Signaling Lymphocytic Activation Molecule F7 Research Articles

Phase II Trial of Elotuzumab with Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM) in the Post-Daratumumab Progression Setting

Introduction: Elotuzumab (Elo) is an immunostimulatory (via natural killer [NK] cell activation) monoclonal antibody (mAb) targeting signaling lymphocytic activation molecule F7 (SLAMF7) that has shown activity in combination with the immunomodulatory drugs (IMiDs) lenalidomide (Len) or pomalidomide (Pom) and dexamethasone (Dex), in patients (pts) with RRMM in the ELOQUENT 2 and 3 trials, respectively. However, in ELOQUENT 2, pts were not Len refractory or previously treated with daratumumab (Dara) and in ELOQUENT 3, <5% of patients were previously treated with Dara. The efficacy of Elo-based regimens in Dara-refractory pts needs prospective evaluation to understand optimal sequencing of regimens in RRMM. We report data from a phase 2 trial evaluating the efficacy of Elo-Pom-Dex (EPd) in pts with Dara-refractory RRMM. Methods: This phase 2 trial (NCT03713294) enrolled pts with RRMM who had disease progression and were refractory to Dara. Key eligibility criteria included: measurable disease as per IMWG criteria, at least one prior line of therapy, adequate marrow/organ function (neutrophil count ≥1.0 x 109, platelets ≥50x 109, creatinine clearance ≥30 mL/min), ECOG performance status ≤2, and disease not refractory to Pom. EPd was dosed as per the ELOQUENT 3 study. The trial utilized a two-stage design with an interim analysis to test the null hypothesis that the true overall response rate (ORR) in this patient population is most 20% vs. the alternative hypothesis that it is at least 40%, with 90% power and 9% type I error. Treatment was given until disease progression, intolerance, or patient refusal. Results: 37 pts were enrolled. Median follow-up time was 23.4 months (95% CI: 14.6-37.2). The median age was 70 years (range: 42-84), 12 (32.4%) pts had ISS III disease and 16 (43.2%) pts had high risk cytogenetics. Pts had received a median of 4 (range: 1-9) prior lines of therapy. Prior anti-MM agents included bortezomib (35; 94.6%), Len (34; 91.9%), carfilzomib (9; 24.3%), ixazomib (9; 24.3%), stem cell transplantation (18; 48.6%) and CAR-T cell therapy (1; 2.7%). The majority of pts (33; 89%) were previously exposed to both a proteasome inhibitor and Len. 25 (67.6%) pts got Dara-based therapy as the immediate line of therapy prior to EPd (after a median of 4 prior lines [range 1-7]) whereas 12 (32%) pts got Dara-based therapy ≥1 line prior to EPd (after a median of 6 prior lines [range 2-9]). ORR in all pts was 35.1% (13 pts), with no CRs, 1 (2.7%) VGPR, and 12 (32.4%) PRs. Four pts (10.8%) achieved an MR and 15 (40.5%) achieved SD. The study met its primary endpoint. The ORR in pts exposed to Len was 11/34 (32.4%) compared to 2/3 (66.7%) in patients not exposed to Len. The ORR in pts with Dara as the immediate prior line of therapy was 44% (11/25) compared to 16.7% (2/12) in pts who had received Dara-based therapy ≥1 line prior to EPd (p=0.15). The median PFS for the entire cohort was 3.7 mth (95% CI: 2.9-11.1) (Figure 1A). The median time to best response was 2.9 mth. The median time to next treatment was 8.5 mth (95% CI: 6.8-20.4). Median PFS of pts with Dara as the immediate prior line of therapy was 4.7 mth (95% CI: 3.2-19.6) compared to 2.8 mth (95% CI: 2.0-NA) in patients who had received Dara-based therapy ≥1 line prior to EPd (p=0.03; Figure 1B). The most common grade 3/4 adverse events were neutropenia (57%), anemia (22%), thrombocytopenia (16%), leucopenia (16%), and fatigue (8%). Conclusion: This was a positive study with EPd showing clinically meaningful benefit in pts with Dara-refractory RRMM. The reported PFS of 3.7 mths is less than the 10.3 mths reported in ELOQUENT 3 trial which suggests that Elo-based regimens are less effective in Dara-refractory pts. Interestingly, pts had a significantly superior PFS if they received EPd immediately following progression on Dara, however they were less heavily pretreated comparted to pts who got EPd ≥1 line after Dara failure. Nonetheless, EPd is an effective regimen in the post-Dara setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Strong prognostic value of SLAMF7 protein expression in patients with lymph node-positive breast cancer.

Breast cancer (BC) in women is the second most commonly diagnosed type of cancer worldwide, and the leading cause of cancer-related mortality among women. To date, surgery is the main treatment option, often combined with other (neo)adjuvant therapeutic modalities to treat this malignancy and prevent relapse. Despite the invasive aspects of the majority of these therapeutic interventions and their associated side-effects, these treatments are still unable to effectively cure this disease and prevent relapse. Thus, there is an urgent need for the identification of more relevant biomarkers for more effective theranostics. Signaling lymphocytic activation molecule F7 (SLAMF7) is a glycosylated cell surface protein that plays a critical role in immune cell functions under both healthy conditions and in cancer. It is specifically targeted by elotuzumab for the treatment of multiple myeloma. The present retrospective study aimed to investigate the expression patterns of SLAMF7 and evaluate its associations with clinicopathological features, including the survival outcomes of patients with BC. The protein expression of SLAMF7 in BC was investigated in 278 lymph node-positive formalin-fixed and paraffin-embedded (FFPE) tissue blocks using tissue microarray and immunohistochemistry techniques. The results revealed a significant association between cytoplasmic SLAMF7 protein expression and several clinicopathological parameters, particularly age at diagnosis (P<0.007), tumor invasion (P<0.008) and vascular invasion (P=0.05). Kaplan-Meier analysis revealed that the overexpression of SLAMF7 was a strong positive prognosticator of both disease-free and disease-specific survival in the patients with BC (log-rank P=0.001 and P=0.008, respectively). This suggests that patients with SLAMF7 protein expression have a higher survival rate and a lower recurrence rate. On the whole, the present study demonstrated that a weak or no SLAMF7 expression was a powerful prognosticator of poor survival outcomes associated with both tumor and vascular invasion. Therefore, elotuzumab (as SLAMF7monoclonal antibody therapy) may be a promising option for targeted therapy worthy of clinical testing in patients with BC.

Elotuzumab, a potential therapeutic humanized anti-SLAMF7 monoclonal antibody, enhances natural killer cell-mediated killing of primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is a rare aggressive B-cell non-Hodgkin's lymphoma with no optimal treatment. Signaling lymphocytic activation molecule-F7 (SLAMF7, CD319), a type I transmembrane glycoprotein highly expressed in multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. SLAMF7 also expresses on several hematopoietic lineages including NK cells. Elotuzumab (Elo), a humanized antibody targeting SLAMF7, is approved by FDA for MM treatment. In this study, we analyzed the expression of SLAMF7 on seven PEL cell lines. All PEL cells and NK cells showed high expression of SLAMF7. NK cells were enriched from PBMCs of healthy donors by MACS and expanded by co-culturing with MHC-class I negative K562 cells in the presence of IL-2 and IL-15. Expanded NK cells showed direct killing, and Elo demonstrated potent ADCC against PEL in an Effector:Target (E:T) dependent manner. Surface expression of CD107a on NK cells also increased in the process of ADCC. We also examined SLAMF7 expression of NK subpopulations and found that the CD56+CD16+ NK subpopulation demonstrated the highest SLAMF7 expression. Full-length-Elo but not F(ab')2-Elo exerts direct engagement to the expressing SLAMF7 on NK cells, promotes CD107a expression, and further augments NK cytotoxicity toward PEL. Elo enhanced survival of PEL-bearing immunodeficient mice with adoptive transfer of human NK cells. Taken together, our results show that NK cells play roles in PEL killing, and Elo causes ADCC/SLAMF7 ligation to boost NK cytotoxicity against PEL, offering promising preclinical evidence of Elo as a therapeutic monoclonal antibody treatment for PEL.

Library-based lead compound discovery for CS-1 protein in multiple myeloma: homology modelling, molecular dynamic simulations, virtual screening and molecular docking

ABSTRACT The signaling lymphocytic activation molecule F7 (CS-1) enables the selective killing of the myeloma cells with minimal side effects on the healthy tissue. In this study, we have modelled the 3D structure of CS-1 followed by performing molecular dynamic simulations. To develop a potential CS-1 modulator, a virtual screening of the ‘Bioactive Compound Database’ was conducted. The screening results have given three interacting regions. The best representative structure of each class and mode of action were revealed. Our study suggests compounds ICG-001, Avanafil, and BPTES, as novel drug candidates at the CS-1 protein target. The molecular dynamic simulation study reveals that the resulted compounds provide different binding patterns over the CS-1 Ig-like V-type domain in which Avanafil and BPTES provide stable interactions with their binding environment located at the bc-hi loops clefts and bc-fg loops clefts, respectively. In contrast, compound ICG-001 shows more flexible and transient non-binding interaction due to the vast binding region over β-sheet strands consisting of H, C and D during the simulation timeline. We conclude that the identified compounds seem to be the best candidates to design a series of new compounds with the ability to bind to CS-1 with potential binding activity to its target.

Universal SLAMF7-Specific CAR T-Cells As Treatment for Multiple Myeloma

Introduction : Signaling lymphocytic activation molecule F7 (SLAMF7, also called CS1) is highly expressed on multiple myeloma (MM) tumor cells but has limited expression in a subset of hematopoietic cells among normal tissues, making it a rational target for chimeric antigen receptor (CAR) T-cell therapy in MM. Currently, most CAR-T cell therapy products are generated from autologous T-cells, which is a major limitation logistically and likely difficult to do for lymphopenic and most critically ill patients. Therefore, we have designed allogeneic “off-the-shelf” engineered CAR T-cells (derived from normal healthy donor peripheral blood mononuclear cells), which contain an inactivation of the TCRα constant (TRAC) gene using TALEN® gene-editing technology to prevent graft-versus-host disease. The SLAMF7 gene is also inactivated using TALEN® in order to minimize the risk of fratricide of SLAMF7-specific CAR+ T-cells (Galetto et al, ASH 2015, Abstract 116). Here, we report in vitro and in vivo efficacy results from double knock-out (KO) (TRAC and SLAMF7) SLAMF7-specific universal CAR T-cells (UCARTCS1) against MM cell lines and primary MM tumor cells.Methods : The function of UCARTCS1 cells was tested in vitro against MM cell line (MM.1S) and primary MM tumor cells using flow-cytometry-based cytotoxicity, degranulation, CFSE proliferation, and multiplex cytokine induction assays. The efficacy of UCARTCS1 was also tested in vivo against primary MM xenografts in human fetal bone implanted into NOD/SCID/IL2rgnull mice (NSG-hu). Double KO (TRAC and SLAMF7) T-cells lacking SLAMF7 CAR served as controls. The potential toxicity of UCARTCS1 against hematopoietic cells has also been assessed in vitro using the cytotoxicity assay.Results : UCARTCS1, but not control double KO T-cells, specifically lysed MM.1S (median, 93% lysis; range, 78-98% with UCARTCS1 vs. median, 17%; range, 15-47% with control T-cells; n=10 experiments) and primary MM tumor cells (n=10 samples) (median 59%; range, 20-90% with UCARTCS1 vs. median 9%; range, 0-36% with control T cells). In agreement with this, we observed specific degranulation in both CD4+ and CD8+ UCARTCS1 cells but not control T-cells in presence of MM.1S cells and primary MM tumor cells. In addition, significant and specific proliferation of both CD4+ and CD8+ UCARTCS1 cells but not control T-cells was observed when they were co-cultured with MM.1S or primary MM tumor samples (n=8). Analysis of culture supernatants for ten cytokines showed that UCARTCS1 cells primarily produced IFN-γ and GM-CSF in presence of primary MM tumor cells (n=6) suggesting a Th1/Tc1 response. On the other hand, UCARTCS1 did not induce any significant lysis of normal donor peripheral blood mononuclear cells or CD34+ hematopoietic cells from bone marrow aspirates of healthy donors.To test the efficacy of UCARTCS1 cells in vivo we injected 1x106 CD138-purified primary MM tumor cells into the NSG-hu mouse model. After the tumor had been established (6-8 weeks with a serum M-protein level >15 µg/ml), mice were treated intravenously with a single injection of either 10x106 total cells/mouse ofUCARTCS1 or control T-cells. Mice treated with control T-cells developed gradual increase in M-protein levels (median, 339 µg/ml; range, 100-700 µg/mL) whereas the M-protein levels rapidly became undetectable in the mice treated with UCARTCS1 cells and remained undetectable until they were euthanized at approximately 50 days after adoptive transfer.Conclusion : Our studies revealed that UCARTCS1 cells specifically target and lyse primary MM tumor cells both in vitro and in vivo . Further, UCARTCS1 cells specifically degranulated, produced Th1/Tc1 cytokines, and proliferated in response to primary MM tumor cells. Our results support further development and testing of this universal “off-the-shelf” allogeneic SLAMF7-specific CAR-T product in patients with MM. DisclosuresGaletto:Cellectis SA: Employment. Gouble:Cellectis SA: Employment. Filipe:Cellectis: Employment. Gariboldi:Cellectis SA: Employment. Thomas:Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Lee:Adaptive: Membership on an entity's Board of Directors or advisory committees; Eutropics Pharmaceuticals: Research Funding; Pimera Inc: Consultancy; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Patel:Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Smith:Cellectis: Employment. Yang:Poseida Therapuetics: Research Funding; Cellectis: Research Funding. Neelapu:Cellectis Inc.: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida Therapeutics, Inc: Research Funding.

Development of an Antibody-Targeted Nanoparticle for Early Detection of Minimal Residual Disease in Multiple Myeloma

Development of methods for the early detection of minimal residual disease (MRD) is a central challenge to the effective treatment of patients with multiple myeloma (MM). The presence of MRD is directly linked to both the durations of treatment response as well as to long-term survival outcomes. Current diagnostic methods utilize serologic biomarkers and/or repeated bone marrow samplings that do not take into account the spatial heterogeneity of the tumor microenvironment; as such, they often lead to false negative results. Available diagnostic imaging agents are not designed to detect plasma-cell populations; they rely on passive tumor accumulation that hinders both their detection specificity and sensitivity.Here, we utilize ultra-small gadolinium-based nanoparticles (Gd-NPs) that are conjugated to monoclonal antibodies to enable magnetic resonance imaging of plasma cells in a murine model of MM. We demonstrate the first example of utilizing a non-invasive imaging agent to improve early detection of MRD after therapeutic administration.To develop a plasma-cell targeted MRI contrast agent that would improve early detection of MRD, we fabricated ultra-small, sub-5 nm Gd-NPs that were conjugated to monoclonal antibodies directed against different receptors on the surfaces of MM cells. We postulated that these ultra-small Gd-NPs would minimally affect antibody targeting upon conjugation and could achieve improved in vivo imaging of plasma cell populations. For targeting of MM cells, we selected antibodies against the signaling lymphocytic activation molecule-F7 (SLAMF7) and the B-cell maturation antigen (BCMA). Both antigens are almost exclusively present on the surfaces of malignant B-cells. To generate our MM-targeted imaging construct, the surfaces of our Gd-NPs were decorated with free N-hydroxysuccinimide (NHS) groups and were conjugated to NHS groups on the surface of anti-SLAMF7 and BCMA antibodies via a bissulfosuccinimidyl suberate crosslinker.An MRI study was undertaken to compare the efficiencies of the various nanoparticle constructs (Gd-NP, NP-SLAMF7, and NP-BCMA) to identify identical plasma cell burdens and as compared to the FDA-approved contrast agent MagnevistTM. Gd uptake in the spine and femurs of animals were visualized using a 7T MRI machine with a T1-GRE sequence. The specificity of each of the administered contrast agents to target MM cells was confirmed by animal sacrifice immediately after MRI; the femurs and vertebral tissues of each animal were harvested for histologic assessment after staining by H&E and by Prussian blue, which showed sheets of marrow-infiltrating plasma cells and which labeled Gd deposits, respectively. This quantification demonstrated the enhanced sensitivity of NP-SLAMF7 and NP-BCMA, as compared to the passive targeting agents Gd-NP and MagnevistTM, to detect plasma cell populations. As soon as 30 min after the intravenous injection of the nanoparticle-antibody complexes, animals that had been administered NP-SLAMF7 demonstrated an ~3.8-fold increase in the SNR for plasmacytomas in the spine while those that had received NP-BCMA exhibited a ~12-fold enhancement. Note that the NP-BCMA conjugate demonstrated better tumor uptake than NP-SLAMF7 (p= 0.0045, one-sided paired t-test), which was attributed to the greater numbers of surface BCMA antigens on MM cells as assessed on a per cellular basis.We subsequently evaluated their targeting efficiencies both in vitro and in vivo prior to performing a comparative study to determine their detection capabilities when compared to other clinically-available diagnosis, such as computed tomography scans and methods levels of serum lambda light-chains. Comparisons of AUC for the SNR detected by each modality and over the entire duration of the experiment further supported the superiority of the NP-BCMA for both early diagnostic of MM and MRD diagnostic.Selection of alternative cell surface targets may also enable detection of MRD in patients diagnosed with leukemia or other hematological malignancies. Ultra-small nanoparticle-antibody complexes are, thus, poised to impact both the diagnosis and treatment of MM. Their successful application may further afford insights into the fabrication of other targeted constructs that may help translate the full potential of nanomedicines to improve the care and survival of cancer patients. DisclosuresNo relevant conflicts of interest to declare.

Galectin-9 bridges human B cells to vascular endothelium while programming regulatory pathways.

Humoral immunity is reliant on efficient recruitment of circulating naïve B cells from blood into peripheral lymph nodes (LN) and timely transition of naive B cells to high affinity antibody (Ab)-producing cells. Current understanding of factor(s) coordinating B cell adhesion, activation and differentiation within LN, however, is incomplete. Prior studies on naïve B cells reveal remarkably strong binding to putative immunoregulator, galectin (Gal)-9, that attenuates BCR activation and signaling, implicating Gal-9 as a negative regulator in B cell biology. Here, we investigated Gal-9 localization in human tonsils and LNs and unearthed conspicuously high expression of Gal-9 on high endothelial and post-capillary venules. Adhesion analyses showed that Gal-9 can bridge human circulating and naïve B cells to vascular endothelial cells (EC), while decelerating transendothelial migration. Moreover, Gal-9 interactions with naïve B cells induced global transcription of gene families related to regulation of cell signaling and membrane/cytoskeletal dynamics. Signaling lymphocytic activation molecule F7 (SLAMF7) was among key immunoregulators elevated by Gal-9-binding, while SLAMF7's cytosolic adapter EAT-2, which is required for cell activation, was eliminated. Gal-9 also activated phosphorylation of pro-survival factor, ERK. Together, these data suggest that Gal-9 promotes B cell - EC interactions while delivering anergic signals to control B cell reactivity.

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7

Chimeric antigen receptors (CARs) are fusion proteins that contain antigen-recognition domains and Tcell signaling domains. Signaling lymphocytic-activation molecule F7 (SLAMF7) is a promising target for CAR Tcell therapies of the plasma cell malignancy multiple myeloma (MM) because SLAMF7 is expressed by MM but not normal nonhematopoietic cells. We designed CARs targeting SLAMF7. We transduced human Tcells with anti-SLAMF7 CARs containing either CD28 or 4-1BB costimulatory domains. Tcells expressing CD28-containing CARs or 4-1BB-containing CARs recognized SLAMF7 invitro. SLAMF7-specific cytokine release was higher for Tcells expressing CARs with CD28 versus 4-1BB domains. In murine solid tumor and disseminated tumor models, anti-tumor activity of Tcells was superior with CD28-containing CARs versus 4-1BB-containing CARs. Because of SLAMF7 expression on some normal leukocytes, especially natural killer cells that control certain viral infections, the inclusion of a suicide gene with an anti-SLAMF7 CAR is prudent. We designed a construct with a CD28-containing anti-SLAMF7 CAR and a suicide gene. The suicide gene encoded a dimerization domain fused to a caspase-9 domain. Tcells expressing the anti-SLAMF7 CAR plus suicide-gene construct specifically recognized SLAMF7 invitro and eliminated tumors from mice. Tcells expressing this construct were eliminated on demand by administering the dimerizing agent AP1903 (rimiducid).

The role of fibrocytes in myelofibrosis and fibrocyte regulation as a novel treatment approach

Recently, monocyte-derived fibroblast-like cells, called fibrocytes, garnered attention as involved in the novel pathogenesis of various fibrotic diseases. They also play a role in the induction of myelofibrosis (MF). Neoplastic fibrocytes are overrepresented in the bone marrow of patients with primary MF, and the suppression of fibrocyte differentiation by serum amyloid P has been shown to remarkably improve MF. Further, thrombopoietin (TPO) or a TPO receptor agonist directly induces fibrocyte differentiation, and fibrocyte elimination reversed the MF phenotype in a murine model. Human fibrocytes highly express signaling lymphocytic activation molecule-F7 (SLAMF7) compared with macrophages. Myeloproliferative neoplasm (MPN) patients harboring JAK2V617F with MF had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. Furthermore, the JAK2V617F allele burden and the tendency to differentiate into fibrocytes of SLAMF7high monocytes was significantly higher than that of JAK2V617Flow monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used to treat multiple myeloma. Elo independently inhibited the differentiation of fibrocytes derived not only from healthy controls but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. Thus, Elo could be a therapeutic agent for MPN patients harboring JAK2V617F with MF.

Angioimmunoblastic T-Cell Lymphoma: Molecular Characterization of Clonal T and B-Cells and a Patient Derived Xenograft Model of Coexisting T and B-Cell Proliferations

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive type of lymphoma that accounts for about 20% of peripheral T-cell lymphomas with a 5 year overall survival rate of 30%. As most patients relapse after anthracycline-containing regimens and newer agents such as histone deacetylase inhibitors, other novel therapeutic approaches are needed. Signaling lymphocytic activation molecule F7 (SLAMF7), a molecule expressed on a subset of T-cells, activated B cells and myeloma cells, is an attractive target to explore based on our previous studies showing SLAMF7 expression in a subset of AITL cases. The association of AITL with Epstein Barr virus (EBV) positive B-cells is nearly always present and the efficacy of treatment in such patients with significant EBV viral load is not well-understood. In this study, we performed the molecular characterization of an aggressive EBV+ AITL case, established a patient-derived xenograft (PDX) AITL model of coexisting T and B-cell proliferations and evaluated novel therapeutic strategies. Methods: Primary tumor cells were injected into a NSG mouse. Flow cytometry, immunohistochemistry (IHC), CISH-EBER and BIOMED 2 PCR based clonality studies were used to confirm the engraftment and compared the consistency of engrafted tumor cells with the primary sample. Genomic DNA extracted from sorted T and B cells and from paired normal neutrophils of the original patient were subjected to Whole Exome sequencing (WES). In vivo AITL PDX model trials were tested for the efficacy of romidepsin (Rom), elotuzumab (Elo), rituximab (Rit) and in combinations of these drugs. Results: A 53 year old woman with AITL was treated with 6 cycles of CHOEP followed by autologous stem cell transplantation. 3 months after transplantation (9 months after diagnosis) she developed progressive fatigue and arthralgias. PET-CT scan showed new cervical, thoracic, abdominal and pelvic lymphadenopathy. A cervical lymph node biopsy was performed to confirm relapse. IHC staining showed atypical T cells expressing CD2, CD3, CD4, CD5, CD7, CD10, BCL6, PD1, SLAMF7 and CXCL13. Scattered CD20+/EBER+ B-immunoblasts were present with focal large clusters/small sheets. Primary tumor cells engrafted in NSG mouse via tail vein injection caused splenomegaly. Flow cytometry assay demonstrated the engraftment of tumor cells in peripheral blood, bone marrow and spleen tissue. CD3+CD19- cells dominated the engrafted cells in all three tissues. Histologic examination and immunophenotyping (IHC and EBER staining) of spleen were consistent with primary tumor tissue. Engrafted tumor cells were capable of serial passage in NSG mice with an increasing malignant B cell percentage that mimics the situation in which the B-cell component masks an underlying T-cell lymphoma in humans. T-cell receptor gene rearrangement assay confirmed the clonal identity of engrafted T-cells matched the primary relapsed tumor. A clonal IGH rearrangement of engrafted B-cells was also detected, while no monoclonal B-cell population was detected in the relapsed AITL sample, possibly due to the low number of EBV+ B-cells present in that biopsy. WES of sorted malignant T-cells showed 33 mutants in 31genes, including RhoA G17V, TET2,STAT3 and VAV1, previously described in AITL or other T-cell lymphomas. In parallel WES assay, 9 mutations were found in 9 genes from sorted EBV+ B immunoblasts. A PDX model using cells harvested from the second passage showed single agent, Elo or Rit, extended the survival of mice compared to the control group (p &amp;lt; 0.05). Rom alone had no such effect (p = 0.27). Combination of Rit with either Elo or Rom further improved survival compared to each single agent exposed cohort (p &amp;lt; 0.05). There was no significant difference between Rit/Elo and Rit/Rom (p = 0.067). PARP cleavage by IHC was higher in the Rit/Rom and Rit/Elo groups compared to other cohorts. Expression of SLAMF7 in a subset of engrafted T and B cells of the control mouse were confirmed via flow cytometry assay. Conclusions: To date, this is the first molecular characterization of AITL tumor cells in comparison with associated EBV+ B cells and use of such a PDX model for therapeutic evaluation of agents targeting both malignant T and B cells simultaneously. The in vivo data support further clinical investigation of applying elotuzumab or romidepsin in combination with rituximab in AITL containing EBV-positive B-cell proliferations. Disclosures Maciejewski: Novartis: Consultancy; Alexion: Consultancy. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Jazz: Consultancy; Cleveland Clinic&amp;Abbvie Biotherapeutics Inc: Patents &amp; Royalties: US8,603,477 B2.

Elotuzumab in Combination with an Immunomodulatory Agent (IMID) in Patients with Multiple Myeloma Refractory to Imids and/or Daratumumab: A Single-Institution Analysis

Background: Elotuzumab (elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7, CD319) has shown activity in combination with dexamethasone and lenalidomide (len) or pomalidomide (pom), in patients with relapsed/refractory (RR) multiple myeloma (MM) in the ELOQUENT 2 and 3 trials, respectively. However, patients enrolled on those trials were not refractory to len or pom respectively and the impact of prior daratumumab (dara) (which can deplete natural killer (NK) cells) was not evaluated. We reviewed the outcomes of RR MM patients treated with elo in combination with either len or pom with respect to prior exposure and refractoriness to IMIDs and dara. Methods: We retrospectively evaluated patients with RR MM who were treated at Moffitt Cancer Center between January, 2017 and July, 2019 with elo in combination with len (elo/len) or pom (elo/pom). We assessed prior therapies and refractoriness to IMIDs and dara. Response was evaluated using the International Myeloma Working Group (IMWG) criteria with added minimal response. Grade 3/4 toxicities were reviewed. This study was approved by the Institutional Review Board. Results: Thirty six patients were identified: 14 on elo/len and 22 on elo/pom. Patient characteristics are outlined in the table. As expected, patients that received elo/pom were more heavily pre-treated, than those who received elo/len, with a median number of 6 prior lines of therapy. The median number of cycles was 9 (range, 2-33) and 3 (range, 1-8) for the elo/len and elo/pom groups, respectively. 21/22 (95%) patients in the elo/pom pts were pom-refractory, whereas 11/14 (79%) of the elo/len patients were len-refractory. For elo/len, the overall response rate (ORR) was 42%, and the median progression-free survival (PFS) was 7.7 months (95% confidence interval, 1.99-10.95, p=0.026) although the ORR was 28.6% in len refractory patients. For elo/pom, the ORR was 14% (for pom refractory patients the ORR was 9.1%) and the median PFS 3.7 months (95% confidence interval, 1.27-6.13 p=0.026). Twenty-three patients (64%) were refractory to dara, with a median time from dara to elo of 13.7 (range, 0.7-33.6) months. Overall survival (OS) and PFS based on the median time from dara to elo were not statistically different. The same analysis based on a 6 months cutoff (assuming shorter dara impact on NK cells) yielded similar results. Thirteen patients remain on treatment at the time of this analysis. Reasons for treatment discontinuation were progressive disease (PD) in 22 (95.7%), adverse event (AE) in 1 (4.3%). Grade 3/4 toxicities were noted in two patients; one patient developed pneumonitis, and another developed infectious complication. Conclusion: The combination of elo with an IMID, such as len or pom, is well tolerated. Elo/IMIDs regimen have modest efficacy in len and pom refractory patients respectively. The timing of and prior dara does not appear to impact the efficacy of elo based therapy. Prospective studies are needed to confirm these findings. Disclosures Shain: Adaptive Biotechnologies: Consultancy; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Baz:AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab

AbstractMonocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

Elotuzumab, Lenalidomide, and Dexamethasone (EloRd) As Salvage Therapy for Patients with Multiple Myeloma: Italian, Multicenter, Retrospective Clinical Experience with 180 Cases Outside of Controlled Clinical Trials

Introduction Elotuzumab (Elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), received marketing approval in Italy for relapsed or refractory multiple myeloma (RRMM), in combination with lenalidomide (R) and dexamethasone (d) (EloRd) in April 2017. Here we report preliminary data of an Italian real-life experience on EloRd as salvage therapy for RRMM patients treated outside of controlled clinical trials. The primary objectives of this study were to assess the toxicity profile and the efficacy of EloRd administered as salvage therapy in a real-world setting. Methods Retrospective data collection received approval from local ethic committee. The cohort included 180 RRMM patients from 28 Italian centers who received at least one cycle of EloRd as salvage treatment between April 2017 and June 2018. Patients were treated with EloRD according to marketing approval as follows: Elo 10 mg/kg i.v. on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 of each following cycle, R 25 mg on days 1 to 21 of each cycle and d at a dose of 40 mg during the week without Elo, and 36 mg on the day of Elo administration. Responsive patients had to reach at least a partial remission (PR). Results Baseline characteristics are shown in Table 1. Median age of the 180 patients was 72 years (range 48-89 years); 53.9% were males (Table 1). The median number of previous therapy regimens was 1 (range 1-7); 69 patients (38.3%) received a previous autologous stem cell transplantation (ASCT). One hundred and ten patients (61.1%) showed a symptomatic relapse, 36 (20%) a biochemical relapse, and 34 cases (18.9%) were refractory to the last therapy, including bortezomib in 12.8% of patients. Forty-four patients (24.4%) had creatinine clearance ≤60 mL/min. Among the 138 cases evaluable for International Scoring System (ISS), 54 (39.1%) had stage I, 56 (40.6%) stage II, and 28 (20.3%) stage III. At last data collection (June 2018), 164 cases were evaluable for response. The median number of courses administered so far was 5 (range 1-18). The overall response rate (ORR) was 78%, with 9 complete remissions (CRs) (5.5%) and 49 very good partial remissions (VGPRs) (35.4%). A significant higher ORR was observed in patients who had received only 1 previous line of therapy than those who had received >1 line (64% vs 37.5%; p=0.004). Age ( After a median follow-up of 6 months (range 1-18 months) 33 patients stopped treatment due to disease progression and 4 due to toxicity (2 cases after 1 cycle for pneumonia, 1 after 1 cycle for dexamethasone-related psychosis, and 1 after 2 cycles for lenalidomide-related severe skin rash). A total of 17 patients died (7 patients from progressive disease; 2 from an infection; 1 from a second neoplasia; 7 from causes unrelated to therapy). Follow-up data regarding PFS and overall survival are not sufficiently mature to be analyzed. Common grade 3 or 4 adverse events were fatigue (18.9%), anemia (17%), neutropenia (16.5%), lymphocytopenia (15.9%), and pneumonia (15.9%). Infusion reactions occurred in 13 patients (7.2%) and were always of grade 1 or 2. Infusion reactions resolved in all patients and no case discontinued treatment. Conclusions Our real world preliminary data confirm that EloRd is an effective and safe regimen for RRMM patients, particularly if used as first salvage regimen, basically resembling results obtained in controlled clinical trials. Disclosures Galli:Celgene: Honoraria; Janssen: Honoraria; Sigma-Tau: Honoraria; Bristol-Myers Squibb: Honoraria. Giuliani:Janssen Pharmaceutica: Other: Avisory Board, Research Funding; Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding. Mangiacavalli:Janssen: Consultancy; Celgene: Consultancy; Cilag: Consultancy. Ballanti:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Zamagni:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Patriarca:Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Petrucci:Takeda Oncology; Amgen; Celgene; BMS; Janssen Cilag: Honoraria, Other: Advisory Board. Offidani:Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

Updated Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC The study9s primary endpoint is PFS, defined as time from AuSCT to PD or death (whichever occurs first), or time of last contact. Secondary objectives are best response, OS, incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Total enrollment of 100 pts is planned. Patients are followed until death, withdrawal of consent or removal from study. Eligible pts received ≤2 lines of induction therapy, and are 60-210 days post-AuSCT. Results: Pts (n=84) have been treated for a median of 16 cycles (2-43). At study entry, 27 (32%) had complete response (CR), 36 (43%) had very good partial remission (VGPR), 20 (24%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 44 pts (52%), VGPR in 31 pts (37%) and PR in 9 pts (11%). For those who have converted to CR on study, median time to CR was 2 months. Of 22 pts in CR who have been tested for minimal residual disease (MRD) to date, 20 are negative by flow cytometry (minimum of 2 million cells evaluated). Three of 20 have converted from VGPR to MRD negativity while on study. With a median follow up of 23 months, 96% of pts (n=81) remain alive. Ten pts have had PD; of these, 6 had high risk cytogenetics. Two died of PD while receiving salvage therapy. One additional pt died on study in VGPR, after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Four pts withdrew for personal reasons, 4 were removed at physician discretion (prolonged cytopenias [1], drug rash [1], worsening memory impairment [1], therapy related myelodysplastic syndrome (t-MDS) [1]), and 2 lost insurance coverage. Estimated 3 year PFS is 81%. High risk cytogenetics adversely affected PFS (p=0.02). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 32% (27), febrile neutropenia 15% (13), thrombocytopenia 8% (7), and anemia 7% (6). Grade 3-4 non-Hematologic AEs (no. of pts): respiratory infections 17% (15), diarrhea 14% (12), fatigue 13% (11), other infections 8% (7), peripheral neuropathy 7% (6), myalgias 6% (5), nausea/vomiting 4% (3), dizziness 2% (2), memory impairment 2% (2), maculopapular rash 2% (2), edema 1% (1). SPMs include intra-epidermal adenocarcinoma of the neck (1), mucinous appendiceal neoplasm (1), t-MDS (1), prostate cancer (1), and melanoma (1). Renal cell carcinoma was diagnosed in 1 pt, 15 months after removal from study for PD. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy during which 33% of 84 pts had improvement in quality of response while on therapy, including 20% who converted to CR. The number of pts experiencing improvement may be underestimated due to ELO interference with paraprotein measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Available data supports conduct of a Phase 3 trial. Disclosures Thomas:Array Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Shah:Karyopharm Therapeutics: Employment. Lee:Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding.

Abstract PR01: Targeting multiple myeloma with universal SLAMF7-specific CAR T-cells

Abstract Background: Recent studies with autologous chimeric antigen receptor (CAR)-redirected T-cells against CD19 have demonstrated long-term durable remissions in patients with B-cell leukemia and lymphoma, indicating that CAR T-cell therapy is a promising approach for refractory malignancies. Signaling lymphocytic activation molecule F7 (SLAMF7, also called CS1) is highly expressed on multiple myeloma (MM) tumor cells and is present in only a subset of hematopoietic cells among normal tissues. Because of its high expression on MM tumor cells and restricted expression in normal cells, SLAMF7 is a potential target for CAR T-cell therapy approach in MM. We had previously demonstrated that allogeneic “off-the-shelf” CAR T-cells lacking the ability to induce graft versus host disease could be generated for universal use by inactivating the TCRα constant (TRAC) gene using TALEN® gene editing technology. We also demonstrated that to minimize the risk of fratricide of SLAMF7-specific CAR+ T-cells, SLAMF7 could be inactivated by TALEN® in the T-cells prior to introduction of the CAR construct (Galetto et al., ASH 2015, Abstract 116). Here, we report the efficacy of these double KO (TRAC and SLAMF7) SLAMF7-specific universal CAR T cells (UCARTCS1) against MM in in vitro and in vivo studies. Methods: We tested the efficacy of UCARTCS1 cells against MM cell lines and primary tumor cells from MM patients for their capacity to specifically a) degranulate when co-cultured with MM tumor cells as determined by CD107a assay, b) lyse MM cell lines and primary MM cells in in vitro cytotoxicity assay, c) produce cytokines in culture supernatants, d) proliferate in presence of MM cells as determined by CFSE proliferation assay, and e) eradicate primary MM tumors in a patient-derived xenograft model as determined by serum tumor immunoglobulin (M-protein) levels and survival analysis. Results: UCARTCS1 but not control double KO T-cells (lacking SLAMF7 CAR) specifically lysed the MM cell line, MM.1S (median, 93% lysis; range, 78-98% with UCARTCS1 vs. median, 17%; range, 15-47% with control T-cells; n=10). UCARTCS1 cells similarly induced significant lysis of tumor cells from primary MM samples (n=10) (median 59%; range, 20-90%) compared to control T cells (median 9%; range, 0-36%). In agreement with this, we observed specific degranulation in both CD4+ and CD8+ UCARTCS1 cells but not control T-cells in presence of MM.1S cells and primary MM tumor cells. In addition, significant and specific proliferation of both CD4+ and CD8+ UCARTCS1 cells but not control T-cells was observed when they were co-cultured with MM.1S or primary MM tumor samples (n=8). Analysis of culture supernatants for ten cytokines (IFN-γ, GM-CSF, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, and TNF-α) showed that UCARTCS1 cells primarily produced IFN-γ and GM-CSF in presence of primary MM tumor cells (n=6), indicating a Th1/Tc1 response. To test the efficacy of UCARTCS1 cells in vivo, we injected 1x106 primary MM tumor cells into human fetal bone implanted under the skin of NSG mice. After the tumor has been established for 6 to 8 weeks and the serum M-protein was sufficiently elevated, mice were treated intravenously with either 10x106 total cells/mouse of UCARTCS1 or control T-cells. Mice treated with control T-cells developed gradual increase in M-protein levels (median, 339 µg/ml; range, 100-700 µg/mL) whereas the M-protein levels rapidly became undetectable in the mice treated with UCARTCS1 cells and remained undetectable until they were euthanized at approximately 50 days after adoptive transfer. Conclusion: Our results demonstrated that UCARTCS1 cells were highly cytotoxic against primary MM tumor cells in both in vitro and in vivo studies. In addition, UCARTCS1 cells specifically degranulated, produced Th1/Tc1 cytokines, and proliferated in response to primary MM tumor cells. These data provide a rationale for evaluating UCARTCS1 cells as a universal “off-the-shelf” allogeneic CART product in patients with MM. This abstract is also being presented as Poster A46. Citation Format: Rohit Mathur, Zheng Zhang, Jin He, Roman Galetto, Agnes Gouble, Isabelle Chion-Sotinel, Stephanie Filipe, Annabelle Gariboldi, Tanooha Veeramachaneni, Elisabet Manasanch, Sheeba Thomas, Hans C. Lee, Krina Patel, Donna Weber, Richard Eric Davis, Robert Orlowski, Julianne Smith, Jing Yang, Sattva S. Neelapu. Targeting multiple myeloma with universal SLAMF7-specific CAR T-cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR01.

Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab.

Monoclonal antibodies (elotuzumab and daratumumab) are the newest class of drugs that have proven to be efficacious antimyeloma agents. Although daratumumab, a CD38 monoclonal antibody, has established its efficacy as a single agent and in combination with immunomodulatory agents and proteasome inhibitors, elotuzumab (signaling lymphocytic activation molecule F7 monoclonal antibody) has proven activity in combination with lenalidomide and dexamethasone. Infusion-related reactions (respiratory and nonrespiratory) seem to be a common theme of adverse events with monoclonal antibodies, although the relative incidence differs across these two agents. Identifying the appropriate pre- and postinfusion medication strategies can help lower the rates of infusion-related reactions and facilitate reduction in infusion times. In this article, we review the incidence of the infusion-related reactions with elotuzumab and daratumumab and their clinical activity in myeloma, review our institutional experience of management of infusion-related reactions, and provide some practical mitigation strategies to reduce their incidence.

Preliminary Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) and after myeloablative AuSCT in patients (pts) with multiple myeloma (MM) (Attal et al. NEJM 2012, McCarthy et al. NEJM 2012,). Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of pts with MM who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report preliminary results of the primary (PFS) and secondary (overall survival and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 28 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2 and q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=27 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until progression. LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC The primary endpoint of the study is PFS, defined as the time from AuSCT to clinical progression or death (whichever occurs first), or the time of last contact. Secondary objectives include best response, overall survival, incidence of second primary malignancies and adverse event (AE) profile. Total enrollment of 100 pts is planned. Pts will be followed for 48 months after the last patient is enrolled in the trial. Eligible pts had received no more than 2 lines of induction therapy, and were between 60-210 days post-AuSCT. Results: Patients (n=55) have been treated for a median of 14 cycles (2-30). At study entry, 13 pts (24%) had complete response (CR), 27 (49%) had very good partial remission (VGPR), 14 (25%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 28 pts (51%), VGPR in 23 pts (42%) and PR in 4 pts (7%). For those who have converted to CR on study, median time to CR has been 5 months. Of 14 pts in CR who have been tested for MRD while on study, 13 are negative by flow cytometry (minimum of 2 million cells evaluated; sensitivity 10 -4-10-5). Two of these 13 have converted from VGPR to MRD negativity at 4 and 14 months on study, respectively. With a median follow up of 21 months, 95% of pts (n=52) remain alive. Three pts (all with high risk disease) had disease progression at 4 (del 17p), 9 (t [4;14]), and 13 (gain 1q) months; of these, 2 have died of progressive disease while receiving salvage therapy. One patient, in VGPR, died on study after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Two pts withdrew for logistical reasons; 2 have been taken off study per physician discretion (prolonged cytopenias (1), drug rash (1)). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 35% (16), thrombocytopenia 9% (4), febrile neutropenia 7% (3), and anemia 7% (3). Grade 3-4 non-Hematologic AEs (no. of pts): diarrhea 17% (8), fatigue 17% (8), pneumonia 15% (7), other infections 15% (7), peripheral neuropathy 11% (5), myalgias 9% (4), nausea/vomiting 7% (3), maculopapular rash 4% (2), dizziness 4% (2), edema 2% (1), memory impairment 2% (1). Renal cell carcinoma was diagnosed in 1 patient, 15 months after removal from study for disease progression. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 44% of 55 pts have had improvement in quality of response while on therapy, including 28% who have converted to CR and 24% who have tested MRD negative. The number of pts who have experienced improvement on study may, in fact, be underestimated in this analysis due to elotuzumab interference with measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Disclosures Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Shah: Kayopharm: Employment. Lee: Pimera Inc: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity9s Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Manasanch: merck: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; celgene: Consultancy; takeda: Consultancy; quest diagnostics: Research Funding. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity9s Board of Directors or advisory committees.

Monoclonal Antibody: A New Treatment Strategy against Multiple Myeloma

2015 was a groundbreaking year for the multiple myeloma community partly due to the breakthrough approval of the first two monoclonal antibodies in the treatment for patients with relapsed and refractory disease. Despite early disappointments, monoclonal antibodies targeting CD38 (daratumumab) and signaling lymphocytic activation molecule F7 (SLAMF7) (elotuzumab) have become available for patients with multiple myeloma in the same year. Specifically, phase 3 clinical trials of combination therapies incorporating daratumumab or elotuzumab indicate both efficacy and a very favorable toxicity profile. These therapeutic monoclonal antibodies for multiple myeloma can kill target cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent phagocytosis, as well as by direct blockade of signaling cascades. In addition, their immunomodulatory effects may simultaneously inhibit the immunosuppressive bone marrow microenvironment and restore the key function of immune effector cells. In this review, we focus on monoclonal antibodies that have shown clinical efficacy or promising preclinical anti-multiple myeloma activities that warrant further clinical development. We summarize mechanisms that account for the in vitro and in vivo anti-myeloma effects of these monoclonal antibodies, as well as relevant preclinical and clinical results. Monoclonal antibody-based immunotherapies have already and will continue to transform the treatment landscape in multiple myeloma.

Emerging combination therapies for the management of multiple myeloma: the role of elotuzumab.

Treatment options for patients with multiple myeloma (MM) have increased during the past decade. Despite the significant advances, challenges remain on which combination strategies will provide the optimal response for any given patient. Defining optimal combination strategies and corresponding companion diagnostics, that will guide clinical decisions are required to target relapsed or refractory multiple myeloma (RRMM) in order to improve disease progression, survival and quality of life for patients with MM. Elotuzumab is a humanized monoclonal antibody that targets signaling lymphocytic activation molecule F7 (SLAMF7), approved by the US Food and Drug Administration (FDA) in 2015 and the European Medicines Agency in 2016 for the treatment of MM. SLAMF7 is expressed in normal and malignant plasma cells and has lower expression on natural killer (NK) cells. Experimental evidence indicates that elotuzumab exhibits anti-myeloma activity through 1) antibody-dependent cell-mediated cytotoxicity, 2) enhancing NK cells cytotoxicity and 3) interfering with adhesion of MM cells to bone marrow stem cells (BMSCs). Although elotuzumab has no single agent activity in patients with RRMM who have received one to three prior therapies, the combination of elotuzumab with anti-myeloma agents, such as immunomodulatory drugs-lenalidomide, or proteasome inhibitors (PIs)-bortezomib, remarkably improved the overall response rates and progression-free survival in MM patients with only minimal incremental toxicity. In brief, the clinical data for elotuzumab indicate that targeting SLAMF7 in combination with the use of conventional therapies is feasible and effective with a tolerable safety profile for the treatment of RRMM.