Quadruple Therapy for Multiple Myeloma

(ASCENT Trial)

Recruiting at 9 trial locations

Overseen By Robert Wittig, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: International Myeloma Foundation

Must not be taking: Chemotherapy, Investigational therapy

Disqualifiers: Active myeloma, Cardiovascular conditions, HIV, Hepatitis, 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: 24

87 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of four medications—carfilzomib, lenalidomide, daratumumab, and dexamethasone—to evaluate their effectiveness in treating high-risk smoldering multiple myeloma. The goal is to determine if this treatment can slow the progression of this blood condition, which often leads to active cancer. Individuals diagnosed with high-risk smoldering multiple myeloma who have not started any treatment might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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, it mentions that other concurrent chemotherapy or investigational therapies are not allowed, except for bisphosphonates, which are considered supportive care.

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

Research has shown that treatments using carfilzomib, daratumumab, dexamethasone, and lenalidomide have been tested in patients with multiple myeloma. In these studies, patients generally tolerated the treatments well, but side effects can occur. Common side effects reported include tiredness, pneumonia, and infections in the upper respiratory tract, such as colds or sinus infections. These effects were observed in patients previously treated for multiple myeloma who tried this combination as a new option.

This combination of drugs has received FDA approval for treating multiple myeloma in certain situations, indicating that it has been reviewed for safety and effectiveness in those cases. However, since this trial is in an earlier phase, ongoing research will continue to monitor its safety and effectiveness for people with high-risk smoldering multiple myeloma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this quadruple therapy for multiple myeloma because it combines four powerful drugs—Carfilzomib, Daratumumab, Dexamethasone, and Lenalidomide—to tackle the cancer from multiple angles. Unlike standard treatments that might use fewer drugs or target the disease in a more limited way, this regimen aims to enhance effectiveness by using a comprehensive approach. Carfilzomib and Daratumumab work by directly attacking and destroying cancer cells, while Lenalidomide boosts the immune system to fight the cancer, and Dexamethasone reduces inflammation and pain. This multi-faceted strategy has the potential to improve outcomes for patients by providing a more robust and sustained attack on the cancer cells.

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

Research has shown that a combination of the drugs carfilzomib, lenalidomide, daratumumab, and dexamethasone effectively treats multiple myeloma, a type of blood cancer. Studies have found that this combination can significantly improve outcomes for patients whose cancer has returned or hasn't responded to other treatments. Specifically, using daratumumab and carfilzomib together increases the number of patients experiencing a reduction in cancer symptoms. The FDA has approved this treatment for multiple myeloma, underscoring its effectiveness. ^{1 3 4 5 6}

Who Is on the Research Team?

Shaji K. Kumar, M.D.

Principal Investigator

Mayo Clinic

Brian Durie, MD

Principal Investigator

International Myeloma Foundation

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with high-risk smoldering multiple myeloma that hasn't been treated. Participants must be willing to use birth control, not have heart failure or HIV, and can't be pregnant or nursing. They should not have other serious health issues or recent major surgery and must agree to follow the study's procedures.

Inclusion Criteria

Provide informed written consent

My smoldering myeloma is high risk and untreated.

Willing to comply with specific contraception requirements

Exclusion Criteria

You have hepatitis B or active hepatitis C infection.

Any medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol

I have heart problems that are not currently under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive carfilzomib, lenalidomide, daratumumab, and dexamethasone for 6 cycles

24 weeks

6 visits (in-person)

Consolidation

Participants continue treatment with carfilzomib, lenalidomide, daratumumab, and dexamethasone for 6 cycles

24 weeks

6 visits (in-person)

Maintenance

Participants receive lenalidomide and daratumumab for 12 cycles

48 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Daratumumab
• Dexamethasone
• Lenalidomide

Trial Overview The study tests a combination of carfilzomib, lenalidomide, daratumumab, and dexamethasone in three phases over several cycles for treating high-risk smoldering multiple myeloma. Each phase has different durations but all aim to evaluate the effectiveness of this regimen.

How Is the Trial Designed?

Group I: Arm A Experimental Treatment 4 Interventions

Non-high dose treatment in 3 phases Induction 6 cycles: carfilzomib, lenalidomide, daratumumab, dexamethasone Consolidation 6 cycles: carfilzomib, lenalidomide, daratumumab, dexamethasone Maintenance 12 cycles: lenalidomide, daratumumab

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?

International Myeloma Foundation

Lead Sponsor

Trials

5

Recruited

430+

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 Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Joaquin Duato

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2014

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

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Trevie, Inc.

Collaborator

Trials

1

Recruited

90+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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

1. 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 ... The efficacy of KYPROLIS in combination with DARZALEX FASPRO and dexamethasone was evaluated in 66 patients with relapsed or refractory multiple ...

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

Daratumumab, carfilzomib, and dexamethasone in ... Overall, D-Kd demonstrated efficacy in PLEIADES, EQUULEUS, and CANDOR, supporting its use for RRMM, including lenalidomide-refractory multiple ...

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

New Treatment Indication for Multiple Myeloma Drug The most common adverse drug reactions in patients treated with daratumumab plus hyaluronidase were fatigue, pneumonia, upper respiratory tract infection and ...

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

Indications & Dosing DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma: In combination with bortezomib, ...

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

FDA approves Darzalex Faspro, Kyprolis, and ... FDA approves Darzalex Faspro, Kyprolis, and Dexamethasone for Multiple Myeloma. ... The main efficacy outcome measure was overall response ...

6. jnjmedicalconnect.com jnjmedicalconnect.com/products/darzalex/medical-content/use-of-darzalex-darzalex-faspro-in-combination-with-carfilzomib-lenalidomide-and-dexamethasone-in-m

DARZALEX® (daratumumab) A summary of clinical data regarding DARZALEX® (daratumumab) and DARZALEX FASPRO® (daratumumab and hyaluronidase) use in combination with ...