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

14 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Multiple myeloma (MM) is a tumor in which malignant plasma cells accumulate in the bone marrow. It can cause organ damage and is not curable. Researchers want to see if a combination drug treatment can help. Objective: To try to prevent or slow down developing MM and its associated organ damage by treating it while still in the smoldering phase with a mix of drugs known as DKd. Eligibility: People ages 18 and older with smoldering MM that is at high risk of converting to symptomatic MM. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Bone survey (x-rays of their bones) Spinal magnetic resonance imaging Bone marrow biopsy (a needle is used to remove bone marrow from their hipbone) Electrocardiogram (to check heart function) Lung function tests Treatment will be given in 28-day cycles. Participants will get daratumumab by injection under the skin. They will get carfilzomib intravenously (IV) through a tube inserted in a vein. They will get dexamethasone as oral tablets or as an IV. They will get all 3 drugs for 8 or 12 cycles. Then they will get daratumumab alone for up to 24 cycles. They may have stem cells collected. Participants will have frequent study visits. At these visits, they will repeat some screening tests. They will complete questionnaires. They will have imaging scans. For these scans, they may receive an oral or IV contrast. Participants will have a follow-up visit 30 days after treatment ends. Then they will have visits every 3-12 months. They will be followed on this study for life.

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.

What data supports the effectiveness of the DKd drug regimen for smoldering multiple myeloma?

The combination of carfilzomib, dexamethasone, and daratumumab has shown substantial effectiveness in treating relapsed or refractory multiple myeloma, as seen in the CANDOR study, which demonstrated improved outcomes compared to carfilzomib and dexamethasone alone. ^{1 2 3 4 5}

Is the DKd regimen safe for humans?

The DKd regimen, which includes carfilzomib, daratumumab, and dexamethasone, has been studied in patients with multiple myeloma and shown to have a tolerable safety profile. Most side effects were mild, but some serious side effects, particularly related to the heart, were observed in a small percentage of patients. ^{2 4 5 6 7}

What makes the DKd drug regimen unique for treating smoldering multiple myeloma?

The DKd regimen combines carfilzomib, daratumumab, and dexamethasone, which is unique because it includes daratumumab, a monoclonal antibody that targets a specific protein on myeloma cells, potentially offering a more targeted approach compared to other regimens that do not include this component. ^{1 3 7 8 9}

Research Team

Elizabeth M Hill, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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.

I am 18 years old or older.

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

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

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

Treatment Details

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.

Participant Groups

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+

Ricardo Attar

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology, University of Buenos Aires

Dr. Anastasia G. Daifotis

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2023

MD

Findings from Research

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]

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 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]

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 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]

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]

References

1. Germany 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). [2023]

2. 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]

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, 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]

5. France pubmed.ncbi.nlm.nih.gov

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

6. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Use and Effectiveness of Carfilzomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma in Europe. [2022]

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

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan. [2021]

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

Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone with and without daratumumab in relapsed multiple myeloma. [2023]