Abstract: Introduction: SMM is a precursor disorder to multiple myeloma (MM) (Rajkumar SV, et al. Blood. 2015;125[20]:3069-3075). Current guidelines for SMM recommend active monitoring, with treatment initiation only upon progression to MM. However, therapeutic intervention at the SMM stage may help delay the progression to MM (Lonial S, et al. J Clin Oncol. 2020;38[11] :1126-1137; Mateos MV, et al. ASH 2022. Abstract 118). DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Given the deep and durable responses and favorable safety profile of DARA monotherapy in patients (pts) with relapsed/refractory MM (Usmani SZ, et al. Blood. 2016;128[1]:37-44), we hypothesized that DARA could delay the progression of SMM to MM. In the primary analysis of the phase 2 CENTAURUS study (NCT02316106), after a 15.8-month median follow-up, DARA monotherapy showed activity and was well tolerated in pts with intermediate- or high-risk SMM (Landgren CO, et al. Leukemia. 2020;34[7] :1840-1852). Activity and tolerability of DARA monotherapy were also observed in CENTAURUS after an additional 10 months of median follow-up (Landgren CO, et al. ASH 2018. Abstract 1994). Here, we present the final analysis of the CENTAURUS study, with a median follow-up of 85.2 months (~7 years). Methods: Eligible pts had a diagnosis of intermediate-risk or high-risk SMM for & lt;5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously (IV) on 1 of 3 dosing schedules. In the Intense dosing arm, pts received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). In the Intermediate dosing arm, pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). In the Short dosing arm, pts received 1 cycle of DARA QW. For pts in the Intense and Intermediate arms, there was an option to extend treatment (Extension phase) with DARA IV or with subcutaneous DARA (DARA SC; DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [2,000 U/mL; Halozyme, Inc.]) Q8W after the end of Cycle 20 per investigator discretion if there was a positive benefit/risk ratio, no grade ≥3 treatment-related toxicity, and at least stable disease had been achieved. Rate of complete response or better (≥CR) was a primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Results: A total of 123 pts (41 pts per arm) were randomized. Median (range) age was 61 (31-81) years. Median duration of study treatment overall during the study was 44.0 months in the Intense arm, 35.2 months in the Intermediate arm, and 1.6 months in the Short arm. A total of 36 pts (21 pts in the Intense arm and 15 pts in the Intermediate arm) continued to receive DARA Q8W in the Extension phase (Cycles 21+). During the Extension phase, median duration of study treatment was 45.2 months in the Intense arm and 46.1 months in the Intermediate arm ( Table 1). 16 pts in the Intense arm and 10 pts in the Intermediate arm switched from DARA IV to DARA SC during the Extension phase. Efficacy results are summarized in Table 2. At a median (range) follow-up of 85.2 (0-94.3) months, ORR and ≥CR rate were higher in the Intense and Intermediate arms than in the Short arm. In the Intense and Intermediate arms combined, the ≥CR rate was 8.5%. Median OS was not reached in any dosing arm; the 84-month OS rate was 81.3%, 89.5%, and 88.1% in the Intense, Intermediate, and Short arms, respectively. Safety results are summarized in Table 1. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 65.9%, 41.5%, and 15.0% of pts in the Intense, Intermediate, and Short arms, respectively; grade 3/4 TEAEs were reasonably related to DARA in 12.2%, 2.4%, and 5.0% of pts, respectively. TEAEs that led to discontinuation of DARA occurred in 7.3%, 2.4%, and 5.0% of pts in the Intense, Intermediate, and Short arms, respectively. Conclusions: Findings from this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in pts with intermediate- or high-risk SMM after a median follow-up of ~7 years. A high proportion (44%) of pts in the Intense and Intermediate arms completed 20 cycles and remained on DARA monotherapy per investigator discretion, with a median duration of additional treatment of 46.0 months (~4 years) in the Extension phase. No new safety concerns were observed with extended follow-up.

Abstract: Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1] :37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up. Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for 〈 5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously on 1 of 3 treatment schedules. Pts on the Long dosing schedule received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). On the Intermediate dosing schedule (Int), pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). Pts on the Short dosing schedule received 1 cycle of DARA QW. Rate of complete response (CR) or better and progressive disease (PD)/death rate (defined as the ratio of pts with an event [PD or death] to the total follow-up for all pts) were co-primary endpoints. CR and PD were defined per 2014 International Myeloma Working Group criteria (Rajkumar et al. Lancet Oncol 2014;15[12] :e538-e548). Biochemical progression and biochemical/diagnostic (BOD) progression were defined as previously reported (Hofmeister CC, et al. ASH 2017. Abstract 510). Results: A total of 123 pts were randomized (41 pts per arm). The median (range) age was 61.0 (31-81) years, and the median (range) time from initial SMM diagnosis to randomization was 6.83 (0.40-56.0) months. In total, 73% of pts were of IgG subtype. Median treatment duration was 25.8 months in both the Long and Int arms and 1.6 months in the Short arm (Table 1). In the Long, Int, and Short arms, 17%, 22%, and 5% of pts, respectively, discontinued treatment; reasons included PD (7%, 10%, and 0%, respectively), adverse events (AEs; 7%, 2%, and 5%, respectively), refusal of further treatment (5% in Int), withdrawal of consent (2% each in Long and Int), and death (2% in Int). At a median (range) follow-up of 25.9 (0-33.2) months, overall response and ≥CR rates were higher in the Long and Int arms than in the Short arm (Table 2); in the combined Long and Int arms, the ≥CR rate was 7%. Median PFS based on SLiM-CRAB criteria was not reached in any arm; 24-month PFS rates were 90% (Long), 82% (Int), and 75% (Short; Figure 1A). PD/death rates indicate a median PFS of ≥24 months in all arms (Table 2). Median PFS based on BOD criteria was reached in the short arm only (14.8 months); 24-month PFS rates were 78% (Long), 70% (Int), and 27% (Short; Figure 1B). Safety results are summarized in Table 1. In all arms, no hematologic treatment-emergent AE was observed in ≥10% of pts, and the rates of grade 3/4 infections were ≤5%. Deaths occurred in 1 pt (2%) in the Int arm (due to heart failure not related to DARA) and 1 pt (2%) in the Short arm (due to PD); no deaths were observed in the Long arm. No deaths occurred within 30 days of the last DARA dose. Conclusions: After median follow-up of 25.9 months, a more pronounced BOD PFS benefit was observed in the Long and Int arms compared with the Short arm. The safety profile of DARA monotherapy in SMM remains consistent with other single-agent DARA studies, and no new safety signals were observed with longer follow-up. Because dose intensity was associated with efficacy in SMM pts, an extended, dose-intensive schedule was selected for an ongoing phase 3 study of DARA monotherapy versus active monitoring in SMM (AQUILA). Disclosures Landgren: Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding. Cavo:AbbVie: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; The Binding Site: Consultancy. Cohen:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Voorhees:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Bioverativ: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Jenner:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Takeda: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Beksac:Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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: 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. Kuppens:Janssen Research & Development: Employment. Bandekar:Janssen Research & Development: Employment. Neff:Janssen Research & Development: Employment. Cortoos:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Qi:Janssen: Employment. Adams:Janssen Pharmaceutical R & D: Employment. Hofmeister:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background The role of upfront autologous stem cell transplantation (ASCT) for younger patients with newly diagnosed (ND) multiple myeloma (MM) has been questioned in the novel agent era. Methods A prospective, multicenter, phase III study was designed to compare (first randomization, R1) (1:1 ratio; stratification according to ISS stage) four 42-day cycles of bortezomib-melphalan-prednisone (VMP) given at the same dosing schedule reported in the VISTA study (NEJM 2008; 359:906-17) vs either a single course or two sequential courses of melphalan at 200 mg/m2 (HDM) followed by single or double ASCT, respectively, as intensification therapy after three to four 21-day cycles of induction therapy with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells. A second randomization (R2) to consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was performed after intensification, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study end point was progression-free survival (PFS) from R1. Results From February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic NDMM were registered. Of these, 1192 were eligible for R1 and were randomly assigned to receive either VMP (n=497 patients) or HDM (1±2 courses) (n=695 patients). Median age was 58 years in both groups, ISS stage III was 21% in VMP and 20% in HDM, while revised ISS stage III was 9% in both groups. Data on cytogenetic abnormalities, as detected by FISH analysis of CD138+ plasma cells, were available in 71% of patients (n=354) randomized to VMP and in 76% of those (n=529) assigned to HDM. The frequency of conventionally defined high-risk cytogenetic changes, including t(4;14) and/or del(17p) and/or t(14;16), was 25% in both arms. Median follow-up from R1 was 26 (IQR: 19-37) months. On an intention-to-treat basis, median PFS was 44 months in the VMP arm and was not yet reached in the HDM arm; 3-year estimates of PFS were 57.5% and 66%, respectively (HR=0.73; 95% CI=0.59-0.90; P=0.003). PFS benefit with HDM was retained across predefined subgroups, including patients with ISS stage I (HR=0.69; CI=0.48-0.98; P=0.037), revised ISS stage II (HR=0.70; CI=0.54-0.91; P=0.008), revised ISS stage III (HR=0.54; CI=0.30-0.97; P=0.040), standard-risk cytogenetics (HR=0.75, CI=0.56-1.01; P=0.055) and a high-risk cytogenetic profile (HR=0.54; CI=0.37-0.80; P=0.002). The probability of achieving a very good partial response or higher quality response was 85.5% in the HDM group vs 74% in the VMP group (odds ratio=1.90; CI=1.42-2.54; P 〈 0.001). In a multivariate Cox regression analysis stratified by ISS, randomization to HDM (HR=0.67; CI=0.53-0.85; P=0.001) and absence of high-risk cytogenetic abnormalities (0.71; CI=0.53-0.95; P=0.021) were the leading independent predictors of prolonged PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident. Detection of minimal residual disease (MRD) after intensification therapy was performed by multiparameter flow cytometry and PET/CT in a subgroup of patients, and details are provided in a separate abstract (E. Zamagni et al). Overall, MRD negativity favorably affected PFS and OS. Conclusions In comparison with VMP as standard-dose intensification therapy, upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses. An updated analysis with a longer follow-up will be reported at the meeting. Results of this phase III study, the largest so far reported, support the conclusion that upfront ASCT still continues to be the reference treatment for fit patients with NDMM, even in the novel agent era. Disclosures Cavo: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Beksac:Celgene, Janssen Cilag Amgen, Novartis, Takeda: Honoraria, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Janssen-Cilag: Other: Advisory Board; Mundipharma: Other: Advisory Board. Hájek:Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; BMS: Honoraria; Celgene: Consultancy, Research Funding. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Galli:Celgene: Honoraria; Janssen: Honoraria; Sigma-tau: Honoraria. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.