DKd Regimen for Smoldering Multiple Myeloma

Overseen By Elizabeth M Hill, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Daratumumab, Carfilzomib, Dexamethasone

Must not be taking: Investigational agents, Proteasome inhibitors

Disqualifiers: COPD, Asthma, 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: 7

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of three drugs—daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone—can slow down or prevent multiple myeloma, a blood cancer, during its early "smoldering" stage. The goal is to stop the cancer from damaging organs before it becomes more serious. Individuals with high-risk smoldering multiple myeloma, which is likely to become active, might be suitable candidates. Participants will receive treatments in 28-day cycles and undergo regular check-ups and tests to monitor progress. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Do I need to stop my current medications to join the trial?

The trial protocol 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 those who have had prior therapy for smoldering multiple myeloma, unless the prior treatment included the current DKd regimen or similar drugs.

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

Research has shown that the combination of three drugs—daratumumab, carfilzomib, and dexamethasone, known as DKd—has been studied for safety in people with multiple myeloma. This combination is generally well-tolerated. In earlier studies, patients experienced some side effects, but these were manageable. Common side effects included fatigue and low blood cell counts, typical for many cancer treatments.

Daratumumab, one of the drugs in DKd, has FDA approval for treating multiple myeloma, indicating its safety. Carfilzomib and dexamethasone also have established safety records in similar treatments.

Overall, while possible side effects exist, existing research indicates that the DKd regimen is safe enough for further studies to help prevent the progression of smoldering multiple myeloma. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for multiple myeloma?

Researchers are excited about the DKd regimen for smoldering multiple myeloma because it combines three powerful treatments: Carfilzomib, Daratumumab, and Dexamethasone. Unlike standard treatments that often rely on single agents, this regimen uses a combination approach to target the cancer more aggressively. Carfilzomib is a proteasome inhibitor that disrupts the protein recycling process in cancer cells, while Daratumumab is a monoclonal antibody that helps the immune system find and destroy myeloma cells. Together, these drugs, along with Dexamethasone, which helps reduce inflammation and support the effectiveness of the other treatments, offer a unique strategy that could potentially improve outcomes for patients with this condition.

What evidence suggests that the DKd regimen could be an effective treatment for smoldering multiple myeloma?

Research shows that the DKd treatment plan, which includes daratumumab, carfilzomib, and dexamethasone, holds promise for treating smoldering multiple myeloma. In this trial, participants will receive this combination therapy. Studies have found that daratumumab can lower the risk of developing active multiple myeloma by 51% in high-risk patients. Carfilzomib effectively reduces leftover cancer cells, achieving this in up to 62% of cases. Dexamethasone, often used with other drugs, enhances treatment responses and outcomes in high-risk patients. While each drug offers its own benefits, using them together may improve their effectiveness and slow disease progression. ^{6 7 8 9 10}

Who Is on the Research Team?

Elizabeth M Hill, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with high-risk smoldering multiple myeloma, a condition where cancer cells are present but not causing symptoms. Participants must have certain levels of M-protein and plasma cells, no severe organ damage or bone lesions, and be able to perform daily activities. Women who can bear children must use contraception.

Inclusion Criteria

My condition is confirmed as smoldering multiple myeloma.

Negative serum or urine pregnancy test required for women of child-bearing potential

Patients must have measurable disease within the past 4 weeks as defined by specific criteria

Exclusion Criteria

Patients seropositive for hepatitis C unless in the setting of a sustained virologic response

I do not have any unmanaged ongoing illnesses.

I cannot take certain medications due to adverse reactions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Participants receive DKd combination therapy for 8 cycles, with an option for 4 additional cycles if MRD negative remission is not attained

8-12 cycles (28 days each)

Frequent visits for blood work and evaluations

Maintenance Treatment

Participants receive daratumumab maintenance therapy for 24 cycles

24 cycles (28 days each)

Visits every 3-6 months for laboratory evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment

Ongoing, with visits every 3-12 months

Follow-up visits every 3-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Daratumumab
• Dexamethasone

Trial Overview The DKd treatment combines daratumumab (injection under the skin), carfilzomib (IV), and dexamethasone (oral/IV) in cycles to prevent or slow down the progression of multiple myeloma from its smoldering phase. The study includes frequent tests, scans, questionnaires, and long-term follow-up.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 3 Interventions

Daratumumab SC (Cycles 1-2: Days 1, 8, 15, 22; Cycles 3-6: Days 1, 15; Cycles =7: Days 1 of the 28-day cycle); Carfilzomib IV (Days 1, 8, 15 of the 28-day cycle); Dexamethasone PO/IV (Days 1, 8, 15, 22 of the 28-day cycle)

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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

Published Research Related to This Trial

In a phase 2 study involving 72 patients with newly diagnosed multiple myeloma, the combination of carfilzomib and dexamethasone (Kd) achieved a remarkable overall response rate of 90%, with 7% of patients reaching a complete response and 58% achieving a very good partial response.

The treatment was generally well-tolerated, with most adverse events being low grade; however, there was an 11.1% incidence of grade 3 or higher cardiovascular events, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. Forsberg, PA., Rossi, AC., Boyer, A., et al.[2020]

The KRd regimen (carfilzomib, lenalidomide, and dexamethasone) demonstrated a high overall response rate of 88.5% in 26 heavily pretreated Japanese patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

While the KRd regimen was generally well tolerated, a higher incidence of hyperglycemia was noted, likely due to dexamethasone, suggesting the need for monitoring blood sugar levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan. Suzuki, K., Ri, M., Chou, T., et al.[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 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]

Carfilzomib, when used in combination with lenalidomide and dexamethasone, significantly prolongs progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma, based on results from the phase III ASPIRE study involving a multinational patient population.

The combination therapy has a manageable safety profile, with low incidences of severe adverse events, suggesting it is a viable treatment option for patients who have received prior therapies, although overall survival data is still pending.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. Hoy, SM.[2018]

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 real-world study of 152 patients with relapsed and/or refractory multiple myeloma treated with carfilzomib plus dexamethasone, the overall response rate was 71.1%, indicating that this treatment is effective in a clinical setting.

Patients classified as trial-unfit had significantly shorter progression-free survival (3.6 months) and overall survival (15.0 months) compared to trial-fit patients (7.3 months and 36.8 months, respectively), highlighting the importance of patient fitness in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment outcomes of carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma, focusing on the impact of trial-fitness: CAtholic REsearch network for Multiple Myeloma study (CAREMM-2203). Park, SS., Goo, SY., Jeon, YW., et al.[2023]

The combination of carfilzomib, pomalidomide, and dexamethasone (KPd) showed a high overall response rate of 79% in patients with relapsed/refractory multiple myeloma, indicating its efficacy as a treatment option.

Adding daratumumab to the KPd regimen (Dara-KPd) resulted in even better outcomes, with an overall response rate of 89% and a significant rate of measurable residual disease negativity, suggesting that Dara-KPd may provide deeper and more durable responses without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma. Derman, BA., Zonder, J., Reece, D., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9713064/

Carfilzomib usage patterns and outcomes in patients with ... Median progression‐free survival for the overall cohort was 6.3 months with overall survival 19.7 months. This study provides a benchmark for carfilzomib‐based ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12466189/

Efficacy and toxicity of treatment of smoldering multiple ... Minimal residual disease (MRD) negativity rate was 62% (95% CI, 42%–81%), and grade 3–4 adverse events (AEs) rate was 36% (95% CI, 30%–43%). As ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02771

Curative Strategy for High-Risk Smoldering Myeloma This curative approach is encouraging and more effective than active MM, with 31% of the patients maintaining the uMRD 4 years after HDM-ASCT.

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/676/530566/Results-of-the-Phase-II-Randomized-Trial-EMN15

Results of the Phase II Randomized Trial EMN15/HOVON147 At least one grade 3-4 (non)-hematologic AE's occurred in 74% versus 53% of KRD versus Rd treated patients. Less patients went off protocol due ...

5. nature.com nature.com/articles/s41467-024-55308-5

Deeper response predicts better outcomes in high-risk ... Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial. Omar Nadeem,; Michelle ...

6. aetna.com aetna.com/cpb/medical/data/900_999/0904.html?ref=counterforcehealth.org

Daratumumab (Darzalex) and Daratumumab and ... C90.02. Multiple myeloma [covered for Darzalex or Darzalex Faspro when used in combination with carfilzomib, pomalidomide and dexamethasone] [ not covered for ...

7. jnj.com jnj.com/media-center/press-releases/u-s-fda-oncologic-drugs-advisory-committee-votes-in-favor-of-the-benefit-risk-profile-of-darzalex-faspro-daratumumab-and-hyaluronidase-fihj-for-high-risk-smoldering-multiple-myeloma

U.S. FDA Oncologic Drugs Advisory Committee votes in ... DARZALEX FASPRO is a foundational therapy in MM, and if approved in this indication, would provide a potential path for earlier intervention.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6676132/

Daratumumab plus carfilzomib and dexamethasone in ... This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy.

9. myeloma.org myeloma.org/fda-odac-votes-support-darzalex-faspro-high-risk-smoldering-myeloma

FDA ODAC Votes in Support of DARZALEX FASPRO for ... If approved, DARZALEX FASPRO would become the first therapy available to delay—or potentially prevent—progression to active multiple myeloma.

10. jnjmedicalconnect.com jnjmedicalconnect.com/products/darzalex/medical-content/darzalex-darzalex-faspro-use-in-smoldering-multiple-myeloma

darzalex - Use in Smoldering Multiple Myeloma ASCENT is a phase 2 study evaluating the safety and efficacy of DARZALEX + carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with high-risk-SMM.