Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study.

Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and <100, and/or clonal BMPCs >50% to <60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS).

Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months).

At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P <0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P <0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P <0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group.

Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%).

Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

Disclosures

Dimopoulos:SANOFI: Honoraria; REGENERON: Honoraria; MENARINI: Honoraria; TAKEDA: Honoraria; GSK: Honoraria; BMS: Honoraria; JANSSEN: Honoraria; BEIGENE: Honoraria; SWIXX: Honoraria; ASTRA ZENECA: Honoraria; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees. Voorhees:AstraZeneca: Consultancy; Lava Therapeutics: Consultancy; GSK: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Schain: Other: Honoraria for lectures and educational material; Bristol Myers Squibb: Consultancy, Other: Honoraria for lectures and educational material; Skylite: Other: Honoraria for lectures and educational material; Novartis: Other: Honoraria for lectures and educational material; Daiichi Sankyo: Other: Honoraria for lectures and educational material; SkylineDx: Other: Honoraria for lectures and educational material; Pfizer: Other: Honoraria for lectures and educational material; Celgene: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Amgen: Other: Honoraria for lectures and educational material; Janssen-Cilag: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; GSK: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Other: Honoraria for lectures and educational material; Oncopeptides: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Sanofi: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Other: Honoraria for lectures and educational material; Targovax: Research Funding. Cohen:Amgen, BMS, GSK, JNJ, Medison, Pfizer, Roche, Sanofi Aventis, Takeda: Consultancy; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hungria:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer and Regeneron: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sandhu:GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb - Celgene: Consultancy, Honoraria; Johnson & Johnson - Janssen: Consultancy, Honoraria. Lindsay:BMS, Amgen, Takeda, BeiGene: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Janssen, Takeda, BMS: Honoraria, Speakers Bureau. Baker:Bayer, Takeda, Pfizer, Daiichi Sankyo, CSL Behring, Roche, Amgen, Celgene, Rigel Pharmaceuticals, Ionis Pharmaceuticals, Abbvie, Sanofi, MorphoSys AG, Acerta Pharma, Jansen-Cileg, Bristol- Myer- Squibb, Boehringer Ingelheim and Astra Zeneca: Research Funding; Bayer, Bristol- Myers Squibb, Cardinal Health and Astra Zeneca. He provided expert testimony for Sandoz: Honoraria; Roche, Janssen-Celeg, CSL Behring, Pharmaxis and George Institute: Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ono: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria; SRL: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Novartis: Honoraria. Kosugi:MSD: Honoraria; Asahi Kasei Pharma, AstraZeneca K.K. , Becton Dickinson K.K., Bristol-Meyers-Squibb K.K., Celgene K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Japan Blood Products Organization, Kissei: Honoraria; Nippon Shinyaku Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; Kissei Pharmaceutical Co., Ltd: Honoraria; Kyowa-Kirin Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; GlaxoSmithKline K.K: Honoraria; Celgene K.K: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Daiichi Sankyo Co., Ltd: Honoraria; Bristol-Myers-Squibb K.K: Honoraria; AstraZeneca K.K: Honoraria; Becton Dickinson K.K: Honoraria; Novartis Pharma K.K: Honoraria; Novo Nordisk Pharma Japan: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Sanofi K.K: Honoraria; Takeda Phamaceutical Co., Ltd: Honoraria. Levin:Janssen, AbbVie: Other: Travel. Beksac:BMS, Janssen, Takeda, Sanofi: Speakers Bureau; BMS, Takeda, Janssen, Menarini, Amgen, GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol:Bristol Myers Squibb/Celgene: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Pfizer, Amgen, Oncopeptides: Honoraria; GSK: Honoraria, Speakers Bureau; Johnson & Johnson, Janssen: Honoraria, Speakers Bureau. Theunissen:Johnson and Johnson, Celgene-BMS, Amgen, Pfizer, Sanofi, Roche, Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Spicka:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bringhen:AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Sanofi: Speakers Bureau; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb, Janssen, Oncopeptides, Pfizer, Stemline Therapeutics, and Takeda: Other: Participation in advisory boards. Uttervall:Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Other: lecture fees . Pula:Abbvie, Janssen: Research Funding; Abbvie, Roche, and Sandoz: Consultancy; Abbvie, AstraZeneca, BeiGene Amgen, Gilead, Celgene, and Janssen: Honoraria. Cowan:Sebia, Janssen, BMS, Sanofi, HopeAI, Adaptive Biotechnologies, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie, Adaptive Biotechnologies, Janssen, BMS, Juno/Celgene, Sanofi, Regeneron, IGM BIosciences, Nektar, Harpoon, Caelum: Research Funding. Moreau:AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Roche, Sanofi: Consultancy, Honoraria. Mateos:Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Salamanca University: Current Employment; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Heidelberg Pharma: Research Funding; Novartis: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Molecular Partners: Research Funding; MorphoSys AG: Research Funding; Pfizer: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; GlycoMimetics Inc.: Research Funding; Karyopharm: Research Funding; Hoffmann-La Roche: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product; Bristol Myers Squibb/Celgene: Other: Grants and/or provision of Investigational Medicinal Product; Merck Sharp and Dohme (MSD): Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Takeda: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; GlaxoSmithKline (GSK): Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Incyte Corporation: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Dietmar Hopp Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Array Biopharma/Pfizer: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma GmbH: Other: Grants and/or provision of Investigational Medicinal Product. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Sha:Janssen: Current Employment, Current holder of stock options in a privately-held company. Rousseau:Janssen: Current Employment, Current holder of stock options in a privately-held company. Li:Janssen: Current Employment, Current holder of stock options in a privately-held company. Dennis:Janssen: Current Employment, Current holder of stock options in a privately-held company. Carson:Janssen: Current Employment, Current holder of stock options in a privately-held company.

Off Label Disclosure:

Daratumumab, a human IgGk monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action, is approved as monotherapy for relapsed/refractory multiple myeloma and in combination with standard-of-care regimens for relapsed/refractory and newly diagnosed multiple myeloma

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2024
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