Abstract: Background: Treatment regimens including a proteasome inhibitor, immunomodulating agent and a monoclonal antibody (moAb) play an emerging role in the treatment of newly-diagnosed multiple myeloma (NDMM). This multicenter phase III trial of the German-speaking Myeloma Multicenter Group (GMMG HD6) investigated the addition of the anti-SLAMF7 moAb elotuzumab to lenalidomide / bortezomib / dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible NDMM. Patients and Methods: Patients were equally randomized into four treatment arms, stratified by International Staging System (ISS). Treatment consisted of four 21-day cycles of RVd (arms A1/A2) or elotuzumab-RVd (arms B1/B2) induction therapy, respectively. High-dose melphalan (HDM) and autologous blood stem cell transplantation (ASCT) were followed by two 21-day cycles of RVd or elotuzumab-RVd consolidation and lenalidomide or elotuzumab-lenalidomide maintenance for two years (arms A1/B1 vs. A2/B2). Primary objective of the trial was determination of the best of four treatment strategies regarding progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), response rates and safety. Results: Between 06/2015 and 09/2017, 564 patients were included in the trial. The evaluable intention-to-treat (ITT) and safety population comprised 559 and 555 patients (A1: n=139/137; A2: n=141/138; B1: n=137/138; B2: n=142/142). Median age at randomization was 59 (range 27-70) years. Baseline characteristics were well balanced between the four treatment arms. Four cycles of induction therapy were completed by 517 patients (92.5% of ITT). At least one HDM/ASCT was applied in 495 (88.6%), of which 116 patients (20.8%) received tandem HDM/ASCT. Consolidation and maintenance therapy were initiated in 469 (83.9%) and 454 (81.2%) patients, respectively. Rates of very good partial response or better (≥VGPR) prior to start of consolidation therapy were 78.9%, 78.2%, 81.5% and 80.7% in arms A1, A2, B1 and B2, respectively (p=0.95). With a median follow-up time of 49.8 months, PFS was not significantly different between the four treatment arms (adjusted log-rank p value stratified by ISS, p=0.86; primary endpoint). OS was similar in all treatment arms (stratified log-rank p=0.43). 3-year PFS/OS rates are 68.8%/89.4%, 68.5%/89.1%, 66.2%/92.5% and 67.2%/89.7% in arm A1, A2, B1 and B2, respectively. Multivariate analyses including age, sex, ISS stage, performance status, serum lactate dehydrogenase level, renal impairment at diagnosis, adverse cytogenetics (del17p, t[4;14] and t[14;16] ) and treatment arms identified ISS stages II and III (hazard ratio [HR]=1.42/2.04, 95% confidence interval [95% CI] = 1.00-2.02/1.36-3.07, p=0.048/ & lt;0.001) and adverse cytogenetics (HR=1.63, 95% CI: 1.19-2.25, p=0.003) as significant predictors for shortened PFS. On induction, consolidation and maintenance treatment, at least one (serious) adverse event (grade ≥3 for all AE or ≥2 for infections and infestations, neuropathy, cardiac disorders and thromboembolic events, and any grade for serious AE) occurred in 95.6%, 91.3%, 92.8% and 89.4% of patients in arm A1, A2, B1 and B2, respectively (p=0.25). Most common system organ classes (SOCs) were "infections and infestations", "neurological disorders", "blood and lymphatic system disorders", and "investigations" with no significant differences between the four treatment arms (p=0.39/0.64/0.13/0.42). Overall AE/SAE during lenalidomide vs. elotuzumab-lenalidomide maintenance were comparable (A1/B1: 65.5% vs. A2/B2: 66.4%,p=0.86), though SOC "infections and infestations" was increased in the elotuzumab-lenalidomide arms (A1/B1: 42.9% vs. A2/B2: 51.4%, p=0.05). Conclusions: This is the first phase III trial evaluating elotuzumab in patients with transplant-eligible NDMM. The addition of elotuzumab to RVd induction/consolidation therapy and lenalidomide maintenance did not result in improved PFS or OS. This is in line with previous reports from the ELOQUENT-1 and SWOG-1211 trials, investigating elotuzumab in non-transplant-eligible and high-risk NDMM, while elotuzumab-based combination therapies are effective in relapsed MM (ELOQUENT-2/-3 trials). Further analyses to identify potential subgroups that benefit from elotuzumab-based treatment in our trial are ongoing. Disclosures Goldschmidt: Incyte: Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Mai: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Besemer: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fenk: Janssen: Honoraria; Amgen: Honoraria; GSK: Honoraria; Takeda: Honoraria; BMS/Celgene: Honoraria. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. Dürig: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hose: LamKap Bio: Consultancy, Current Employment; BMS: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Amgen: 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, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Metzler: GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy. Schieferdecker: Sebia: Consultancy. Mahlberg: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; GSK: Honoraria. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Astra Zeneca: Honoraria; MSD: Consultancy; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Fujifilm: Honoraria; Roche: Research Funding; Gilead: Research Funding; Ipsen Bioscience: Research Funding; MacroGenics: Research Funding. Martens: Celgene: Consultancy; Sanofi-Aventis: Consultancy. Weisel: Adaptive Biotechnologies: 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, Research Funding; Amgen: 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; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raab: Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salwender: Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. OffLabel Disclosure: Lenalidomide and ELotuzumab in first line therapy prior to autologous stem cell transplantation, Elotuzumab in maintenance after autologous transplantation.

Abstract: Introduction: Elotuzumab, a monoclonal antibody targeting SLAM family member 7 protein (SLAMF7) on multiple myeloma (MM) cells, has shown promise in relapsed/refractory MM when combined with immunomodulatory agents. However, its effectiveness in newly diagnosed patients did not show improved progression-free survival (PFS) nor overall survival. In a previous study we demonstrated that elotuzumab specifically depleted high SLAMF7 expressing regulatory CD8 + T cells by macrophage induced antibody dependent phagocytosis. This study aimed to identify immunological predictive factors for elotuzumab efficacy, enabling improved risk stratification and personalized treatment decisions based on the detection and quantification of SLAMF7-positive T cell subsets. Patients and Methods: This pre-planned accompanying immunological research analyzed samples from the German-Speaking Myeloma Multicenter Group (GMMG) HD6 clinical trial (NCT02495922). The trial investigated elotuzumab in combination with lenalidomide/bortezomib/dexamethasone induction and consolidation, followed by lenalidomide maintenance in transplant-eligible newly diagnosed MM patients and found no progression-free or overall survival advantage with the addition of elotuzumab in any treatment sequence. Peripheral blood samples were collected at three time points: trial inclusion (T1), after induction therapy (T2), and during consolidation or maintenance therapy (T3). Flow cytometry was used to assess T cell subpopulations. Results: Elotuzumab during induction therapy significantly reduced the percentage of regulatory SLAMF7 high expressing CD8 + CD28 - ( p & lt; 0.001) and effector CD8 + T cells ( p & lt; 0.001) in MM patients after induction therapy and during maintenance therapy. A T2 landmark multivariate analysis (after induction therapy) revealed that a higher percentage of effector CD8 + T cells at T1 showed a borderline advantageous effect on the progression-free survival (PFS) ( HR = 0.98 [CI 95% 0.97; 1.00], p = 0.010) regardless of the study arm. Further, in a multivariate analysis a high regulatory CD8 + T cell level at T2 was associated with an adverse PFS in patients receiving elotuzumab in addition to lenalidomide during consolidation and maintenance (PFS from T2 for high vs. low regulatory CD8 + T cell levels at T2, HR = 3.64 [CI 95% 1.58; 8.36] , p = 0.002 for patients that received elotuzumab during consolidation and maintenance only; regulatory CD8 + T cells at T2 [high versus low] HR = 5.93 [CI 95% 2.30; 15.26], p & lt; 0.001 for patients that received elotuzumab during induction, consolidation and maintenance). Conclusion: The efficacy of elotuzumab in MM patients may be influenced by the frequency of regulatory CD8 + T cells after induction therapy. As high levels of regulatory CD8 + T cells showed adverse progression-free survival in MM patients, the assessment of the level of regulatory CD8 + SLAMF7 + T cells could be a prerequisite for MM patients' response to elotuzumab. This study highlights the importance of T cell level-driven immunological treatment approaches when utilizing elotuzumab.

Abstract: Introduction: The German-Speaking Myeloma Multicenter Group (GMMG) has initiated a randomized multicenter phase III trial on the effect of elotuzumab in VRD (bortezomib, lenalidomide, dexamethasone) induction/consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD6 trial, NCT02495922). The study compares four cycles induction therapy with VRD vs. VRD + elotuzumab, followed by standard intensification (i.e. mobilization and stem cell transplantation), two cycles consolidation with VRD/VRD + elotuzumab and lenalidomide maintenance +/- elotuzumab. The primary endpoint is determination of the best of four treatment strategies regarding progression-free survival. Here we present a first analysis of stem cell mobilization within this study. Patients and Methods: We performed a retrospective analysis of collection data on all patients who underwent peripheral blood stem cell (PBSC) collection between trial initiation in June 2015 and June 2016. Only patients with completely available datasets in respect of mobilization were considered (n=111). The vast majority of 99 patients (89%) received chemomobilization with CAD (cyclophosphamide, adriamycin, dexamethasone) followed by 5-10 µg G-CSF /kg body weight (bw) /d (starting day +9 until completion of PBSC collection), while in one case (1%) dexamethasone was omitted and in 10 cases (9%) cyclophosphamide mono was administered. One patient underwent steady-state mobilization with G-CSF only (10µg /kg bw /d). 55/111 patients received VRD (50%), whereas the remaining patients received VRD + elotuzumab. According to the recommendations of the study group, PBSCs for three stem cell transplants were to be collected. One transplant ideally consisted of ≥2.5 x10^6 CD34+ cells /kg bw, but in the event of poor mobilization as low as ≥2.0 x10^6 CD34+ cells /kg bw would be considered acceptable. Results: The median number of collected CD34+ cells was 10.4 x10^6 /kg bw (range 2.88 to 23.01 x10^6 /kg bw). Overall, 92 patients (83%) collected ≥7.5 x10^6 CD34+ cells /kg bw and another 12 patients (11%) collected between 6.0 and 7.5 x10^6 CD34+ cells /kg bw, resulting in three transplants, respectively. Only 7 patients (6%) collected below 6.0 x10^6 CD34+ cells /kg bw; 5 of them had been treated in the VRD-arm without elotuzumab. Due to insufficient PBSC mobilization after conventional treatment, 14 patients (13%) received a rescue mobilization with plerixafor, from which 12 patients collected ≥6.0 x10^6 CD34+ cells /kg bw. Overall, 7 serious adverse events (SAEs) occurred during mobilization phase, 4 of them in the study arm with elotuzumab. Conclusions: Cyclophosphamide-based chemomobilization after induction therapy with VRD is feasible. Efficient PBSC collection of ≥6.0 x10^6 CD34+ cells /kg bw could be performed in 104 of 111 patients (94%), with a low incidence of SAEs. The need for rescue mobilization was not higher than that of comparable previous GMMG treatment protocols. The addition of elotuzumab during induction phase did not impede PBSC collection. Disclosures Wuchter: Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Munder:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Fenk:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Medac: Other: Travel, accomodations or expenses; Baxalta: Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel, accomodations or expenses; Janssen: Consultancy, Honoraria; Celgene: Other: Travel, accomodations or expenses; BMS: Consultancy, Honoraria. Weisel:Onyx: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.