Bortezomib/Carfilzomib + Lenalidomide + Dexamethasone for Multiple Myeloma

Not currently recruiting at 936 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: ECOG-ACRIN Cancer Research Group

Must not be taking: Zidovudine, Stavudine

Disqualifiers: Uncontrolled hypertension, Heart failure, 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: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different drug combinations to determine which is more effective for treating newly diagnosed multiple myeloma, a type of blood cancer. One group will receive bortezomib (Velcade), lenalidomide, and dexamethasone, while another group will receive carfilzomib (Kyprolis), lenalidomide, and dexamethasone. Both bortezomib and carfilzomib block certain enzymes to stop cancer cell growth. Lenalidomide aids the immune system in killing cancer cells, and dexamethasone is a chemotherapy drug that halts cancer cell growth. The trial seeks participants diagnosed with symptomatic multiple myeloma who have not yet received extensive treatment. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not have had more than one cycle of prior chemotherapy or more than 160 mg of dexamethasone for treating multiple myeloma, and you should not have been treated with lenalidomide, bortezomib, or carfilzomib before.

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

A previous study found that patients with multiple myeloma generally tolerated the combination of bortezomib, lenalidomide, and dexamethasone well. The FDA has already approved bortezomib and lenalidomide for treating multiple myeloma, confirming their safety for this condition.

Research has also shown that carfilzomib, when combined with lenalidomide and dexamethasone, is well-tolerated. Even patients who have undergone several previous treatments manage this combination well, with controllable side effects.

In both treatment groups, some side effects may occur. However, these drugs have been used successfully in other studies, indicating they are relatively safe for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple myeloma because they explore new combinations and delivery methods that could improve patient outcomes. Bortezomib and carfilzomib are both proteasome inhibitors, but carfilzomib has shown potential for fewer side effects and longer-lasting effects when administered over an extended infusion time. Lenalidomide, used in multiple arms of this trial, is a type of immunomodulatory drug that can enhance the immune system's ability to fight cancer, and its continuous use is being tested for its long-term benefits. The strategic combination of these drugs with dexamethasone, a steroid that helps reduce inflammation and kill cancer cells, aims to maximize the treatment's effectiveness while managing side effects. This approach could offer a more comprehensive attack on cancer cells than the current standard treatments.

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

This trial will compare different treatment combinations for multiple myeloma. Research has shown that the combination of bortezomib, lenalidomide, and dexamethasone, which participants in Arm A may receive, effectively treats newly diagnosed multiple myeloma. Patients have responded well and lived longer with this treatment. Arm B will test another combination—carfilzomib, lenalidomide, and dexamethasone—which studies indicate works well, even for patients who have undergone several previous treatments. This combination has also been linked to longer survival in multiple myeloma patients. Both treatment options include lenalidomide, which helps the immune system attack cancer cells, while bortezomib and carfilzomib inhibit the enzymes that cancer cells need to grow. ^{2 3 6 7 8}

Who Is on the Research Team?

Shaji Kumar

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for newly diagnosed multiple myeloma patients who've had certain prior chemotherapies but not treatments for symptomatic myeloma. They must agree to specific programs, meet contraceptive requirements, and have acceptable organ function and blood counts. HIV+ individuals can join if they meet extra criteria.

Inclusion Criteria

I had cancer before but meet the specific criteria for this trial.

I have had blood clots but am willing to take blood thinners if not already.

I have been diagnosed with a type of blood cancer called multiple myeloma and it's causing symptoms.

Exclusion Criteria

Pregnant women

I have not received treatments outside of my assigned therapy, including stem cell transplant.

I am currently breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive either bortezomib, lenalidomide, and dexamethasone or carfilzomib, lenalidomide, and dexamethasone for multiple courses

36 weeks

Multiple visits per course

Maintenance

Patients receive lenalidomide daily for either a limited duration of 24 courses or indefinitely until disease progression

24 months or indefinite

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

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

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Carfilzomib
• Dexamethasone
• Lenalidomide

Trial Overview The study compares two drug combinations: Bortezomib with Lenalidomide and Dexamethasone versus Carfilzomib with the same drugs. It aims to find out which combination is more effective in stopping cancer cell growth by blocking enzymes or boosting the immune system.

How Is the Trial Designed?

Group I: Arm D (lenalidomide) Experimental Treatment 3 Interventions

Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Arm C (lenalidomide) Experimental Treatment 3 Interventions

Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity.

Group III: Arm B (carfilzomib, lenalidomide, dexamethasone) Experimental Treatment 5 Interventions

Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

Group IV: Arm A (bortezomib, lenalidomide, dexamethasone) Experimental Treatment 5 Interventions

Patients receive bortezomib SC or IV on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide PO daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses 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?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Carfilzomib, when used in combination with lenalidomide and dexamethasone, significantly prolongs progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma, based on results from the phase III ASPIRE study involving a multinational patient population.

The combination therapy has a manageable safety profile, with low incidences of severe adverse events, suggesting it is a viable treatment option for patients who have received prior therapies, although overall survival data is still pending.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. Hoy, SM.[2018]

In a study comparing lenalidomide-dexamethasone (len/dex) and melphalan-prednisone-lenalidomide (MPR) in 89 elderly patients with myeloma, both treatments showed similar efficacy in terms of time to progression, progression-free survival, and overall survival, indicating that either regimen can be effective for this patient group.

However, MPR was associated with significantly higher rates of severe hematologic toxicities, such as neutropenia and thrombocytopenia, suggesting that while both treatments are effective, len/dex may be a safer option with fewer severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. Gay, F., Vincent Rajkumar, S., Falco, P., et al.[2018]

In a study involving 929 patients with relapsed or refractory multiple myeloma, carfilzomib combined with dexamethasone significantly improved median progression-free survival (18.7 months) compared to bortezomib with dexamethasone (9.4 months), indicating greater efficacy of carfilzomib.

While both treatments had serious adverse events, carfilzomib was associated with a higher rate of serious adverse events (48%) compared to bortezomib (36%), suggesting that while carfilzomib may be more effective, it also carries a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Dimopoulos, MA., Moreau, P., Palumbo, A., et al.[2022]

In the ENDURANCE trial involving patients with newly diagnosed multiple myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve progression-free survival compared to the standard treatment of bortezomib, lenalidomide, and dexamethasone (VRd).

These findings suggest that KRd may not be a more effective treatment option than the current standard of care for patients with NDMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. Skarzynski, J.[2021]

In a phase 3 study involving 466 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib, dexamethasone, and daratumumab (KdD) significantly improved progression-free survival compared to carfilzomib and dexamethasone alone (Kd), with a hazard ratio of 0.63, indicating a 37% reduction in the risk of disease progression.

Despite a higher incidence of grade 3 or higher adverse events in the KdD group (82%) compared to the Kd group (74%), the overall safety profile was considered favorable, with similar rates of treatment discontinuation due to adverse events in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Dimopoulos, M., Quach, H., Mateos, MV., et al.[2020]

In a study of 75 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib and dexamethasone (Kd56) showed a 60% overall response rate and a median progression-free survival (PFS) of 10 months, indicating its efficacy in a real-world clinical setting.

The treatment was well tolerated, with a low rate of adverse events, including no cases of neuropathy and only 10% of patients experiencing cardiovascular events above grade 3, suggesting a favorable safety profile for elderly and heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. Del Giudice, ML., Gozzetti, A., Antonioli, E., et al.[2023]

In a study of 1162 multiple myeloma patients, those treated with the combination of thalidomide, melphalan, and prednisone (MPT) showed significantly better overall survival (OS) rates compared to those treated with melphalan and prednisone (MP) alone, with median OS of 4.2 years for MPT versus 2.2 years for MP in the first line of treatment.

The relative risk of death was reduced by 39% in the MPT group compared to the MP group in the first line of therapy, indicating that MPT is a more effective treatment option for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma--a retrospective population based study of 1162 patients. Lund, J., Uttervall, K., Liwing, J., et al.[2013]

In a study involving 792 patients with relapsed multiple myeloma, the combination of carfilzomib with lenalidomide and dexamethasone significantly improved progression-free survival, with a median of 26.3 months compared to 17.6 months for the control group.

The carfilzomib group also showed a higher overall response rate (87.1% vs. 66.7%) and better health-related quality of life, indicating a favorable risk-benefit profile despite similar rates of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Stewart, AK., Rajkumar, SV., Dimopoulos, MA., et al.[2022]

The MUK Five trial is a phase II study comparing the effectiveness of a new combination treatment (carfilzomib, cyclophosphamide, and dexamethasone) against the standard treatment (cyclophosphamide, bortezomib, and dexamethasone) in patients with multiple myeloma at first relapse, involving participants who have received no more than one prior treatment.

The trial aims to determine if the new combination (CCD) is at least as effective as the standard treatment (CVD) in achieving significant response rates, while also assessing the potential benefits of maintenance therapy with carfilzomib for improving progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma. Brown, S., Hinsley, S., Ballesteros, M., et al.[2022]

Citations

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Comparison of Response and Survival Outcomes in Standard ... Introduction: The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is highly effective for newly diagnosed myeloma (NDMM) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3324254/

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

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. clinicaltrials.gov clinicaltrials.gov/study/NCT01440582

Combination Therapy of Lenalidomide/Bortezomib ... Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for ...

5. 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 ...

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26252787/

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: SWOG S1211.