Quadruple Therapy + Stem Cell Transplant for Multiple Myeloma

Recruiting at 21 trial locations

Overseen By Sergio Giralt, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Plasma cell leukemia, POEMS syndrome, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

41 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test any good and bad effects of giving a combination of study drugs before and after autologous stem cell transplant.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, there is a 4-week washout period (time without taking certain medications) required for some treatments, but not for maintenance single-agent imid or monoclonal antibody therapies.

What data supports the effectiveness of the drug combination used in the Quadruple Therapy + Stem Cell Transplant for Multiple Myeloma?

Research shows that combining drugs like daratumumab, carfilzomib, lenalidomide, and dexamethasone is effective in treating multiple myeloma, especially in newly diagnosed cases. These combinations have shown promising results in improving patient outcomes, even though some studies indicate they may not always be superior to other standard treatments. ^{1 2 3 4 5}

Is the quadruple therapy with stem cell transplant generally safe for humans?

The combination of carfilzomib, daratumumab, lenalidomide, and dexamethasone has shown tolerable safety in patients with multiple myeloma, including those with relapsed or refractory conditions. ^{1 2 5 6 7}

What makes the Quadruple Therapy + Stem Cell Transplant treatment for multiple myeloma unique?

This treatment combines four drugs—Carfilzomib, Daratumumab, Dexamethasone, and Lenalidomide—with a stem cell transplant, which is a novel approach for multiple myeloma. The combination of these drugs targets the cancer cells in different ways, potentially improving outcomes compared to standard treatments that use fewer drugs or do not include a stem cell transplant. ^{1 4 8 9 10}

Research Team

Gunjan Shah, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults aged 18-75 with multiple myeloma that has worsened after 1 to 3 treatments. They must have enough healthy stem cells saved, good kidney function, and no severe heart or liver issues. Women who can get pregnant and men must use birth control. People with HIV, uncontrolled illnesses, recent major surgery, CNS myeloma involvement, significant neuropathy or allergic reactions to the drugs are excluded.

Inclusion Criteria

Your disease can be measured according to specific guidelines from the International Myeloma Working Group.

My heart pumps well, with an ejection fraction over 40%.

I've had one treatment cycle for my disease within the last 60 days and waited 4 weeks since the last dose.

Exclusion Criteria

My blood test shows more than 20% plasma cells.

I have been diagnosed with POEMS syndrome.

I have not had major surgery in the last 3 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive four 28-day cycles of Dara-CRd before autologous stem cell transplant

16 weeks

Hematopoietic Cell Transplantation (HCT)

Eligible patients undergo HCT with high dose melphalan conditioning

1 week

Post-Transplant Treatment

Sixty to ninety days after HCT, patients receive another 4 cycles of Dara-CRd

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Autologous Hematopoietic Cell Transplantation
• Carfilzomib
• Daratumumab
• Dexamethasone
• Lenalidomide

Trial Overview The study tests a combination of Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab given before and after an autologous stem cell transplant in patients with relapsed/refractory multiple myeloma. The goal is to see the effects of this regimen on the disease's progression.

Participant Groups

Group I: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab & HCT Experimental Treatment 5 Interventions

After receiving four 28-day cycles of Dara-CRd, eligible patients will then undergo HCT with high dose melphalan conditioning. Sixty to ninety days after HCT, patients will receive another 4 cycles of Dara-CRd.

Carfilzomib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Kyprolis for:

• Multiple myeloma

Approved in European Union as Kyprolis for:

• Multiple myeloma

Approved in Canada as Kyprolis for:

• Multiple myeloma

Approved in Japan as Kyprolis for:

• Multiple myeloma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Janssen Pharmaceuticals

Industry Sponsor

Trials

87

Recruited

208,000+

Joaquin Duato

Janssen Pharmaceuticals

Chief Executive Officer since 2022

MBA from ESADE Business School

John (Jack) Lawrence

Janssen Pharmaceuticals

Chief Medical Officer since 2023

MD from University of Virginia School of Medicine

Findings from Research

The combination therapy of daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd) was well tolerated in a study of 22 patients with newly diagnosed multiple myeloma, with a high overall response rate of 95%.

Most treatment-emergent adverse events were mild, with the most common being diarrhea and lymphopenia, and infusion-related reactions were primarily mild, indicating a favorable safety profile for D-KRd therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma. Jakubowiak, A., Usmani, SZ., Krishnan, 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 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]

In the phase 3 CANDOR study involving 466 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib, daratumumab, and dexamethasone (KdD) demonstrated a significantly longer median progression-free survival of 28.6 months compared to 15.2 months for carfilzomib and dexamethasone (Kd), indicating KdD's potential as a new standard-of-care treatment.

While KdD showed improved efficacy, it was associated with a higher incidence of grade 3 or worse treatment-emergent adverse events (87% in KdD vs. 76% in Kd), including thrombocytopenia and pneumonia, highlighting the need for careful monitoring of patients receiving this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Usmani, SZ., Quach, H., Mateos, MV., et al.[2022]

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]

Isatuximab combined with carfilzomib and dexamethasone (Isa-Kd) demonstrated significantly better progression-free survival (PFS) compared to daratumumab combined with lenalidomide and dexamethasone (Dara-Rd) in patients with relapsed and/or refractory multiple myeloma, based on a matching-adjusted indirect comparison of 179 patients from the IKEMA trial and 286 patients from the POLLUX trial.

Patients receiving Isa-Kd experienced lower rates of treatment-emergent adverse events (TEAEs) compared to those on Dara-Rd, indicating a potentially safer profile for Isa-Kd in this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparison of isatuximab plus carfilzomib and dexamethasone with daratumumab plus lenalidomide and dexamethasone in relapsed multiple myeloma. Richter, J., Lin, PL., Garcia-Horton, V., et al.[2023]

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 phase 2 study involving 46 patients with newly diagnosed multiple myeloma, the quadruplet regimen of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) achieved a stringent complete response (sCR) and/or measurable residual disease (MRD)-negativity rate of 58% after 8 cycles, indicating significant efficacy without the need for autologous stem cell transplant (ASCT).

The study demonstrated a 3-year progression-free survival (PFS) rate of 72% overall, and an impressive 92% for patients who achieved MRD-negativity, suggesting that MRD-guided therapy could allow for reduced treatment exposure while maintaining effective outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study. Derman, BA., Kansagra, A., Zonder, J., et al.[2023]

References

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

Daratumumab Plus Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma. [2022]

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

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

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

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

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. [2022]

6. England 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. [2020]

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

Matching-adjusted indirect comparison of isatuximab plus carfilzomib and dexamethasone with daratumumab plus lenalidomide and dexamethasone in relapsed multiple myeloma. [2023]

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

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation. [2021]

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

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study. [2023]