Canada, Japan for the following indications:

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?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Daratumumab, when combined with lenalidomide and dexamethasone (DRd) or bortezomib and dexamethasone (DVd), showed an overall response rate of 80% in 171 heavily treated patients with relapsed/refractory multiple myeloma, indicating its efficacy in this challenging patient population.

Patients receiving the DRd combination experienced better progression-free survival (PFS) compared to those on DVd, with PFS rates of 84% and 77%, respectively, while the treatment was generally safe, with common side effects including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. Fazio, F., Franceschini, L., Tomarchio, V., et al.[2022]

In a study of 737 patients with newly diagnosed multiple myeloma, the addition of daratumumab to lenalidomide and dexamethasone significantly reduced the risk of disease progression or death, with a hazard ratio of 0.56, indicating a 44% lower risk compared to the control group.

Patients receiving daratumumab had a higher rate of complete response (47.6% vs. 24.9%) and a greater percentage achieving minimal residual disease status (24.2% vs. 7.3%), although they also experienced more severe side effects like neutropenia and pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. Facon, T., Kumar, S., Plesner, T., et al.[2023]

In the phase 3 MAIA trial involving 737 patients, the combination of daratumumab, lenalidomide, and dexamethasone significantly improved both progression-free survival (not reached vs. 34.4 months in the control group) and overall survival (hazard ratio 0.68) in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation.

The safety profile of the treatment was consistent with previous findings, with no new safety concerns identified, although higher rates of neutropenia and pneumonia were observed in the daratumumab group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Facon, T., Kumar, SK., Plesner, T., et al.[2021]

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 real-world study of 47 patients with relapsed/refractory multiple myeloma treated with daratumumab, bortezomib, and dexamethasone (DVd), the overall response rate was 78%, indicating that this combination is an effective treatment option.

The treatment was found to be safe, with mostly mild adverse events and no cases leading to permanent drug interruptions, and the median progression-free survival was 10 months, suggesting good durability of response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of daratumumab, bortezomib and dexamethasone in relapsed/refractory multiple myeloma in Slovakia. Harvanová, Ľ., Štulajterová, V., Guman, T., et al.[2021]

Daratumumab, when combined with lenalidomide and dexamethasone or bortezomib and dexamethasone, significantly improves progression-free survival in patients with multiple myeloma who have received prior therapy, with reductions in the risk of disease progression or death by 63% and 61%, respectively.

The most common side effects reported were infusion reactions, diarrhea, and upper respiratory infections, with neutropenia and thrombocytopenia noted as important warnings, indicating that while daratumumab is effective, monitoring for these adverse reactions is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Daratumumab for Treatment of Multiple Myeloma After One Prior Therapy. Bhatnagar, V., Gormley, NJ., Luo, L., et al.[2022]

Lenalidomide combined with dexamethasone has been shown to be effective for treating relapsed/refractory multiple myeloma, and it has received approval from both the FDA and EMA for patients who have undergone at least one prior therapy.

The most common serious side effects include cytopenias and infections, but an expert panel has provided management strategies to minimize these risks, ensuring that patients can receive the full benefits of the treatment without unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Palumbo, A., Dimopoulos, M., San Miguel, J., et al.[2018]

Intravenous daratumumab, when combined with bortezomib, thalidomide, and dexamethasone, significantly improves treatment outcomes for adults with newly diagnosed multiple myeloma, leading to higher rates of stringent complete response and prolonged progression-free survival, as shown in the phase III CASSIOPEIA trial.

The addition of daratumumab has a minimal impact on overall toxicity, with the most common serious side effects being blood-related issues, indicating it is a relatively safe option for patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. Lamb, YN.[2021]

In a study involving elderly myeloma patients, both treatment regimens—bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd)—showed similar effectiveness in managing the disease.

The two treatment approaches also resulted in comparable levels of toxicity, suggesting that either regimen can be safely used for elderly patients with myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Together for better? Cavo, M.[2021]

Bortezomib treatment in 32 multiple myeloma patients significantly decreased various T cell populations and natural killer (NK) cells, indicating a potential negative impact on cellular immunity.

In contrast, Daratumumab monotherapy increased overall T cell counts, particularly CD3+ and CD4+ T cells, while also causing a significant depletion of NK cells, suggesting it may be more targeted and less immunosuppressive than Bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Bortezomib Regimens and Daratumumab Monotherapy on Cellular Immunity in Multiple Myeloma Patients. Kakoo, A., Rasheed, T., Al-Attar, M.[2021]

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]

References

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

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. [2022]

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

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. [2023]

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

Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. [2021]

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

Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma. [2019]

5. Slovakia pubmed.ncbi.nlm.nih.gov

Real-world effectiveness and safety of daratumumab, bortezomib and dexamethasone in relapsed/refractory multiple myeloma in Slovakia. [2021]

6. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Daratumumab for Treatment of Multiple Myeloma After One Prior Therapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. [2018]

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

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. [2021]

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

Together for better? [2021]

10. Iran pubmed.ncbi.nlm.nih.gov

Effect of Bortezomib Regimens and Daratumumab Monotherapy on Cellular Immunity in Multiple Myeloma Patients. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. [2021]