KRd vs VRd Regimens for Multiple Myeloma

((COBRA) Trial)

Overseen By Andrzej Jakubowiak

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Chicago

Must not be taking: Bortezomib, Lenalidomide, others

Disqualifiers: Amyloidosis, Plasma cell leukemia, 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: Varies by participant

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two different treatment combinations for individuals newly diagnosed with multiple myeloma, a type of blood cancer. One group will receive a combination of carfilzomib (Kyprolis), lenalidomide, and dexamethasone, while the other group will receive bortezomib (Velcade), lenalidomide, and dexamethasone. The goal is to determine which combination more effectively treats the cancer. Individuals newly diagnosed with multiple myeloma who have not yet received treatment might be suitable for this study. As a Phase 3 trial, this study 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 information does not specify if you need to stop taking your current medications. However, you must not have received prior treatment with bortezomib or lenalidomide, and you should not have participated in another investigational study recently.

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

Previous studies have shown that the KRd treatment (Carfilzomib, Lenalidomide, Dexamethasone) is well tolerated. Patients generally found it safe, even after many prior treatments. One study showed it improved survival for those with relapsed multiple myeloma.

The VRd treatment (Bortezomib, Lenalidomide, Dexamethasone) also has a good safety record. Research indicates it is generally tolerable and effective. Some side effects, such as lower blood cell counts and reactions during infusions, have been noted when combined with additional drugs, but these are manageable.

Past research has demonstrated the safety of both treatments for patients. However, individual experiences may vary, so discussing options with a healthcare provider is important. ^{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 offer novel combinations of existing drugs that may enhance effectiveness. The KRd regimen incorporates carfilzomib, a newer proteasome inhibitor, which is believed to cause deeper and more sustained responses compared to the older bortezomib used in the VRd regimen. Carfilzomib's unique mechanism of action targets cancer cells more selectively, potentially resulting in fewer side effects and better patient outcomes. Meanwhile, the VRd regimen remains a strong contender, providing a shorter, 21-day cycle that may lead to faster treatment responses. Both regimens aim to improve upon the standard of care by offering tailored approaches that optimize the use of lenalidomide and dexamethasone alongside these proteasome inhibitors.

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

Research shows that both KRd and VRd treatments work well for multiple myeloma. In this trial, participants will join one of two groups: the KRd Arm or the VRd Arm. The KRd Arm includes carfilzomib, lenalidomide, and dexamethasone. Studies have found that KRd helps patients live longer, even if their cancer has returned or hasn't responded to other treatments. This combination is generally well-tolerated and effective for patients who have tried several other treatments. The VRd Arm uses bortezomib, lenalidomide, and dexamethasone, and is also very effective, especially for those newly diagnosed with multiple myeloma. It is generally easy for patients to handle and has been successful in improving their health. Both treatments have strong evidence supporting their effectiveness for multiple myeloma. ^{3 4 6 7 8}

Who Is on the Research Team?

Andrzej Jakubowiak, MD

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed multiple myeloma who haven't had chemotherapy or extensive radiotherapy. They must not have used bortezomib or lenalidomide before and should be fit enough for potential future stem cell transplant, though it's deferred during the trial. Participants need functioning major organs, no severe heart conditions, and can't be pregnant. Women of childbearing potential must use two forms of contraception.

Inclusion Criteria

Voluntary written informed consent

I haven't had radiation to more than half of my pelvis.

I am fully active or can carry out light work.

Exclusion Criteria

I haven't had serious heart issues like uncontrolled chest pain or heart failure in the last 6 months.

You have signs that your disease is getting worse according to specific guidelines.

I have had a blood clot in my lungs before or currently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the KRD regimen (carfilzomib, lenalidomide, dexamethasone) in 28-day cycles or the VRD regimen (bortezomib, lenalidomide, dexamethasone) in 21-day cycles

Varies by participant

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Carfilzomib
• Dexamethasone
• Lenalidomide

Trial Overview The study compares two drug combinations: Carfilzomib with Lenalidomide and Dexamethasone (KRd) versus Bortezomib with Lenalidomide and Dexamethasone (VRd). It aims to determine which regimen is more effective in treating patients who are new to treatment for multiple myeloma.

How Is the Trial Designed?

Group I: VRD Arm Experimental Treatment 3 Interventions

Patients assigned to this group will receive a combination of Bortezomib, lenalidomide and dexamethasone in 21-day cycles. Doses will vary

Group II: KRD Arm Experimental Treatment 3 Interventions

Patients assigned to this group will receive a combination of carfilzomib, lenalidomide, and dexamethasone in 28 day cycles. Doses will vary

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?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

In a study of 389 newly diagnosed multiple myeloma patients, those treated with carfilzomib, lenalidomide, and dexamethasone (KRd) showed significantly better progression-free survival (PFS) and event-free survival (EFS) compared to those treated with bortezomib, lenalidomide, and dexamethasone (VRd), particularly in high-risk patients.

The 5-year PFS was 67% for KRd versus 56% for VRd, and the 5-year overall survival (OS) was 90% for KRd compared to 80% for VRd, indicating that KRd may offer better long-term outcomes for patients with multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib, Lenalidomide and Dexamethasone (VRd) vs Carfilzomib, Lenalidomide and Dexamethasone (KRd) as Induction Therapy in Newly Diagnosed Multiple Myeloma. Tan, CR., Derkach, A., Nemirovsky, D., et al.[2023]

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 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]

Citations

1. 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.

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/647/503047/Comparison-of-Response-and-Survival-Outcomes-in

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) ...

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/s41408-024-01177-6

Impact of lenalidomide-bortezomib-dexamethasone ... These results provide real-world evidence that patients with NDMM and RI who receive front-line RVd for ≥3 cycles may have improved renal function regardless ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6349658/

The Safety Profile of Concurrent Therapy for Multiple ... However, higher rates of thrombocytopenia, neutropenia, and infusion reactions were seen when daratumumab was added to bortezomib and dexamethasone. These ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10460706/

Efficacy and safety analysis of bortezomib-based triplet ... During the follow-up period, the best outcome assessments achieved were 53.8% complete response (CR) and 84.6% excellent partial response (VGPR) ...

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

Clinical perspectives on the optimal use of lenalidomide ... The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has consistently demonstrated a tolerable safety profile with significant ...