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

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing two different combinations of medications for patients who have just been diagnosed with multiple myeloma. The medications work by killing cancer cells and boosting the immune system's ability to fight the cancer. A new type of therapy has shown promising results in treating multiple myeloma.

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.

What data supports the effectiveness of the drug regimens KRd and VRd for treating multiple myeloma?

In a study comparing KRd and VRd regimens for newly diagnosed multiple myeloma, the 5-year progression-free survival (PFS) was 67% for KRd and 56% for VRd, indicating that KRd may be more effective in delaying disease progression. However, another trial found that KRd did not significantly improve PFS compared to VRd, suggesting that both regimens are effective but may have similar outcomes. ^{1 2 3 4 5}

What safety data exists for the KRd and VRd regimens in treating multiple myeloma?

The safety of the VRd (bortezomib, lenalidomide, and dexamethasone) and KRd (carfilzomib, lenalidomide, and dexamethasone) regimens has been evaluated in studies for newly diagnosed multiple myeloma. These studies primarily focused on treatment outcomes, but they also assessed safety, indicating that both regimens are commonly used and generally considered safe for this condition. ^{1 2 4 6 7}

How does the KRd regimen differ from the VRd regimen for multiple myeloma?

The KRd regimen uses carfilzomib, a next-generation proteasome inhibitor, instead of bortezomib in the VRd regimen, which may offer improved outcomes for some patients with multiple myeloma, although studies show mixed results on its superiority. ^{1 2 3 4 8}

Research Team

Andrzej Jakubowiak, MD

Principal Investigator

University of Chicago

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. [2022]

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

Bortezomib, Lenalidomide and Dexamethasone (VRd) vs Carfilzomib, Lenalidomide and Dexamethasone (KRd) as Induction Therapy in Newly Diagnosed Multiple Myeloma. [2023]

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

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

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

Bortezomib, lenalidomide and dexamethasone (VRd) vs carfilzomib, lenalidomide and dexamethasone (KRd) as induction therapy in newly diagnosed multiple myeloma. [2023]

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

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. [2022]

6. Australia pubmed.ncbi.nlm.nih.gov

Peripheral blood stem cell mobilisation following bortezomib, lenalidomide and dexamethasone induction for multiple myeloma: a real-world single-centre experience. [2023]

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

Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial. [2018]

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

KRD vs. VRD as induction before autologous hematopoietic progenitor cell transplantation for high-risk multiple myeloma. [2022]