Quadruple Therapy + Stem Cell Transplant for Multiple Myeloma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of four drugs alongside stem cell transplants to treat multiple myeloma, a type of blood cancer. The researchers aim to determine the treatment's effectiveness and potential side effects. Individuals with multiple myeloma that has relapsed or worsened after 1 to 3 previous treatments might be suitable for this study. Participants will receive the study drugs—Carfilzomib (Kyprolis), Daratumumab (Darzalex), Dexamethasone, and Lenalidomide—both before and after their stem cell transplant. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Studies have shown that using Carfilzomib, Daratumumab, Dexamethasone, and Lenalidomide together is generally safe for people with multiple myeloma. Research indicates that this combination is well-tolerated, with many patients experiencing only mild side effects. In one study, patients who had tried other treatments before did not report any severe side effects when using this combination.

Another study tested these drugs together and found them effective against multiple myeloma, with side effects that were mostly manageable. The most common issues were tiredness and low blood counts, but these were usually not severe.

All these drugs have already received FDA approval for treating multiple myeloma, meaning they have passed several safety tests. So far, the data suggest that using them together is safe, with known side effects similar to those when each drug is used alone. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the quadruple therapy of Carfilzomib, Daratumumab, Dexamethasone, and Lenalidomide for multiple myeloma because it combines powerful drugs that target the cancer in multiple ways. Unlike standard treatments, which might use fewer agents, this approach uses Daratumumab, an antibody that directly attacks cancer cells, alongside Carfilzomib, a proteasome inhibitor that disrupts the cancer cell's waste disposal system. The combination, followed by a stem cell transplant, aims to enhance effectiveness and potentially extend remission periods. This comprehensive approach may offer a more aggressive attack on the cancer, giving hope for better outcomes.

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

Research has shown that a combination of four drugs—carfilzomib, lenalidomide, dexamethasone, and daratumumab—works well in treating multiple myeloma, especially when paired with a stem cell transplant. In this trial, participants will receive this combination, known as Dara-CRd, followed by an autologous hematopoietic cell transplantation (HCT). Studies indicate that this drug mix improves outcomes for patients with high-risk multiple myeloma. One study noted significant improvements in patient response to this treatment. Another study found that using these drugs before and after a stem cell transplant could be effective for patients facing their first relapse. The evidence strongly supports these drugs as a promising treatment option for multiple myeloma. ^{6 7 8 9 10}

Who Is on the Research Team?

Gunjan Shah, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Pharmaceuticals

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

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 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]

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 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]

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 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]

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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/143/20/2029/515075/Daratumumab-carfilzomib-lenalidomide-and

Daratumumab, carfilzomib, lenalidomide, and dexamethasone ... Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10622318/

Carfilzomib, lenalidomide and dexamethasone followed by ... Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma.

3. astctjournal.org astctjournal.org/article/S1083-8791(15)01077-0/fulltext

Carfilzomib (CFZ, Kyprolis®), Lenalidomide (LEN, Revlimid ... Carfilzomib (CFZ, Kyprolis®), Lenalidomide (LEN, Revlimid®), and Dexamethasone (DEX) (KRd) Combined with Autologous Stem Cell Transplant (ASCT) Shows Improved ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265021023430

P-216: Daratumumab, Carfilzomib, Lenalidomide, & ... We present the interim analysis of a phase II multicenter trial evaluating the efficacy of daratumumab, carfilzomib (27 mg/m2 twice weekly), lenalidomide, & ...

5. nature.com nature.com/articles/s41408-024-01045-3

Final analysis of a phase II trial of daratumumab ... We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-darzalex-faspro-kyprolis-and-dexamethasone-multiple-myeloma

FDA approves Darzalex Faspro, Kyprolis, and ... This cohort enrolled 66 patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy. Patients received ...

7. amgen.com amgen.com/newsroom/press-releases/2021/12/fda-approves-new-kyprolis-carfilzomib-combination-regimen-with-darzalex-faspro-daratumumab-and-hyaluronidasefihj-and-dexamethasone-for-patients-with-multiple-myeloma-at-first-or-subsequent-relapse

FDA Approves New KYPROLIS® (carfilzomib ... KYPROLIS in combination with subcutaneous treatment regimen provides further options and convenience for patients with relapsed/refractory multiple myeloma.

8. bloodcancerunited.org bloodcancerunited.org/resources/newsroom/fda-approval-new-treatment-indication-multiple-myeloma-drug

New Treatment Indication for Multiple Myeloma Drug Today's FDA approval was based on results from the phase 3 APOLLO study, which was presented at the American Society of Hematology (ASH) 2020 Annual Meeting.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9989580/

Daratumumab, carfilzomib, and dexamethasone in ... Daratumumab, carfilzomib, and dexamethasone in relapsed or refractory myeloma: final analysis of PLEIADES and EQUULEUS

10. darzalexhcp.com darzalexhcp.com/indications-and-dosing/

Indications & Dosing In a pooled safety population of 1249 patients with multiple myeloma (N=1056) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as ...