Quadruple Therapy for Multiple Myeloma

(ADVANCE Trial)

Not currently recruiting at 6 trial locations

Overseen By Philip Arlen

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Miami

Must be taking: Thromboprophylactic agents

Must not be taking: Anti-CD38 therapies

Disqualifiers: Plasma cell leukemia, Amyloidosis, COPD, 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

Duration: 32 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new drug combinations to determine if they manage multiple myeloma, a type of blood cancer, more effectively than the usual treatment. Researchers compare two new drug combinations to standard care, assessing their safety and effectiveness. Individuals with newly diagnosed multiple myeloma who experience symptoms affecting daily life, such as bone pain or anemia (low red blood cell count), may be suitable for this study. Participants will receive one of the treatment combinations, which include Carfilzomib (Kyprolis), Daratumumab (Darzalex), Dexamethasone, and Lenalidomide, and will be monitored for cancer response. As a Phase 2 trial, this research measures 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, if you have been on certain treatments for multiple myeloma, a 2-week period without those medications is required before starting the trial.

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

Research has shown that the combination of carfilzomib, lenalidomide, dexamethasone, and daratumumab (often called KRD+DARA) is generally safe and well-tolerated. One study found that many patients responded well to this treatment. Another study noted that 83.7% of patients experienced serious side effects, but these were similar to those seen with standard treatments.

For the carfilzomib, lenalidomide, and dexamethasone (KRD) combo, research indicates it is also well-tolerated. Patients have had good results, even if they had other treatments before. While many patients reported serious side effects, these were similar to what is typically seen with similar treatments.

Overall, both combinations appear safe, with expected but manageable side effects. This offers hope for effective options in managing multiple myeloma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the quadruple therapy for multiple myeloma because it adds the drug daratumumab to an existing combination of carfilzomib, lenalidomide, and dexamethasone. Daratumumab is a monoclonal antibody that targets CD38, a protein highly expressed on multiple myeloma cells, enhancing the immune system's ability to attack the cancer. This approach aims to improve outcomes by leveraging different mechanisms to fight the disease more effectively than the current standard of care, which often involves combinations like bortezomib, lenalidomide, and dexamethasone (VRD). By potentially increasing the depth of response and prolonging remission, this regimen offers hope for improved patient outcomes.

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

Research shows that the combination of carfilzomib, lenalidomide, and dexamethasone (KRD), which participants in Arm B of this trial may receive, effectively treats multiple myeloma. Studies have found that this combination can lead to significantly better outcomes, such as longer periods without disease progression and higher chances of achieving minimal residual disease (MRD) negativity. Participants in Arm C of this trial will receive KRD with the addition of daratumumab (KRD+DARA), which appears to improve outcomes even further. One study reported that KRD+DARA achieved a higher rate of MRD negativity compared to KRD alone. This suggests that both treatments could be strong options for managing multiple myeloma. ^{6 7 8 9 10}

Who Is on the Research Team?

Carl Landgren, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

Adults aged 18-75 with newly diagnosed Multiple Myeloma, able to perform daily activities (ECOG 0-2), and have good heart, kidney, liver, and blood function. Participants must not have had more than one cycle of prior MM treatment or exposure to certain drugs. They should be free from significant heart disease, uncontrolled diabetes or hypertension, severe lung conditions like COPD, and active infections including HIV and COVID-19.

Inclusion Criteria

I am able to care for myself and perform daily activities.

I have been recently diagnosed with Multiple Myeloma.

I am able to have children, not pregnant, and use birth control.

Exclusion Criteria

I do not have severe stomach issues, nerve pain, drug allergies, or recent major surgery.

I do not have HIV, hepatitis B or C, or active COVID-19.

I have conditions like leukemia, COPD, high blood pressure, or diabetes that are not well-controlled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either VRD, KRD, or DKrd on a 21 or 28 day cycle for up to 8 cycles, depending on the arm. Participants achieving a PR or better continue treatment, while those with less than PR after 4 cycles go off study therapy.

32 weeks

Maintenance

Participants who are MRD positive may receive an ASCT before initiating maintenance therapy with Lenalidomide for up to 2 years. MRD negative participants go directly to maintenance therapy.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of progression-free survival and overall survival.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Daratumumab
• Dexamethasone
• Lenalidomide

Trial Overview The trial is testing if a combination of carfilzomib, lenalidomide & dexamethasone (KRD) alone or with Daratumumab (KRD+DARA) is safer/more effective for controlling multiple myeloma compared to the standard care combo of lenalidomide, bortezomib & dexamethasone (VRD).

How Is the Trial Designed?

Group I: Arm C- Carfilzomib, Lenalidomide and Dexamethasone with Daratumumab (DKrd) Experimental Treatment 8 Interventions

Participants in this group will receive Carfilzomib, Lenalidomide, Dexamethasone with Daratumumab, Acetaminophen, Diphenhydramine and Montelukast on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.

Group II: Arm B - Carfilzomib, Lenalidomide and Dexamethasone (KRD) Experimental Treatment 4 Interventions

Participants in this group will receive Carfilzomib, Lenalidomide and Dexamethasone on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.

Group III: Arm A - Bortezomib, Lenalidomide and Dexamethasone (VRD) Experimental Treatment 4 Interventions

Participants in this group will receive Bortezomib, Lenalidomide and Dexamethasone on a 21 day treatment cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years.

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?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

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 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]

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 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]

Lenalidomide combined with dexamethasone has been shown to be effective for treating relapsed/refractory multiple myeloma, and it has received approval from both the FDA and EMA for patients who have undergone at least one prior therapy.

The most common serious side effects include cytopenias and infections, but an expert panel has provided management strategies to minimize these risks, ensuring that patients can receive the full benefits of the treatment without unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Palumbo, A., Dimopoulos, M., San Miguel, J., et al.[2018]

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]

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]

Citations

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Efficacy Analysis of Bortezomib Combined with Lenalidomide ... Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients ...

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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) ...

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Daratumumab, Bortezomib, Lenalidomide, and ... The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for ...

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Bortezomib, Lenalidomide and Dexamethasone (VRd) vs ... Overall, we found better outcomes associated with KRd compared to VRd, including depth of response with patients achieving ≥ CR rate (25% vs. 41%, P < 0.01), 5- ...

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Clinical perspectives on the optimal use of lenalidomide ... Combinations of lenalidomide, bortezomib, and dexamethasone (RVd) are recommended for the treatment of newly diagnosed multiple myeloma (NDMM).

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Original Study Real-World Use of carfilzomib-lenalidomide ... Carfilzomib administered as either KRd or Kd was effective and well tolerated, even in patients with multiple prior LOTs, confirming the safety and response ...

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Superior outcomes and high-risk features with carfilzomib ... With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among ...

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