Drug Combinations for Multiple Myeloma

Recruiting at 397 trial locations

Overseen By Dana Sparks

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Southwest Oncology Group

Disqualifiers: Prior systemic therapy, Grade 4 neuropathy, Uncontrolled hypertension, 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: 7

510 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which combination of four drugs best treats multiple myeloma, a cancer affecting blood cells. It examines three different drug combinations to control the disease and prevent its return. The study targets individuals newly diagnosed with multiple myeloma who are not receiving a stem cell transplant and are considered frail or of intermediate fitness based on health and daily activity levels. Participants should not have received prior treatments for multiple myeloma, except for certain allowed therapies. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

A previous study found that the combination of daratumumab and hyaluronidase-fihj with lenalidomide and dexamethasone was generally well-tolerated. However, some reports noted serious reactions, including fatal ones, with products containing daratumumab. Participants should be aware of possible side effects, although these serious events are uncommon.

In contrast, the combination of bortezomib with lenalidomide and dexamethasone has been widely used to treat multiple myeloma. The FDA has approved this combination for this condition, indicating a known safety record. While some participants may experience side effects, these treatments are generally considered safe.

As this is a Phase 3 study, earlier phases have already tested the treatments, providing more information on safety. Participants should discuss any concerns with the study team to understand personal risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments in this trial for multiple myeloma because they explore different combinations of existing drugs to find more effective therapies. Unlike the standard of care, which often includes bortezomib, lenalidomide, and dexamethasone, these trial arms incorporate daratumumab with hyaluronidase-fihj to potentially enhance treatment effectiveness. Daratumumab targets the CD38 protein on myeloma cells, and combining it with hyaluronidase-fihj allows for subcutaneous administration, which can be more convenient and may reduce infusion-related reactions. These innovative combinations aim to improve patient outcomes by leveraging complementary mechanisms of action.

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

Research shows that combining the drugs daratumumab, hyaluronidase-fihj, lenalidomide, and dexamethasone effectively treats multiple myeloma. In this trial, participants in Arm II (DRd-R) and Arm III (DRd-DR) will receive this combination, which studies indicate can help prevent cancer progression for an extended period. Additionally, participants in Arm I (VRd-Lite) will receive lenalidomide, bortezomib, and dexamethasone, a combination shown to work well for newly diagnosed myeloma patients, with many responding positively. These treatments are effective options for managing multiple myeloma and are supported by strong clinical evidence. ^{2 3 6 7 8}

Who Is on the Research Team?

Sikander Ailawadhi

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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.

I have chronic hepatitis B but it's undetectable with treatment.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Daratumumab and Hyaluronidase-fihj
• Dexamethasone
• Lenalidomide

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.

How Is the Trial Designed?

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 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?

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+

Published Research Related to This Trial

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 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]

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 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]

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]

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]

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]

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]

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]

Citations

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Lenalidomide, bortezomib, and dexamethasone ... Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01440582

Combination Therapy of Lenalidomide/Bortezomib ... Combination Therapy of Lenalidomide/​Bortezomib/​Dexamethasone and Panobinostat in Transplant Eligible New Diagnosed Multiple Myeloma (MM) Patients.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2312054

Daratumumab, Bortezomib, Lenalidomide, and ... An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients

4. nature.com nature.com/articles/s41408-024-01120-9

Quadruplet therapy for newly diagnosed myeloma The combination of lenalidomide, bortezomib, and dexamethasone (RVd) was shown to be highly effective in newly diagnosed myeloma (NDMM) patients ...

5. haematologica.org haematologica.org/article/view/haematol.2022.282624

Clinical perspectives on the optimal use of lenalidomide ... Combinations of lenalidomide, bortezomib, and dexamethasone (RVd) are recommended for the treatment of newly diagnosed multiple myeloma (NDMM).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4558587/

Phase I safety data of lenalidomide, bortezomib ... Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma.

7. nature.com nature.com/articles/bcj201562.pdf

Phase I safety data of lenalidomide, bortezomib, ... Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679-686.

8. ashpublications.org ashpublications.org/blood/article/116/5/679/107744/Lenalidomide-bortezomib-and-dexamethasone

Lenalidomide, bortezomib, and dexamethasone combination ... Bortezomib does not increase thromboembolic risk in multiple myeloma and may offer a protective effect with thalidomide/lenalidomide-based therapy: review of ...