Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma

Author(s): Meletios A. Dimopoulos, M.D.¹; Peter M. Voorhees, M.D.²; Fredrik Schjesvold, M.D., Ph.D.³; Yael C. Cohen, M.D.⁴; Vania Hungria, M.D., Ph.D.⁵; Irwindeep Sandhu, M.D.⁶; Jindriska Lindsay, M.D.⁷; Ross I. Baker, M.D.⁸; Kenshi Suzuki, M.D., Ph.D.⁹; Hiroshi Kosugi, M.D., Ph.D.¹⁰; Mark-David Levin, M.D., Ph.D.¹¹; Meral Beksac, M.D.¹²; Keith Stockerl-Goldstein, M.D.¹³; Albert Oriol, M.D.¹⁴; Gabor Mikala, M.D., Ph.D.¹⁵; Gonzalo Garate, M.D.¹⁶; Koen Theunissen, M.D.¹⁷; Ivan Spicka, M.D., Ph.D.¹⁸; Anne K. Mylin, M.D., Ph.D.¹⁹; Sara Bringhen, M.D., Ph.D.²⁰; Katarina Uttervall, M.D., Ph.D.²¹; Bartosz Pula, M.D., Ph.D.²²; Eva Medvedova, M.D.²³; Andrew J. Cowan, M.D.²⁴; Philippe Moreau, M.D.²⁵; Maria-Victoria Mateos, M.D., Ph.D.²⁶; Hartmut Goldschmidt, M.D., Ph.D.²⁷; Tahamtan Ahmadi, M.D., Ph.D.²⁸; Linlin Sha, Ph.D.²⁹; Annelore Cortoos, M.D.³⁰; Eva G. Katz, Ph.D., M.P.H.³¹; Els Rousseau, Ph.D.³²; Liang Li, Ph.D.²⁹; Robyn M. Dennis, M.D.³¹; Robin Carson, M.D.³³; S. Vincent Rajkumar, M.D.³⁴; for the AQUILA Investigators*;

Source: DOI: 10.1056/NEJMoa2409029

Dr. Anjan Patel's Thoughts

The AQUILA trial compared daratumumab to active monitoring in high-risk smoldering multiple myeloma, demonstrating a significant improvement in progression-free survival (PFS) (84% vs 54% at 48 months) and a trend toward better overall survival (OS) (94% vs 86% at 48 months). Dara also achieved a higher rate of deep responses, with 60% of patients reaching minimal residual disease (MRD) negativity compared to none in the monitoring arm. This looks like a game-changer to delay progression, but we’ll need to weigh the toxicity profile carefully in practice and wait for survival data.

BACKGROUND

Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

METHODS

In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.

RESEARCH SUMMARY

Daratumumab for High-Risk Smoldering Multiple Myeloma

RESULTS

Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.

CONCLUSIONS

Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)

Author Affiliations

¹Alexandra General Hospital, National and Kapodistrian University of Athens, Athens; ²Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine, Charlotte, NC; ³Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo; ⁴Tel-Aviv Sourasky (Ichilov) Medical Center and Tel Aviv University, Tel Aviv, Israel; ⁵Clínica Medica São Germano, São Paulo; ⁶Cross Cancer Institute, University of Alberta, Edmonton, Canada; ⁷Kent and Canterbury Hospital, Canterbury, United Kingdom; ⁸Perth Blood Institute, Murdoch University, Perth, WA, Australia; ⁹Japanese Red Cross Medical Center, Tokyo; ¹⁰Ogaki Municipal Hospital, Ogaki City, Japan; ¹¹Albert Schweitzer Hospital, Dordrecht, the Netherlands; ¹²Ankara University, Ankara, Turkey; ¹³Washington University School of Medicine, St. Louis; ¹⁴Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona; ¹⁵South Pest Central Hospital, National Institute for Hematology and Infectious Diseases, Budapest, Hungary; ¹⁶Hospital Alemán, Buenos Aires; ¹⁷Jessa Hospital, Hasselt, Belgium; ¹⁸Charles University and General Hospital, Prague, Czech Republic; ¹⁹Rigshospitalet, University of Copenhagen, Copenhagen; ²⁰SSD Clinical Trials in Oncol-ematologia e Mieloma Multiplo, AOU Città della Salute e della Scienza di Torino, Turin, Italy; ²¹Medical Unit Hematology, Karolinska University Hospital, Stockholm; ²²Institute of Hematology and Transfusion Medicine, Warsaw, Poland; ²³Knight Cancer Institute, Oregon Health and Science University, Portland; ²⁴University of Washington and Fred Hutchinson Cancer Center, Seattle; ²⁵University Hospital Hôtel-Dieu, Nantes, France; ²⁶University Hospital of Salamanca, IBSAL, and Cancer Research Center, IBMCC, Salamanca, Spain; ²⁷GMMG Study Group at University Hospital Heidelberg, Internal Medicine V, Heidelberg, Germany; ²⁸Genmab US, Plainsboro, NJ; ²⁹Janssen Research and Development, Shanghai, China; ³⁰Janssen Scientific Affairs, Horsham, PA; ³¹Janssen Research and Development, Raritan, NJ; ³²Janssen Research and Development, Beerse, Belgium; ³³Janssen Research and Development, Spring House, PA; ³⁴Mayo Clinic, Rochester, MN;

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