ALBERT

Description: Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of 〈 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos: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; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Description: Although survival in AL patients is related in part to the number of marrow clonal plasma cells (PC) (1, 2), staging for AL patients is based on end-organ damage without a clear role for cytogenetic aberrations in clonal PC. Recently several groups have described potential roles for gain 1q and t(11;14) as prognostic markers in AL, and possibly as predictive of response to therapy (3-5). In multiple myeloma, del 17p is a cytogenetic aberration present in about 10% at diagnosis and its prognostic impact depends on the percentage of clonal PC with del 17p (6). The relevance of del 17p in AL is undefined. We report our initial analysis of the outcomes and survival of the first multinational retrospective study of AL patients with del 17p as a feature of their clonal plasma cell disease and include preliminary findings from an age-based case-control analysis. AL patients with del 17p were identified and their clinical characteristics and outcomes summarized. Methods for determining the presence of del 17p were reviewed. We compared the overall survival (OS) of patients in whom del 17p was identified in 〈 or ≥ 50% of clonal cells, and evaluated the impact of bortezomib-based therapy and cardiac stage on OS in newly diagnosed and relapsed patients. These cases were then matched for age (± 5 years) with a control cohort from the Amyloidosis Treatment and Research Center in Pavia, IT, representing a subset of patients reported previously (7). Differences between cases and controls for OS were evaluated by Kaplan-Meier with statistical significance by the log-rank test. P 〈 0.05 was the threshold for significance. Thirty-four AL patients with del 17p in clonal cells were identified, 30 at diagnosis and 4 at relapse. Thirty-one cases had del 17p assessed on CD138-selected marrow cells and 3 on marrow mononuclear cells; for the latter, the percentage of marrow PC was used to estimate the del 17p fraction. Commercially available methods were used at all centers. Median age was 66 years and males constituted 53% of cases. Cardiac involvement was present in 72% of cases, 41% of whom had stage III involvement. Ninety-four percent had free light-chain (FLC) clones of lambda isotype with a median difference between involved and uninvolved FLC (dFLC) of 249mg/L and a median percentage of marrow PC of 18%. In all 34 cases the median percentage of clonal PC with del 17p by FISH was 42% (range 2-93%) while in newly diagnosed AL patients it was 37%. Eighty-three percent of cases had del 17p in combination with other cytogenetic abnormalities including t(11;14) in 36% and gain 1q in 18%. Among the newly diagnosed cases, 32% had ≥ 50% of clonal cells with del 17p and had a median OS of 23.5 months while those with 〈 50% survived a median of 33 months (P = 0.12). Seventy-three percent of patients responded to initial therapy and 32% had ≥ VGPR. Twenty-three percent had a cardiac response to initial therapy. There was no difference in OS between patients who had bortezomib-based therapy and those who did not, and no difference between the OS of cardiac stage 1/2 and stage 3 patients. One patient with 37% del 17p and a complex karyotype at baseline progressed at relapse to both advanced AL cardiac involvement and plasma cell leukemia with over 90% del 17p containing PC, suggesting that del 17p may confer risk in AL as in MM under certain circumstances. In the preliminary case-control analysis, OS was no different between cases and controls (Fig 1, P = 0.32). Recent data indicate that the more common cytogenetic abnormalities in AL, namely t(11;14) and gain 1q, are associated with differences in response to melphalan or bortezomib. In this series of AL cases with del 17p, we find suggestive evidence that high levels of clonal cells with del 17p may confer a poorer prognosis than already exists as a consequence of the tropism of AL light chains for the heart. We are seeking more cases for inclusion in this series and conducting both a multivariate analysis and a detailed case-control comparison which may shed light on this issue. References (1) Comenzo et al. Blood 2001;98(3):714-20. (2) Warsame et al. Blood Cancer Journal 2015;5, e-310, e-pub 1 May 2015 (3) Bochtler et al. Amyloid. 2014 Mar;21(1):9-17. (4) Bochtler et al. J Clin Oncol. 2015 Apr 20;33(12):1371-8. (5) Zhou et al. Clin Lymphoma Myeloma Leuk 2012;12(1):49-58. (6) An et al. Clin Cancer Res; 21(9); 2148-56. (7) Palladini et al. Blood 2015, e-pub 18 May 2015 Figure 1. Figure 1. Disclosures Hegenbart: Janssen: Honoraria. Landau:Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Avet-Loiseau:onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hansen:Celgene GmbH: Honoraria. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Comenzo:Janssen: Research Funding; Prothena: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Research Funding; Karyopharm: Research Funding.

Description: Chronic extensive, severe graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality following an allogeneic hematopoietic stem cell transplant (HSCT). Patients with progressive chronic GVHD (cGVHD) following standard treatments have limited options. Patients with extensive refractory cGVHD have a decreased performance status (PS) and an increased non-relapsed mortality. Extensive sclerodermatous cGVHD responds poorly to standard treatments. Colchicine is a well-known anti-inflammatory drug that has been used in the treatment of many inflammatory disorders (1). We report a series of 8 patients with extensive cGVHD who were refractory to multiple lines of therapy and then were treated with colchicine. All patients had improvements in ECOG PS, skin GVHD and/or oral GVHD after starting colchicine. All patients were able to decrease their immunosuppressive therapies (IST) after starting colchicine. We retrospectively examined 8 patients with refractory extensive cGVHD, treated with colchicine (0.6 mg QD or BID). IST for cGVHD was defined by the following: steroids, extracorporeal photopheresis (ECP), imatinib, mycophenolate mofetil (MMF), tacrolimus, bortezomib, montelukast, cyclophosphamide (Cy), pentostatin, and rituximab. National Institutes of Health 2014 cGVHD consensus criteria (2) were used to grade the cGVHD prior to colchicine and at the time of best response after colchicine was started. Baseline patient characteristics are listed in Table 1. Conditioning regimen for allogeneic HSCT consisted of PPT (ECP, pentostatin, TBI) (4/8), busulfan/Cy (2/8), Cy-TLI (1/8), or Cy/TBI (1/8). GVHD prophylaxis involved CSA/MTX (7/8), tacrolimus/MTX (1/8) and ATG in addition to CSA/MTX (1/8). Median number of organs involved in cGVHD was 4.5 (range 2-5). All patients had extensive cGVHD with skin (8/8), oral (8/8), eye (8/8), GI (7/8), lung (6/8), liver (2/8), and/or genital (2/8) involvement. Median number of failed IST was 3.5 (range 1-6). Patients failed steroids (7/8), ECP (6/8), MMF (5/8), imatinib (3/8), cyclophosphamide (2/8) and bortezomib (1/8). Median number of IST immediately before colchicine was 2.5 (range 1-6). Most patients required twice daily dosing of colchicine (5/8). Median follow-up since beginning colchicine was 11 weeks (range 3-67 weeks). At best response with colchicine, all patients had clinical improvement of chronic GVHD (Figure 1). Patients with extensive cGVHD of the skin, including all patients with extensive sclerodermatous changes, responded to the addition of colchicine, and had steroid and MMF doses lowered, and/or were stopped on IST. Median number of IST fell to 2 (range 0-5). Four patients had a reduction in the number of IST. One patient was taken off 4 IST (ECP, imatinib, Cy and MMF). Another patient was able to stop ECP. Five patients had a reduction in prednisone with median reduction of 5mg (range 5-40 mg), while 2 had reductions in the total daily dose of MMF. Adverse events were uncommon and included 2 patients with grade 1-2 diarrhea. The most severe adverse event was grade 2 diarrhea in one patient that led to eventual discontinuation of colchicine. No hematologic toxicity was observed. The rest (7/8) continued on colchicine therapy. In conclusion, patients with extensive cGVHD involving the skin and mouth, refractory to multiple lines of IST, experienced clinical improvement on colchicine. Toxicity was limited to mild GI side effects. These observations need to be validated in a prospective clinical trial. References (1) Slobodnick et al. Am J Med. 2015 May;128(5):461-70. (2) Jagasia et al. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. Epub 2014 Dec 18. Table 1. Baseline Characteristics Variable Frequency (%) Age, median (range), yr 57 (30-65) Donor/recipient gender Sex-mismatched female/male 1 (13%) Sex-matched 7 (88%) Race White/Caucasian 7 (88%) Disease category Acute myeloid leukemia 4 (50%) Myelofibrosis 2 (25%) Aplastic anemia 1 (13%) Lymphoblastic lymphoma 1 (13%) Remission status at transplantation CR 8 (100%) Graft source BM 1 (13%) PBSC 7 (88%) Donor type Matched sibling 4 (50%) Matched unrelated 3 (38%) Mismatched 1 (13%) GVHD type Progressive 3 (38%) Overlap syndrome 2 (25%) De novo 3 (38%) Figure 1. Figure 1. Disclosures Off Label Use: Colchicine will be discussed as treatment for GVHD. Comenzo:Karyopharm: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Janssen: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Roberts:Millenium: Speakers Bureau. Miller:Biogen Idec: Consultancy; AbbVie: Speakers Bureau; Millennium: Speakers Bureau; Onynx: Speakers Bureau.

Description: Introduction: Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is insufficient to induce clinical response in relapsed or refractory (R/R) multiple myeloma (MM). We postulated that combining atezolizumab (A; anti-PD-L1) with daratumumab (D; anti-CD38), which targets myeloma cells and has immunomodulatory activity, may alter the tumor microenvironment (TME) to favor cytotoxic T-cell activation and clinical activity. To assess the immunologic efficacy of this combination, we studied changes in CD8+ T cells in D-naïve and D-refractory pts from a Phase Ib study (GO29695; NCT02431208). Methods: Flow cytometry was performed using longitudinal peripheral blood (PB) and bone marrow aspirates (BMA) to characterize CD8+ cytotoxic T cells using 8 color flow panels. RNA sequencing (RNAseq) and dual-plex immunohistochemistry (IHC) (CD138/CD8, CD8/Ki-67, CD138/osteoclast) were performed using longitudinal CD138+ fraction and bone biopsies, respectively. For IHC, CD138+ cell masses of 〉5000μm2 were defined as tumor clusters. Osteoclasts were enumerated based on TRAP positivity and morphology. Table 1 shows on-treatment changes in Cohorts D1-D3. Table 2 shows baseline data in Cohorts A, B, D1-D3, and E. The median (bootstrap 95% CI) is used to describe the data. Results: 9/36 (25%) pts in cohorts D1-3 showed clinical efficacy (partial response or better); all were D-naïve. We studied CD8+ T-cell activation and proliferation (%CD8+HLA-DR+Ki-67+), the pharmacodynamic marker for A (Herbst et al. Nature 2014), in PB. All D-naive pts showed on-treatment increase in %CD8+HLA-DR+Ki-67+ cells in the periphery (C1D15-C2D1) compared to baseline, which was not observed in D-refractory pts (Table 1). In BMA, the increase in %CD8+HLA-DR+Ki-67+ (C2D15-C4D1) was observed in D-naïve pts with clinical response to A-D (sensitive), but not in non-responders (resistant) or D-refractory pts (all resistant), suggesting that sensitive pts have an immune-supportive TME. Preliminary IHC staining also showed an increase in CD8+Ki-67+ T cells in two responders after treatment. Gene enrichment analysis (RNAseq data, n=20) showed upregulation of an innate immune response signature, which appeared to be driven by a 'macrophage activation' gene signature post-treatment, in the CD138+ fraction of responders. To understand the mechanisms regulating sensitivity to treatment, we studied the spatial localization of CD8+ T cells with respect to CD138+ tumor cells by IHC. A higher density of CD8+ T cells within tumor clusters was seen at baseline in sensitive versus resistant pts, but this was not observed outside of tumor clusters (Table 1). In addition, the number of osteoclasts in the tumor region was higher in resistant pts, suggesting that these cells may contribute to the inhibition of T-cell function as reported(An et al. Blood 2016). This hypothesis was further supported by higher osteoclast numbers in D-refractory pts at baseline (Table 2), for whom an on-treatment increase in %CD8+HLA-DR+Ki-67+ cells was not observed in PB or BMA. Interestingly, higher median fluorescence intensity of PD-1 on CD8+ T-effector cells and on CD8+ T-effector memory cells was observed at baseline in D-naïve relative to D-refractory pts, while the level of PD-L1 expression on tumor cells was similar. An increase in activated proliferating T cells (%CD8+HLA-DR+Ki-67+) observed after treatment in D-naïve responders suggests that high PD-1 expression in this subset is not a marker of CD8+ T-cell exhaustion, but of functional capability. Conclusions: Clinical efficacy of A-D therapy in R/R MM pts is associated with higher CD8+ cell density in tumor clusters and lower osteoclast numbers in the tumor region at baseline, and an on-treatment increase in activated CD8+ T-cell populations in the bone marrow. The lack of a D-monotherapy arm in this study makes it difficult to assess the individual contribution of A to T-cell activation. The data presented, albeit a small number of samples from a Phase Ib study, support the hypothesis that the TME, including CD8+ T cells, tumor cells, and cells of myeloid lineage such as osteoclasts, has significant impact on the immunologic and clinical efficacy of combination therapy. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential for long-term disease control. Disclosures Raval: Roche: Employment, Equity Ownership. Cho:Agenus: Research Funding; Genentech: Honoraria, Research Funding; Takeda: Research Funding; BMS: Consultancy; The Multiple Myeloma Research Foundation: Employment; Celgene: Honoraria, Research Funding; GSK: Consultancy. Green:Genentech Inc.: Employment. Wassner Fritsch:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ma:Genentech: Employment. Chang:Roche Canada: Employment. Yan:F. Hoffmann-La Roche Ltd, Mississauga, Canada: Employment. Kockx:HistoGeneX: Equity Ownership. Shen:Genentech, Inc.: Employment. Huw:Roche/ Genentech: Employment, Equity Ownership. Balestiere:Genentech: Employment. Lipkind:Roche/Genentech: Employment. Huang:F. Hoffmann-La Roche Ltd: Employment. Byrtek:Genentech: Employment; Roche: Equity Ownership. Colburn:Genentech: Employment; Roche: Equity Ownership. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Venstrom:F. Hoffmann-La Roche Ltd: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. OffLabel Disclosure: Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDââ‚â'¬Ã'ÂL1, or are not eligible for any platinumââ‚â'¬Ã'Âcontaining chemo regardless of PDââ‚â'¬Ã'ÂL1 status, or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.

Description: Background Despite recent advances, treatment of relapsed refractory multiple myeloma (RRMM) remains a challenge. Venetoclax, a BH3 mimetic, is an oral, specific, and potent small molecule inhibitor of BCL-2 that has been approved for treatment of 17p-deleted CLL and in combination with azacitidine or decitabine in AML patients 〉/= 75 years of age.Pre-clinical and clinical studies suggest that bcl-2 inhibition can induce MM cell death and may synergize with bortezomib and dexamethasone. Based on this, several prospective clinical trials of venetoclax in RRMM have been performed. However, clinical use of this targeted therapeutic for salvage therapy in RRMM has not been well described. Methods We performed a single-center, retrospective chart review of all patients with RRMM diagnosed after January 1, 2009 who were treated with off-label use of venetoclax. The goal of this study was to describe the clinical characteristics of these patients, assess the response to salvage treatment with venetoclax as determined by the International Myeloma Working Group (IMWG) criteria, and assess the toxicities during salvage treatment with venetoclax in an academic practice setting. Results 43 patients were identified. Median number of lines of prior therapy was 7 (range 2-13). 12 patients had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), t(14;20), t(4,14), gain (1q), or nonhyperdiploidy. Of the 36 patients with cytogenetics/FISH available, 8 had t(11;14). 34 patients were refractory to bortezomib. 40 patients had progressed after carfilzomib, 36 after pomalidomide, and 41 after anti-CD38 antibody therapy. 39 patients were treated with venetoclax in combination with a proteasome inhibitor (bortezomib (n=36); carfilzomib (n=3)). 23 patients were treated with venetoclax, proteasome inhibitor, and dexamethasone. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily (11 received 〈 800mg/daily as a final dose and one received 〉800 mg/daily as final dose). Overall patients were on treatment for a median of 67 days (range 2-855). 2 patients received intermittent venetoclax therapy, defined as being off venetoclax for at least 3 months before restarting. Best response by IMWG criteria include; CR 5%( 2/43), VGPR 12% (5/43) and PR 16% (7/43) for an overall response rate of 33% (14/43). In addition, MR was seen in 5% (2/43) and stable disease in 9% (4/43). Fifty-one percent (22/43) had progressive disease (PD). Out of the 8 patients who had t(11;14), best responses were: 2 VGPR, 2 PR, 1 SD, and 3 PD for a response rate of 50% (4/8) in this subgroup. Median time to best response for all responding patients was 90 days (range 15-305) and median duration of response was 206 days (range 28-820). At time of data collection, median follow-up time from venetoclax treatment initiation was 192 days (range 8-1058). Four patients have not progressed and remain on therapy, 23 patients remain alive, and 4 patients have been lost to follow-up for over 6 months. The most common treatment related AEs were cytopenias including leukopenia in 26 /43 (60%) patients, neutropenia in 19/43 (44%) patients, and thrombocytopenia in 22/43 (51%) patients. Non-hematologic toxicities included diarrhea in 12/43 (30%) patients, nausea/vomiting in 15/43 (35%) patients, infections in 11/43 (26%) patients, and fatigue in 23/43 (53%) patients. 8/43 (19%) patients required dose reduction, 7/43 (16%) patients required temporary discontinuation of treatment, and 4/43 (9%) patients required permanent discontinuation due to treatment related AEs. 38/43 (88%) patients had any grade treatment related AEs, 27/43 (63%) patients had grade 〉/= 3 AEs and 2/43 (5%) patients had treatment related SAEs. One patient had a treatment related death from an infectious complication (CMV pneumonitis). Conclusions Venetoclax is an active and well-tolerated agent in relapsed multiple myeloma. Furthermore, it is easily administered in the outpatient setting. Additional areas of research with this therapy include understanding the importance of t(11:14) for response and selecting the best anti-MM partner for combination therapy. Disclosures Ledergor: Venetoclax: Other: off-label use; Immunai: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Shah:Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This study is looking at the safety and efficacy of venetoclax in relapsed refractory myeloma patients who are treated off-label since venetoclax is not currently approved for multiple myeloma

Description: Systemic immunoglobulin light chain (LC) amyloidosis (AL) is a potentially fatal disease caused by immunoglobulin LC produced by clonal plasma cells. These LC form both toxic oligomers and amyloid deposits disrupting vital organ function. Despite reduction of LC by chemotherapy, the restoration of organ function is highly variable and often incomplete. Organ damage remains the major source of mortality and morbidity in AL. This review focuses on the challenges posed by emerging therapies that may limit the toxicity of LC and improve organ function by accelerating the resorption of amyloid deposits.

Description: Introduction: Proteasome inhibitor (PI) resistance remains a major clinical challenge in multiple myeloma (MM). As the proteasome plays a central role in cellular protein homeostasis, we hypothesized both PI treatment and resistance might rewire protein transport and recycling pathways, thereby leading to broad changes in cell surface protein expression. Defining the cell surface proteome has become increasingly important in MM to quantify immunotherapy target expression, identify potential biomarkers of drug response or resistance, and reveal proteins mediating interaction with the tumor microenvironment. Unbiased mass spectrometry approaches allow for profiling of hundreds of surface proteins simultaneously, allowing for novel protein discovery and extending beyond the limits of flow or mass cytometry. Methods: PI-resistant cells derived from cell lines AMO-1, L363, and RPMI-8226, and ARH-77 were grown in 90nM Bortezomib or Carfilzomib as previously described (Soriano et al, Leukemia (2016)). N-glycoproteomics was performed in triplicate on PI-resistant and parental lines. Briefly, glycosylated cell surface proteins were biotinylated prior to enrichment with Neutravidin beads and downstream LC-MS analysis. For perturbation studies, AMO-1 and RPMI-8226 cells were treated for 48 hours with Bortezomib, Lenalidomide, or CB-5083 prior to N-glycoproteomics. Flow cytometry was performed to validate surface protein abundance changes in PI-resistant lines, as well as with MM cell lines and ex vivo MM patient bone marrow mononuclear cells (PBMCs) treated with bortezomib and lenalidomide. For ex vivo MM patient cell surface proteomics, plasma cells were isolated from PBMCs with anti-CD138 magnetic beads prior to N-glycoproteomic analysis. Mass spectrometry data was analyzed in Maxquant and statistical analysis was performed in Perseus and R. Results: Supporting our hypothesis, we found that the MM surfaceome is broadly re-wired in the PI-resistant state. Using N-glycoproteomics, we identified EVI2B, CD53, CD50, and ITGB7 as downregulated and CD151, CD10, and SERC3 as upregulated in PI-resistant myeloma cell lines (up and downregulated defined as at least a +/- log2 fold change of 1.5 and p 〈 .05). Notably, ITGB7 is under development as an immunotherapy target for MM (Hosen et al, Nat Med (2017)). To understand how surface remodeling in the PI-resistant state compares with short-term exposure to PI, we treated MM cells with bortezomib and again found broad surfaceome remodeling, including loss of immunotherapy target BCMA. We identified GITR, CD53, and ITGB7, among other proteins, as downregulated in both bortezomib-exposed and PI-resistant MM, suggesting that expression of proteins involved in therapeutic resistance might be rapidly modulated in initial cycles of therapy. To compare surfaceome changes identified in PI-exposure and resistance and those seen under anti-MM therapeutics with alternative mechanisms of action, we performed N-glycoproteomics on MM cells treated with the clinical immunomodulating agent Lenalidomide and the cytotoxic p97/VCP inhibitor CB-5083. Interestingly, we found MUC1, a proposed myeloma oncoprotein, to be upregulated under lenalidomide in AMO-1 but downregulated in the PI-resistant state. We validated surface protein abundance changes in PI-resistant MM cell lines and drug-treated MM cell lines or ex-vivo MM patient samples by flow cytometry. For additional validation, we are currently optimizing methods for N-glycoproteomics on CD138+ cells isolated from primary MM patient bone marrow aspirates. Initial results suggest several markers identified in cell lines are also highly expressed in primary PI-resistant MM. Conclusions: Unbiased N-glycoproteomics reveals broad cell surface protein remodeling in PI-resistant MM. Short-term treatment with bortezomib or lenalidomide also leads to significant surface alterations, with differential expression of proteins including MUC1, GITR, and BCMA potentially playing a role in drug resistance and informing rational combination with immunotherapies. Disclosures Martin: Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wong:Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding. Wiita:Indapta Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Protocol Intelligence: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; UCSF: Patents & Royalties.

Description: The treatment of newly diagnosed patients with AL has dramatically improved with the use of the first-in-class proteasome inhibitor bortezomib in initial therapy (Kastritis et al., Haematologica, 2007). Overall hematologic response rates of 62% have been reported in a large series with 43% of patients achieving very good partial (VGPR) or complete responses (CR), i.e.〉 VGPR (Palladini et al., Blood, 2015). In fact, bortezomib-based therapy is now commonly used as front-line treatment in lieu of transplant or as cytoreduction prior to ASCT. However, patients who have suboptimal hematologic responses such as partial or no response (PR, NR) to bortezomib-based therapy are likely to have inferior overall survival (Palladini et al., JCO, 2012). The clinical efficacy of risk-adapted melphalan (MEL) and autologous stem cell transplantation (ASCT) as a second-line option for such patients has not been formally studied. We report on 12 patients, 8 men and 4 women with a median age of 58 (range, 53-70) with suboptimal responses to initial therapy who were referred for and underwent ASCT after a median of 4 cycles of bortezomib-based therapy (range, 2-8). Eight patients had NR with median involved FLC values at diagnosis and post initial therapy/pre-SCT of 180 (74-648) and 265mg/L (116-410) respectively while 4 had PR with medians of 1401 (250-9750) and 94mg/L (43-1620); in neither case were comparisons significant by paired t-test. Seven patients had 2 organs involved and 5 had one. Eight patients had cardiac involvement, seven stage 2 and one stage 3. Six patients had renal involvement, one stage 1, four stage 2, and one stage 3. Two had GI involvement. All patients were mobilized successfully with filgrastim and plerixafor as previously described (Kaul et al., BMT, 2014). A median of 9.8 x 106 CD34+ cells/kg (range, 5.4-23.3) were collected. All patients received melphalan at doses of 200 mg/m2 (4 patients, 33%), 140 mg/m2 (7 patients, 58%), and 100 mg/m2 (1 patient, 8%). A median of 6.6 x 106 CD34 cells/kg (4.5-14.0) were infused. All patients engrafted and all had their post-SCT hematologic responses assessed. There was one treatment-related death at 2 months post-SCT in a 70 year old woman who had stage 2 cardiac and stage 2 renal disease, received MEL 100 mg/m2 and had improved her hematologic response status from NR to PR. Overall post-SCT, 75% of patients achieved 〉 VGPR including 42% who achieved CR (n=5). Eight patients have received consolidation with bortezomib and/or lenalidomide based regimens, with four patients achieving CR. Two patients are about to start consolidation. With a median follow-up of 27 months (1-42), two renal and four cardiac responses have been achieved. Median overall survival post-SCT has not been reached (Figure). In conclusion, risk-adapted melphalan and ASCT is a safe, feasible, timely and effective second-line therapy for patients with AL who have suboptimal responses to bortezomib-based initial therapy. Figure Figure. Disclosures Comenzo: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding.

Description: Autologous stem cell transplantation (SCT), a standard therapy for patients with multiple myeloma (MM), has been offered continuously for over 25 years at our center. During this time, there have been significant advances in therapy and marked improvements in survival. We performed a single-center retrospective study comparing patients transplanted from 1988-2000 (cohort A) and 2001-2012 (cohort B). We evaluated differences at, toxicities of, and outcomes with and after SCT. This comparison highlights the contributions of advances in SCT-related conditioning regimens, supportive care and the impact of new therapeutic agents on patient outcomes. Data were extracted from two internal clinical and stem cell databases and from medical chart reviews of all patients undergoing SCT for MM from 1988-2012. Disease responses were assessed with IMWG response criteria. The National Death Index was queried for patients lost to follow-up, without date of death, or without cause of death. Progression-free (PFS) and overall survival (OS) were defined as time from SCT to progression and/or death and estimated by Kaplan-Meier (two-sided log rank test). Patients with a second SCT or allogeneic SCT were censored at the date of second SCT. Multivariate analysis was performed using Cox's Proportional Hazard Regression models. We calculated adjusted survival probabilities by employing a stepwise model selection to identify significant covariates. Factors that were significant at 0.15 level were kept in the final model. Patient characteristics of the cohorts (A=63, B=116) including gender, lab values at diagnosis, renal and skeletal involvement, M-protein isotypes, staging, pre-SCT screening and infectious disease testing, were no different. Cohort A was younger at SCT (54 vs 57 years) and transplanted later post-diagnosis. More in cohort A had been treated with melphalan (MEL) (48% vs 4%) and palliative radiation (XRT) to bone lesions (54% vs 26%) pre-SCT. MM disease status was significantly different at SCT for A and B (Table 1). Three quarters of patients in cohort A were mobilized with cyclophosphamide and G-CSF (Cy-G) but 23% were collected in steady-state or after GM-CSF, while 99% in cohort B were mobilized with Cy-G or G alone. Notable aspects of conditioning regimens and peri-transplant complications are shown in Table 1. Exposure to prior XRT in cohort A correlated with development of secondary MDS/AML. OS post-SCT differed between the two cohorts (2.8 vs 7.9 years, P 〈 0.01) (Figure 1). No patients in cohort A received a novel agent pre-SCT compared to 68% in cohort B including 〉30% of cohort B receiving pre-SCT bortezomib. CR/VGPR status at SCT predicted improved OS (P = 0.04) while pre-SCT exposure to oral MEL predicted worse OS (HR 1.97, P = 0.02). Patients in cohort A died shortly after post-SCT relapse, whereas those in cohort B lived longer after relapse (1.0 vs 2.7 years, P 〈 0.01). Median OS of patients who received a novel agent at any time was not reached compared to 3.4 years for others. Cause of death differed between the two cohorts. More patients died of MM progression in cohort B (80% vs 58%), while more patients died of transplant related causes or secondary MDS in cohort A (19% vs 2%). In sum, we demonstrate a clear improvement in outcomes of MM patients selected to undergo first SCT over the past 25 years. OS has improved alongside reductions in TRM. Novel agents have contributed to these improvements although advances in SCT and supportive care are also important contributors. Further research into more efficacious treatments, such as monoclonal antibody therapy, is required to continue the improvements in SCT for MM. Table 1. Variable Cohort A1988 - 2000(N = 63) (%) Cohort B2001 - 2012(N = 116) (%) P -value Months from diagnosis to SCT 12.7 (5.6-95.3) 8.9 (4.2-50.6) 〈 0.01 Patients 〉 64 years old 3 (5) 19 (16) 0.024 MM status at SCT CR 15 (24) 31 (27) 〈 0.01 VGPR 2 (3) 27 (23) PR 29 (48) 40 (34) SD 5 (8) 9 (8) Refractory 6 (10) 5 (4) Relapsed 5 (8) 4 (3) Conditioning regimen MEL 140 7 (11) 15 (13) 〈 0.01 MEL 200 2 (3) 99 (85) MEL 140/TBI 41 (65) 2 (2) MEL 140/TBI/Cy 12 (19) 0 (0.00) MEL 140/Cy 1 (2) 0 (0.00) Days in hospital for SCT 24 (13 - 64) 20 (11 - 36) 〈 0.01 Failure to engraft for platelets 9 (14) 1 (1) 〈 0.01 Treatment-related mortality (100d) 6 (10) 1 (1) 〈 0.01 MM response post-ASCT CR 26 (46) 59 (53) 〈 0.01 VGPR 6 (11) 31 (28) PR 21 (38) 18 (16) SD 2 (4) 4 (4) Relapsed 1 (2) 0 (0) Secondary MDS/AML 6 (10) 0 (0) 〈 0.01 Figure 1. Figure 1. Disclosures Relias: Genentech: Speakers Bureau. Miller:Biogen Idec: Consultancy; AbbVie: Speakers Bureau; Millennium: Speakers Bureau; Onynx: Speakers Bureau. Comenzo:Prothena: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees.