A landmark advancement in the treatment of newly diagnosed multiple myeloma patients has emerged from the recently presented ADVANCE clinical trial data, signaling a significant shift in therapeutic strategy for this blood cancer. This large, multi-center randomized study, spearheaded by the Sylvester Comprehensive Cancer Center at the University of Miami, introduces a potent four-drug regimen by incorporating the targeted immunotherapy agent daratumumab into the established KRd combination—carfilzomib, lenalidomide, and dexamethasone. The compelling findings, unveiled at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, suggest that adding daratumumab substantially enhances treatment efficacy while maintaining a favorable safety profile, setting a new standard of care.
Multiple myeloma, characterized by malignant plasma cell proliferation within the bone marrow, remains a formidable clinical challenge. Despite continuous therapeutic innovations, achieving deep and durable responses that translate into improved progression-free survival continues to be the focus of research. The KRd regimen, combining carfilzomib—a proteasome inhibitor that disrupts protein degradation—lenalidomide, an immunomodulatory agent, and dexamethasone which modulates inflammation and immunity, has long been a backbone of induction therapy. Daratumumab targets the CD38 surface protein abundantly expressed on myeloma cells, facilitating antibody-dependent cellular cytotoxicity and direct tumor cell apoptosis, thereby offering a mechanistically complementary approach.
The ADVANCE trial enrolled 306 participants, all newly diagnosed multiple myeloma patients suitable for intensive therapy. These patients, robustly screened for comorbidities such as cardiovascular disease to optimize safety, were randomized evenly to receive either the traditional KRd triplet or the experimental quadruplet DKRd regimen. This trial design allowed direct comparative analysis of the two treatment strategies on minimal residual disease (MRD) negativity rates—a prognostic marker increasingly recognized for its correlation with long-term outcomes.
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After eight cycles of induction therapy, the DKRd cohort demonstrated a remarkable 59% rate of MRD negativity, markedly surpassing the 36% observed in the KRd group. MRD negativity is defined as the absence of detectable myeloma cells at extremely sensitive thresholds, indicating an exceptionally deep response to therapy. This achievement not only reflects the enhanced anti-myeloma activity of daratumumab addition but also suggests that a greater proportion of patients are attaining remission at a molecular level, potentially translating to more durable disease control.
Beyond response depth, progression-free survival was compellingly superior in the daratumumab-containing arm, with 86% of patients remaining free from disease progression at a median follow-up of 32.7 months, compared to 79% in the KRd cohort. While these data are still maturing and require longer follow-up to confirm overall survival benefits, this early signal underscores the clinical relevance of the four-drug regimen as a transformative therapy that can meaningfully prolong disease control intervals.
Importantly, the safety profile of DKRd was comparable to KRd, with no substantial increase in severe adverse events, a critical consideration in regimens involving potent biologics and chemotherapeutics. Careful patient selection—excluding those with frailty or significant cardiac dysfunction—and stringent pre-treatment evaluations including cardiac monitoring through EKG and echocardiography contributed to mitigating risks. This speaks to the importance of integrating personalized approaches in applying intensive combination therapies, allowing maximal therapeutic benefit without compromising safety.
The mechanistic synergy between the four agents accounts for the regimen’s potency. Carfilzomib’s disruption of proteasomal degradation causes accumulation of toxic proteins leading to myeloma cell apoptosis. Lenalidomide enhances host immune surveillance by stimulating T cell and natural killer cell activity while inhibiting pro-inflammatory cytokines. Dexamethasone exerts immunosuppressive yet anti-inflammatory effects, reducing tumor-promoting microenvironmental stimuli. Daratumumab’s targeted binding to CD38 invokes direct cytotoxicity and immune-mediated tumor clearance. This multifaceted attack on both the tumor cells and their supportive niche likely underlies the improved response rates and clinical outcomes.
The ADVANCE trial builds upon the promising results of the earlier MANHATTAN trial, a preliminary single-arm study that demonstrated a 71% MRD-negative rate using the same quadruplet regimen, albeit in a smaller cohort. While the MANHATTAN data validated the concept, the controlled comparison within ADVANCE provides definitive evidence for the superiority of DKRd over KRd, thereby guiding therapeutic decision-making more confidently.
The implications of this research extend beyond immediate treatment improvements. By achieving high rates of MRD negativity early in therapy, patients may defer or even forgo autologous stem cell transplantation—a historically universal component of myeloma management. Instead, stem cell collection is preserved while patients transition directly to maintenance therapy with lenalidomide, potentially reducing treatment-related morbidity and improving quality of life.
At Sylvester and numerous collaborating institutions nationwide—including MD Anderson, Memorial Sloan Kettering, Moffitt, and others—the DKRd regimen is rapidly being integrated into clinical practice. Leading clinicians acknowledge how these findings have already transformed initial treatment paradigms, reflecting a broader trend in oncology to capitalize on combination immunotherapy and targeted agents.
Cutting-edge molecular analyses are ongoing to elucidate the underlying biological factors influencing individual patient responses and resistance mechanisms. Understanding how tumor heterogeneity impacts sensitivity to these agents is pivotal for future precision medicine approaches and the design of next-generation regimens.
Looking ahead, Dr. C. Ola Landgren, director of the Sylvester Myeloma Institute and study lead, envisions further trials testing combinations of DKRd with bispecific T cell engagers—an emerging immunotherapeutic class designed to recruit and activate T cells in the tumor microenvironment. Such innovative combinations may potentiate anti-myeloma immunity even more profoundly, moving closer to potential cure.
This paradigm-shifting study not only offers hope to the thousands of patients diagnosed annually with multiple myeloma but also exemplifies the evolving landscape of cancer therapy—where targeted agents and immunotherapies converge to redefine disease management. As the treatment arsenal expands, personalized, safe, and effective regimens like DKRd pave the way for improved survivorship and quality of life.
Subject of Research: Multiple myeloma treatment with daratumumab plus KRd therapy
Article Title: New Four-Drug Combination Sets a New Standard for Newly Diagnosed Multiple Myeloma
News Publication Date: May 29, 2025
Web References:
Sylvester Comprehensive Cancer Center: https://umiamihealth.org/sylvester-comprehensive-cancer-center
ASCO Meeting Presentation: https://meetings.asco.org/2025-asco-annual-meeting/16380?presentation=246412#246412
National Cancer Institute Multiple Myeloma Facts: https://seer.cancer.gov/statfacts/html/mulmy.html
Image Credits: Photo by Sylvester Comprehensive Cancer Center
Keywords: Multiple myeloma, blood cancer, myeloma, clinical trials, drug studies
Tags: ADVANCE clinical trial findingsASCO 2025daratumumab immunotherapyfour-drug treatment combinationKRd regimen effectivenessmultiple myeloma treatment advancementsnew standard of care multiple myelomaplasma cell malignancy researchprogression-free survival improvementssafety profile of cancer therapiestherapeutic innovations in oncologyUniversity of Miami cancer research