Abstract: Background: In patients with newly diagnosed multiple myeloma (ndMM) who are ineligible for autologous stem cell transplantation (ASCT), bortezomib, melphalan, and prednisone regimen (VMP) is standard of care as a first-line treatment in most regions of the world. Daratumumab is a new monoclonal antibody aimed to improve outcomes in ndMM. The ongoing ALCYONE study demonstrated significant improvement in progression-free survival (PFS) and overall response rate (ORR) for the combination of daratumumab plus VMP (D-VMP) compared to VMP in transplant-ineligible ndMM patients (Mateos, 2018). While direct head-to-head randomized controlled trials (RCTs) are lacking, it is important to assess how D-VMP compares with other treatment regimens used in clinical practice for ndMM patients who are ineligible for ASCT. Aims: The aim of this study is to investigate the comparative effectiveness (PFS, ORR) of D-VMP with other relevant treatment regimens used in patients with ndMM who are ineligible for ASCT. Methods: We conducted a Bayesian network meta-analysis (NMA) based on RCTs identified through a systematic literature review (SLR). Both fixed effects and random effects models were tested. The results are depicted in a network of evidence, forest plots, ranking histograms and probabilities of D-VMP being better than the comparator treatment regimens. Results: The SLR revealed 25 RCTs conducted in patients with ndMM who are ineligible for ASCT. For PFS, the NMA included 20 RCTs covering 20 treatments and for ORR, the NMA included 20 RCTs covering 21 treatments. Random-effects model is preferred for PFS as well as for ORR as this model showed lower deviance information criterion (DIC), and as the homogeneity assumption was violated for PFS. The results for both PFS and ORR are summarized in Table 1. For PFS and ORR, D-VMP ranked first in the evidence of network. For PFS, D-VMP was statistically significantly more effective compared to 10 out of the 19 treatment regimens. For ORR, D-VMP was significantly more effective as compared to 12 out of the 20 treatment regimens. Conclusion: In the absence of head-to-head RCTs, NMAs allow delineation of the comparative effectiveness of different treatments. This NMA suggests that D-VMP has a higher potential of being effective in improving ORR and PFS in patients with ndMM who are ineligible for transplant compared to other available treatment options. Updated results based on a 1-year update of ALCYONE will be presented at the meeting. References: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528 Disclosures San-Miguel: Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria. Facon:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen: 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; Takeda: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: 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; Adaptive Biotechnologies: 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; AbbVie: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. van Beekhuizen:Ingress Health: Consultancy. Pisini:Janssen Research & Development, LLC: Employment. Nair:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment.

Abstract: Introduction: Daratumumab-bortezomib-melphalan-prednisone (D-VMP) is a novel treatment regimen for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplantation (ASCT). D-VMP is currently being investigated and compared to bortezomib-melphalan-prednisone (VMP) in the ALCYONE trial, and demonstrated a significant benefit for D-VMP over VMP in terms of progression-free survival (PFS) [1] . Recently, a systematic literature review and a network meta-analysis (NMA) were conducted to compare D-VMP against all other available treatments in that indication. However, the reliability of an NMA on overall survival (OS) may be limited due to several factors. First, OS data from the ALCYONE trial is still immature. Second, within the OS network of evidence, four MP trials showed similar PFS, yet large differences were observed in OS for MP. This is an indication of effect modification due to subsequent therapies and thus violation of the similarity assumption. The four MP trials are a bridge to key approved comparators lenalidomide-dexamethasone (Rd) and melphalan-prednisone-thalidomide (MPT), which have been investigated in the FIRST trial. To overcome these challenges faced in the OS NMA, an unanchored matching-adjusted treatment comparison (MAIC) was conducted to assess the relative OS between D-VMP and Rd continuous, Rd 18, and MPT. In addition, the analysis was extended to also include PFS. Methods: Individual patient data from the ALCYONE trial were adjusted to match the aggregated baseline characteristics of the FIRST trial. Patient level OS and PFS data of FIRST trial were generated based on the Guyot algorithm. The considered baseline characteristics were median age, male (%), ECOG status (%), ISS state (%), IgG serum (%), creatinine clearance (%), and high-risk cytogenetic profile. After matching patients, a Cox proportional hazard model was fitted. In both analyses, the null hypothesis of no difference in relative treatment effect in OS and PFS between D-VMP and each of the three treatment arms of the FIRST trial was tested using the log-rank test. To assess the impact of matching patients, a naïve unanchored comparison between D-VMP and FIRST treatments arms was conducted in addition to the MAIC. Results: The results of the MAIC are summarized in Table 1. Significant results are denoted with an asterisk. OS for D-VMP is significantly longer than for both MPT and Rd 18. When comparing OS for D-VMP with Rd continuous, there is a trend in favour of D-VMP. D-VMP performs significantly better than the three comparator treatments in terms of PFS. In all analyses, the HR point estimates are in favour of D-VMP. Conclusion: This MAIC showed a significant OS benefit for D-VMP compared to Rd 18 and MPT, and a trend favouring D-VMP vs Rd continuous in newly diagnosed multiple myeloma patients who are ineligible for ASCT. Additionally, this analysis supports a previously conducted NMA on PFS and suggests that D-VMP provides a consistent and statistically significant PFS benefit relative to Rd continuous, Rd 18, and MPT. Since ALCYONE is a more recent trial than FIRST, a potential limitation is that the OS results might be biased by better subsequent therapies being available in ALCYONE. However, the impact of this is expected to be limited due to the immaturity of survival data and the large proportion of patients in the D-VMP arm of ALCYONE who had not yet progressed at the time of the datacut. This MAIC, which provides a more robust method to compare OS outcomes than an NMA, shows OS benefits and confirms PFS benefits for D-VMP compared to Rd continuous, Rd 18 and MPT. [1] Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Disclosures Dimopoulos: Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: 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, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. van Beekhuizen:Ingress Health: Consultancy. Nair:Janssen Research & Development, LLC: Employment. Pisini:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment.

Abstract: Introduction : Daratumumab (DARA) is a human CD38 antibody approved in combination with standard-of-care (SoC) regimens in pts with NDMM who are TIE. DARA-based treatments showed significantly improved progression-free survival (PFS) in pts with TIE NDMM in ongoing phase 3 studies ALCYONE (DARA + bortezomib/melphalan/prednisone [D-VMP] vs VMP) and MAIA (DARA + lenalidomide/dexamethasone [D-Rd] vs Rd continuous). An NMA allows estimation of the relative efficacy of regimens not compared in head-to-head trials. A previous NMA examined D-VMP and D-Rd vs comparators (Facon T et al., EHA 2019), excluding the SWOG S0777 study (bortezomib/lenalidomide/dexamethasone [VRd]; Durie BG, et al. Lancet 2017) as it enrolled both transplant-eligible (TE) and TIE pts, and data for pts who are TIE only (~50% [aged ≥65 y and frail] ) were unavailable. In this NMA, D-Rd and D-VMP had the highest probabilities of being more effective than reference treatment Rd continuous in terms of PFS. Recently, VRd received EMA approval for treatment of TIE NDMM based on SWOG S0777, but results specific to TIE pts are still unavailable. Recent NMAs of TIE pts (Blommestein HM et al., Haematologica, 2019; Weisel et al., EHA 2019; Cao Y et al., Clin Lymphoma Myeloma Leuk, 2019) have included data from the the intent-to-treat (ITT) population of SWOG S0777, though its inclusion violates the similarity assumption. Here, we present a sensitivity analysis of the previously-conducted NMA including all pts who received VRd in SWOG S0777 for a comprehensive view of the comparative effectiveness of DARA-based treatments in TIE NDMM. Methods: VRd was included as part of a sensitivity analysis of the previous NMA based on the ITT population, reporting PFS and overall survival (OS). The Guyot method was used to estimate OS hazard ratios (HRs) for pts aged ≥65 y (proxy for TIE) from SWOG S0777 (Durie BG et al., ASH 2018). Median follow-up in ALCYONE and MAIA was 27.8 months and 28.0 months, respectively. Based on a systematic literature review conducted through January 2019, both PFS and OS were extracted and synthesized in Bayesian NMAs. Choice of fixed- or random-effects (FE or RE) model was based on lowest deviance information criterion (DIC) and/or presence of heterogeneity in the network. Rd continuous was selected as reference, as it was commonly included in guidelines across regions. For PFS and OS, HR 〈 1 indicates the comparison is not in favor of Rd continuous. In addition to the previous NMA, we also report an NMA sensitivity analysis including only comparators approved by the EMA that are relevant for the European, Middle East and/or Africa (EMEA) region (EMEA NMA). Results: Global NMA: RE model was used for both PFS and OS. Compared with Rd continuous, the PFS HR for VRd in the sensitivity analysis was 0.74 (95% credible interval [CrI], 0.42-1.30), which was similar to SWOG S0777 (0.71; [96% Wald confidence interval [CI] , 0.56-0.91]) and higher than HRs for D-Rd (0.55; 95% CrI, 0.31-0.97) and D-VMP (0.58; 95% CrI, 0.20-1.62; Table). For OS, the SWOG S0777 HR estimated by Guyot algorithm for pts aged ≥65 y was 0.80 (95% CI, 0.56-1.16). Compared with Rd continuous, the OS HR for VRd in the sensitivity analysis was 0.80 (95% CrI, 0.51-1.26), which was similar to SWOG S0777 and higher than D-Rd (0.78; 95% CrI, 0.51-1.18). EMEA NMA: FE model was used for both PFS and OS. Compared with Rd continuous, the PFS HR for VRd in the sensitivity analysis was 0.74 (95% CrI, 0.60-0.92), which was higher than HRs of D-Rd (0.55; 95% CrI, 0.43-0.71) and D-VMP (0.64; 95% CrI, 0.41-1.02). Compared with Rd continuous, the OS HR for VRd in the sensitivity analysis was 0.80 (95% CrI, 0.55-1.17), which was higher than for D-Rd (0.78; 95% CrI, 0.56-1.09). These results are consistent with the Global NMA, but differ slightly as the EMEA NMA has fewer evidence-loops (only EMEA SoC regimens were included). Conclusions: This study demonstrated favorable efficacy outcomes for DARA-based regimens vs other relevant frontline options, such as VRd, for pts with NDMM who are TIE. Limitations of the sensitivity analysis include lack of comparative trial data and demographic differences between pts from SWOG S0777 and trials of frontline MM treatments for pts who are TIE included in our network. The majority of SWOG S0777 pts are TE ( 〈 65 y), who often have better prognoses than TIE pts (≥65 y), and thus violates the similarity assumption of NMAs. However, DARA-based regimens still showed a comparative clinical advantage. Disclosures Facon: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau. Dimopoulos:Sanofi Oncology: Research Funding. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Mateos:Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Heeg:Ingress-Health: Employment. Van Beekhuizen:Ingress-health: Consultancy. Pisini:Janssen: Employment, Equity Ownership. Nair:Janssen: Employment, Equity Ownership. Lam:Janssen: Employment, Equity Ownership. Slavcev:Janssen: Employment, Equity Ownership. He:Janssen: Employment, Equity Ownership.