Clinical Status and Design

The NCT04933539 trial, led by the U.S. National Cancer Institute (NCI), is a single-arm Phase 2 study enrolling 14 patients with high-risk asymptomatic multiple myeloma (HR-SMM). Recruitment has been completed and the study is currently in follow-up. The actual start date was October 31, 2022, with a primary completion date expected on August 31, 2026, and an overall completion date expected on October 31, 2032. The primary endpoint is the rate of MRD-negative complete remission (CR), measured by flow cytometry after a maximum of 12 cycles of induction therapy. Given the small sample size, the study should be interpreted as a signal-finding exploratory trial rather than a confirmatory trial for commercial use, aiming to assess whether intensive early treatment can achieve deep molecular remission.

Composition and Mechanism of DKd

DKd consists of subcutaneous Darzalex Faspro (daratumumab and hyaluronidase-fihj), intravenous Kyprolis (carfilzomib), and dexamethasone. Daratumumab, marketed by Johnson & Johnson (JNJ) and licensed from Genmab (GMAB), is a monoclonal antibody targeting CD38 on plasma cells. Carfilzomib, developed by Amgen (AMGN), irreversibly inhibits the chymotrypsin-like activity site of the 20S proteasome (PSMB5). Dexamethasone activates the glucocorticoid receptor NR3C1 to enhance myeloma cell apoptosis and anti-inflammatory effects. Patients receive eight cycles of DKd every 28 days, with an additional four cycles if MRD-negative remission is not achieved, followed by up to 24 cycles of daratumumab monotherapy maintenance.

Regulatory Changes and Clinical Implications

At the time the study began, the standard strategy for high-risk SMM was watchful waiting. However, on November 6, 2025, the FDA approved Darzalex Faspro monotherapy for this indication based on the results of the AQUILA Phase 3 trial. Prior to this, the FDA Oncologic Drugs Advisory Committee had voted 6 to 2 in favor of the drug's benefit-risk profile on May 20, 2025. The European Union Executive Committee also approved subcutaneous daratumumab monotherapy on July 23, 2025. As a result, the key question for this Phase 2 trial has shifted from whether treatment can outperform no treatment to whether adding carfilzomib and dexamethasone to the already approved daratumumab monotherapy can deepen MRD-negative remission. Conversely, for the addition of carfilzomib—which carries cardiovascular and renal toxicity and requires intravenous administration—to be justified in patients who remain asymptomatic for long periods, data on durability and safety beyond deep remission will be necessary.

Market Potential and Competitive Landscape

The global multiple myeloma treatment market was valued at USD 29.24 billion in 2025 and is projected to reach USD 49.79 billion by 2034. DARZALEX generated USD 14.351 billion in global sales in 2025, while KYPROLIS generated USD 1.412 billion. High-risk SMM is an early-stage disease with an incidence of approximately 5 per 100,000 in the U.S., and the approved Darzalex Faspro monotherapy serves as the direct competitive benchmark. Clinical alternatives include the watchful waiting strategy and the lenalidomide-dexamethasone combination with Phase 3 evidence, while the ECOG-ACRIN Phase 3 NCT03937635 trial is evaluating the addition of daratumumab to lenalidomide-dexamethasone. For DKd to establish competitive advantage, it must demonstrate clinical superiority over monotherapy daratumumab not only in MRD results from a small single-arm study, but also in progression-free survival, delay of active myeloma transformation, quality of life, and cumulative toxicity.