AUTHORS
S. Vincent Rajkumar, MD, Peter Voorhees, MD2, Fredrik Schjesvold, MD,PhD3, Yael C. Cohen, MD4, Vania Hungria, MD, PhD5, Irwindeep Sandhu, MD, FRCPC6, Jindriska Lindsay7, Ross Baker, MBBS, BSc, FRACP, FRCPA8, Kenshi Suzuki, MD9, Hiroshi Kosugi, MD, PhD10, Mark-David Levin, MD, PhD11, Meral Beksac, MD12, Keith Stockerl-Goldstein, MD13, Albert Oriol Sr, MD14, Gabor Mikala, MD, PhD15, Gonzalo Garate, MD16, Koen Theunissen17, Ivan Špicka18, Anne Mylin19, Sara Bringhen, MD, PhD20, Katarina Uttervall, MD, PhD21, Bartosz Pula, MD, PhD22, Eva Medvedova, MD23, Andrew J. Cowan, MD24, Philippe Moreau Sr, MD, PhD25, Maria-Victoria Mateos Jr, MD, PhD26, Hartmut Goldschmidt, MD27, Tahamtan Ahmadi, MD, PhD28, Linlin Sha29, Els Rousseau, PhD30, Liang Li31, Robyn Dennis, MD32, Robin Carson, MD33, Meletios-Athanasios (Thanos) C. Dimopoulos, MD34
AFFILIATIONS
1 Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States
2 Atrium Health/Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, North Carolina, United States
3 Oslo Myeloma Center, Department of Hematology, Oslo University Hospital; KG Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway
4 Tel-Aviv Sourasky (Ichilov) Medical Center; Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
5 Clinica Médica São Germano, São Paulo, Brazil
6 Cross Cancer Institute, Edmonton, AB, Canada
7 East Kent Hospitals University NHS Foundation Trust, Kent and Canterbury Hospital, Canterbury, United Kingdom
8 Perth Blood Institute, Murdoch University, Perth, Australia
9 Japanese Red Cross Medical Center, Department of Hematology, Tokyo, Japan
10 Ogaki Municipal Hospital, Ogaki City, Japan
11 Albert Schweitzer Hospital, Dordrecht, Netherlands
12 Ankara University, Ankara, Turkey, Ankara, Turkey
13 Washington University School of Medicine, St. Louis, Missouri, United States
14 Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
15 South Pest Central Hospital, National Institute for Hematology and Infectious Diseases, Budapest, Hungary
16 Hospital Alemán, Buenos Aires, Spain
17 Jessa Hospital, Hasselt, Belgium
18 Charles University and General Hospital, Prague, Czech Republic
19 Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
20 Hematology Division, AO Santa Croce e Carle, Cuneo, Italy
21 Medical Unit Hematology, Karolinska University Hospital, Stockholm, Sweden
22 Institute of Hematology and Transfusion Medicine, Warsaw, Poland
23 Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, United States
24 University of Washington, Seattle, Washington, United States
25 University Hospital Hôtel-Dieu, Nantes, France
26 University Hospital of Salamanca, IBSAL, and Cancer Research Center, IBMCC, Salamanca, Spain
27 Internal Medicine V, Hematology, Oncology and Rheumatology, GMMG Study Group, Heidelberg University Hospital; National Center for Tumor Diseases, Heidelberg, Germany
28 Genmab, Princeton, New Jersey, United States
29 Johnson & Johnson, Shanghai, China
30 Johnson & Johnson, Beerse, Belgium
31 Johnson & Johnson, Shanghai, China
32 Johnson & Johnson, Raritan, New Jersey, United States
33 Johnson & Johnson, Spring House, Pennsylvania, United States
34 National and Kapodistrian University of Athens, Athens, Greece
ABSTRACT
Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder that precedes active multiple myeloma (MM); patients with high-risk SMM carry an increased risk of progression to MM requiring systemic myeloma treatment. Whether early therapeutic intervention can delay progression to MM and confer a survival benefit has remained a question central to the field. In the primary analysis of the phase 3 AQUILA study (NCT03301220), daratumumab (Dara) subcutaneous monotherapy significantly reduced the risk of progression to active MM or death versus active monitoring (clinical cutoff 1 May 2024), with an overall survival (OS) benefit in favor of Dara monotherapy and no new safety signals. Here, we report the final analyses of AQUILA (clinical cutoff 4 May 2026), including long-term progression-free survival (PFS), PFS on first subsequent therapy (PFS2), OS, and time to first-line (1L) MM treatment, with a median follow-up of ~7.4 years (2 additional years), representing the most comprehensive long-term evidence base in high-risk SMM to date.
Methods: Eligible patients were ≥18 years of age with a confirmed diagnosis (≤5 years) who met IMWG 2014 criteria for SMM, and were considered to have high-risk SMM defined as clonal bone marrow plasma cells (BMPC) ≥10% plus ≥1 risk factor (IgA SMM, serum protein ≥3 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and <100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC >50% to <60%) at study entry. Patients were randomized 1:1 to subcutaneous Dara or active monitoring for up to 39 cycles, 36 months or until confirmed disease progression, whichever came first. The primary endpoint was PFS, defined as progression to active MM per IMWG 2014 criteria or death. Secondary endpoints included PFS2, OS, and time to 1L MM treatment. Outcomes are reported for the intent-to-treat (ITT) population and for subgroups based on the IMWG 2020 high-risk criteria (BMPC >20%, monoclonal spike >2 g/dL, serum FLC ratio >20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria).
Results: 390 patients were randomized (Dara, n=194; active monitoring, n=196). At final analysis, median follow-up was 88.8 months, with 80.8% of patients followed for ≥5 years. Dara treatment led to a significant 52% reduction in the risk of progression to active MM or death versus active monitoring (HR 0.48; 95% CI, 0.36–0.63; P<0.0001), with median PFS of 82.5 versus 34.9 months, respectively, corresponding to approximately a 4-year delay in progression to active MM. PFS benefit was generally consistent across subgroups, including IMWG 2020 risk subgroups. PFS2 also significantly improved with Dara treatment versus active monitoring (HR 0.63; 95% CI, 0.41–0.96; nominal P=0.0309), indicating no detrimental impact of prior Dara treatment on outcomes after progression. Of 64 deaths, fewer occurred with Dara versus active monitoring (12.4% [n=24] versus 20.4% [n=40]). OS was significantly improved with Dara, with a significant 48% reduction in risk of death (HR 0.52; 95% CI, 0.32–0.87; P=0.0108). The 7-year OS rate was 87.8% versus 78.7%, respectively.
Time to 1L MM treatment was significantly delayed by 52% with Dara versus active monitoring (median not reached versus 50.2 months; HR 0.48; 95% CI, 0.36–0.64; P<0.0001); fewer Dara versus active monitoring patients received therapy for active MM (40.9% versus 59.2%), reflecting reduced and delayed treatment burden. No new safety concerns were reported with additional follow-up. Second primary malignancies occurred in 9.8% (Dara) and 11.7% (active monitoring) of patients, with hematologic second primary malignancies occurring in 2.1% and 4.1% of patients, respectively.
Conclusions: In the final analyses of AQUILA, the largest phase 3 trial in high-risk SMM to date, Dara monotherapy demonstrated significant improvement in OS at a median follow-up of ~7.4 years. Early Dara treatment delayed time to active MM and the need for active MM therapy, and did not compromise the efficacy of subsequent MM therapy. The effect of limited-duration Dara therapy persisted throughout the follow-up period, despite end of therapy at 3 years, demonstrating substantial clinical benefit beyond progression delay. Together, these data support Dara monotherapy as an effective, approved interception strategy in which early treatment of a precursor state meaningfully alters the disease course in patients with high-risk SMM.
DISCLOSURES
S. Vincent Rajkumar, MD: OpenMedicine - Current holder of stock options in a privately-held company; OpenMedicine - Current equity holder in private company; UpToDate - Patents & Royalties; IntegraConnect - Consultancy (Includes expert testimony)