Investigating macrophage function as a mechanism of resistance to daratumumab in relapsed refractory multiple myeloma patients.

e20547 Background: Daratumumab (Dara), an anti-CD38 antibody, has a variety of Fc-dependent immune effector mechanisms of action including macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). However, it remains unclear which mechanism, when disrupted, drives in vivo resistance. Given widespread use of this agent for treatment of multiple myeloma, identifying how to overcome Dara resistance has become an urgent clinical need. We hypothesized that inhibiting macrophage activity, via increased plasma cell surface expression of the CD47 “don’t eat me” signal, could be a mechanism of acquired Dara resistance. Methods: We retrospectively identified 11 patients with relapsed refractory multiple myeloma who progressed on Dara and had sequential bone marrow core biopsies before and after Dara with both samples containing > 20% plasma cells. Nine patients had sufficient material for analysis. Core biopsy slides were stained and analyzed for expression of CD47 (H-scoring for total intensity on plasma cells, as well as annotation of membrane vs. cytosolic localization), CD68 (cell counts of macrophages), and CD4/CD8/FOXP3 triple stain (cell counts of CD4 and CD8 effector and regulatory T-cells). Results: Median age was 57 years. Median R-ISS stage was 2. Two patients had high-risk cytogenetics at diagnosis. Median time from diagnosis to progression on Dara was 56.3 months (95% CI 37.43 – 88.92). Median overall survival was 69.5 months (95% CI: 46.5 – 97.1). Plasma cells in all samples expressed CD47 (H-score median = 96, range 43 - 290). However, in contrast to our hypothesis, there was no significant change in CD47 H-score at progression on Dara (H-score median = 100, range 29 – 140). Furthermore, we observed no significant change in CD68+ macrophage counts nor CD68+ localization at Dara progression. We did note a trend toward CD47 expression shifting from membrane to cytosol at Dara resistance ( p = 0.14). Consistent with prior studies, in our cohort we observed no influx in Tregs but a markedly increased CD8/CD4 ratio at resistance ( p = 0.01). Conclusions: In vitro and murine studies have proposed ADCP as an important mechanism of Dara efficacy. However, we did not observe signatures of resistance in patients being driven by this pathway. Our work suggests that anti-CD47 therapy, leading to activation of macrophages to eliminate tumor cells, will potentially be efficacious for both the Dara-naïve and Dara-refractory settings.

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Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function

Blood ◽

10.1182/blood-2011-06-364521 ◽

2012 ◽

Vol 119 (9) ◽

pp. 2074-2082 ◽

Cited By ~ 33

Author(s):

Yu-Tzu Tai ◽

Holly M. Horton ◽

Sun-Young Kong ◽

Erik Pong ◽

Hsing Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Surface Expression ◽

Cell Surface Expression ◽

Immune Effector ◽

Bone Marrow Plasma ◽

Therapeutic Monoclonal Antibodies

Abstract HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance FcγR binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti-HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B–dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via FcγR-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM.

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The Anti-Kappa Monoclonal Antibody MDX-1097 Synergizes with Immunomodulatory Drugs to Enhance Antibody-Dependent Cell Cytotoxicity of Multiple Myeloma Cells

Blood ◽

10.1182/blood.v120.21.4012.4012 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4012-4012

Author(s):

Andrew R Cuddihy ◽

Parisa Asvadi ◽

Rosanne Dunn ◽

Tiffany T. Khong ◽

Andrew Spencer

Keyword(s):

Cell Death ◽

Plasma Cells ◽

Surface Expression ◽

Cell Surface Expression ◽

Immune Effector ◽

Effector Cells ◽

Dependent Cell ◽

In Vitro Treatment

Abstract Abstract 4012 Multiple Myeloma (MM) is a cancer caused by the proliferation of malignant clonal plasma cells in the bone marrow and accounts for 10% of all hematologic malignancies. Recent advances have been made in the treatment and management of MM, however, despite these advances the majority of patients will ultimately relapse and die from their disease within 3–5 years from diagnosis. Several novel therapeutic approaches, including the use of antibody-based therapies, are being investigated to further improve the treatment of MM. MDX-1097 is a chimeric monoclonal antibody being assessed as a single agent in a Phase 2 clinical trial for the treatment of kappa light-chain restricted (κ-type) MM. MDX-1097 binds to the kappa myeloma antigen (KMA), a tumor-specific membrane-associated protein expressed on malignant plasma cells from patients with K-type MM. Previously we have demonstrated that MDX-1097 exerts its anti-tumour effects through multiple mechanisms, including antibody-dependent cell cytotoxicity (ADCC) in the presence of either normal human peripheral blood mononuclear cells (PBMCs) or purified natural killer (NK cells). The immunomodulatory drugs (IMiDs) lenalidomide (Revlimid) and pomalidomide (Actimid) are currently in use or being assessed for the treatment of MM. These IMiDs have been shown to exert their anti-tumor effects both directly, via apoptotic mechanisms, and indirectly via a number of different mechanisms including the augmentation of NK-dependent cellular cytotoxicity. In this study we report that IMiDs and MDX-1097 co-operate to promote enhanced ADCC of MM cells. In vitro treatment of normal PBMCs with IMiDs led to a 1.4-fold higher level of ADCC-mediated cell death of MDX-1097 spiked JJN3 cells (a κ-type MM cell line) compared with vehicle-treated PBMCs from the same donor. Similarly, in vivo lenalidomide exposed PBMCs isolated from a MM patient were, on average, 1.8-fold more effective in killing MDX-1097 spiked JJN3 cells in vitro compared to PBMC obtained from the same patient prior to lenalidomide treatment. Treatment of JJN3 cells with IMiDs resulted in significantly increased cell surface expression of KMA (lenalidomide: 1.9-fold, p < 0.001; pomalidomide: 2.3-fold, p < 0.01). These IMiD-treated JJN3 cells, when spiked with MDX-1097 were 1.7-fold more susceptible to ADCC-mediated cell death in the presence of untreated PBMCs, compared to JJN3 cells treated with vehicle alone. This difference in sensitivity to ADCC mediated cell death is presumably due to increased KMA expression resulting in more binding sites for MDX-1097, therefore facilitating recruitment of PB immune effector cells. Furthermore, combining IMiD-treated PBMCs with IMiD-treated, MDX-1097 spiked JJN3 cells resulted in a further increment in ADCC-mediated JJN3 cell death. This study demonstrates that in vivo and in vitro treatment of PBMCs with IMiDs engages the PB immune effector cells, leading to increased ADCC-induced κ-type MM cell death in vitro in the presence of MDX-1097. IMiDs also increase cell surface expression of KMA, leading to increased MDX-1097 binding and in turn also enhancing ADCC-induced MM cell killing. Our data provides a rationale for the clinical evaluation of a combination therapy involving both IMiDs and MDX-1097 for the treatment of k-type MM. Disclosures: Cuddihy: Immune System Therapeutics Ltd: Research Funding. Asvadi:Immune System Therapeutics Ltd: Employment. Dunn:Immune System Therapeutics Ltd: Employment, Equity Ownership. Spencer:Immune System Therapeutics Ltd: Research Funding.

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A Monoclonal IgM Antibody With Specificity To Heat Shock Protein GRP78/BIP Shows Anti- Myeloma Activity In Vitro and In Vivo, Synergy In Combination With Lenalidomide and Safety In a Pilot Phase I Study

Blood ◽

10.1182/blood.v122.21.3213.3213 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3213-3213

Author(s):

Leo Rasche ◽

Stephanie Braendlein ◽

Johannes Duell ◽

Stefan Knop ◽

Valentina Dubljevic ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Phase I ◽

Plasma Cells ◽

Pilot Phase ◽

Myeloma Cells ◽

Refractory Multiple Myeloma ◽

Igm Antibody

Abstract Monoclonal antibodies have entered the therapy of multiple myeloma (MM) and are currently being evaluated in phase I-III trials. PAT-SM6 is a fully human IgM antibody that specifically binds to a cancer-specific cell surface variant of the chaperone molecule glucose regulated protein 78 (GRP78). Finding a GRP78 cancer-specific form on the surface of cancer cells, but not normal cells in vivo, presents an opportunity for cancer-specific targeting. This antibody is able to specifically target primary myeloma cells without showing cross-reactivity to healthy tissues (including plasma cells from healthy donors). Moreover, antibody treatment in vitro led to apoptosis in primary myeloma cells (Rasche L; PLOS One 2013). In vitro,PAT-SM6 was combined with Lenalidomide and/or Bortezomib and Dexamethasone in double and triple combinations on myeloma cell lines. Synergistic and additive cytotoxic effects were analyzed using the Chou-Talalay method. All double and triple combinations showed synergistic effect with a combination index (CI) <1. In all double combinations, low doses of agents appear more effective than high doses. In triple, PAT-SM6 + Dexamethasone + Lenalidomide seem to be the most efficient combination (CI from 0.005 to 0.011). In vitro data is further supported by positive in vivodata using PAT-SM6 in a 5T33 multiple myeloma mouse model. Upon injection of 5T33 cells mice developed multiple myeloma disease with clinical, biological and genetic characteristics similar to those of the human disease. A total of 6 doses PAT-SM6 were given i.p. followed by the collection of serum and bone marrow samples. Doses >10mg/kg resulted in a significant reduction of plasma cells in the bone marrow (up to 54%) and a reduction of blood levels (up to 48%) of M protein. No cytotoxicity was observed. Based on these results we performed a Phase I clinical trial to examine the tolerability and safety of the PAT-SM6 antibody in patients with relapsed / refractory multiple myeloma. A pilot Phase I dose-escalating study was initiated (NCT01727778). Relapsed myeloma patients according to IMWG criteria were treated in different dose cohorts (0.3, 1,3 and 6mg/kg/dose) with at least four doses of PAT-SM6 as single agent in a two week cycle. A serological staging was performed on day 36. At the date of the abstract submission 9/12 subjects were treated. PAT-SM6 therapy was very well tolerated. No dose limiting toxicity (DLT), no related SAE and no related adverse events greater than grade 3 were observed. Mild leucopenia seemed to be a specific side effect. At date of submission 8 patients are evaluable for response. Two out of 8 patients showed stable disease according to IMWG criteria. In summary, PAT-SM6 provides a very promising approach for the immune therapy of patients with relapsed and refractory multiple myeloma. Disclosures: Braendlein: Patrys Ltd: Consultancy. Dubljevic:Patrys Ltd: Employment. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Topp:Patrys Ltd: Honoraria.

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Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

Applied Sciences ◽

10.3390/app11104451 ◽

2021 ◽

Vol 11 (10) ◽

pp. 4451

Author(s):

Coralia Cotoraci ◽

Alina Ciceu ◽

Alciona Sasu ◽

Eftimie Miutescu ◽

Anca Hermenean

Keyword(s):

Multiple Myeloma ◽

Survival Rate ◽

Plasma Cells ◽

Inhibition Of Proliferation ◽

In Vivo Experiments ◽

Clonal Proliferation ◽

Hematological Cancers ◽

Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

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IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

10.1101/2021.02.22.431638 ◽

2021 ◽

Author(s):

Kristin Roseth Aass ◽

Robin Mjelle ◽

Martin H. Kastnes ◽

Synne S. Tryggestad ◽

Luca M. van den Brink ◽

...

Keyword(s):

Multiple Myeloma ◽

Oxidative Phosphorylation ◽

Plasma Cells ◽

Inflammatory Diseases ◽

Mitochondrial Respiratory Chain ◽

Gene Signature ◽

Growth And Survival ◽

Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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PD-L1hi plasmablasts limit the T cell response during the acute phase of parasite infections

10.1101/2020.06.10.142067 ◽

2020 ◽

Author(s):

Melisa Gorosito Serrán ◽

Facundo Fiocca Vernengo ◽

Laura Almada ◽

Cristian G Beccaria ◽

Pablo F Canete ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Cell Activation ◽

Mononuclear Cells ◽

Plasma Cells ◽

Chronic Phase ◽

Surface Expression ◽

T Cell Response

ABSTRACTDuring infections with protozoan parasites or virus, T cell immunosuppression is generated simultaneously with a high B cell activation. Here, we show that in T. cruzi infection, all plasmablasts detected had higher surface expression of PD-L1, than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in an antigen-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection express PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. PD-L1hi plasmablasts suppressed T cell response, via PD-L1, in vitro and in vivo. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, which precede the germinal center (CG) response, are a suppressive population in infections that may influence T cell response.Brief summaryPathogens develop different strategies to settle in the host. We identified a plasmablats population induced by pathogens in acute infections which suppress T cell response.

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A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Leukemia ◽

10.1038/leu.2016.388 ◽

2016 ◽

Vol 31 (8) ◽

pp. 1743-1751 ◽

Cited By ~ 86

Author(s):

S Hipp ◽

Y-T Tai ◽

D Blanset ◽

P Deegen ◽

J Wahl ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cell ◽

Plasma Cells ◽

Ex Vivo ◽

Xenograft Model ◽

Selective Lysis ◽

Bispecific T Cell Engager

Abstract B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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Characterization of Nonrandom Chromosomal Gains and Losses in Multiple Myeloma by Comparative Genomic Hybridization

Blood ◽

10.1182/blood.v91.8.3007.3007_3007_3010 ◽

1998 ◽

Vol 91 (8) ◽

pp. 3007-3010 ◽

Cited By ~ 103

Author(s):

Juan C. Cigudosa ◽

Pulivarthi H. Rao ◽

M. Jose Calasanz ◽

M. Dolores Odero ◽

Joseph Michaeli ◽

...

Keyword(s):

Multiple Myeloma ◽

Comparative Genomic Hybridization ◽

Plasma Cells ◽

Comparative Genomic ◽

Genomic Hybridization ◽

Banding Analysis ◽

Chromosomal Changes ◽

Gains And Losses

Clonal chromosomal changes in multiple myeloma (MM) and related disorders are not well defined, mainly due to the low in vivo and in vitro mitotic index of plasma cells. This difficulty can be overcome by using comparative genomic hybridization (CGH), a DNA-based technique that gives information about chromosomal copy number changes in tumors. We have performed CGH on 25 cases of MM, 4 cases of monoclonal gammopathy of uncertain significance, and 1 case of Waldenstrom's macroglobulinemia. G-banding analysis of the same group of patients demonstrated clonal chromosomal changes in only 13 (43%), whereas by CGH, the number of cases with clonal chromosomal gains and losses increased to 21 (70%). The most common recurrent changes detected by CGH were gain of chromosome 19 or 19p and complete or partial deletions of chromosome 13. +19, an anomaly that has so far not been detected as primary or recurrent change by G-banding analysis of these tumors, was noted in 2 cases as a unique change. Other recurrent changes included gains of 9q, 11q, 12q, 15q, 17q, and 22q and losses of 6q and 16q. We have been able to narrow the commonly deleted regions on 6q and 13q to bands 6q21 and 13q14-21. Gain of 11q and deletion of 13q, which have previously been associated with poor outcome, can thus be detected by CGH, allowing the use of this technique for prognostic evaluation of patients, without relying on the success of conventional cytogenetic analysis.

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L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1

The Journal of Cell Biology ◽

10.1083/jcb.200203024 ◽

2002 ◽

Vol 157 (7) ◽

pp. 1223-1232 ◽

Cited By ~ 90

Author(s):

Andrew W. Schaefer ◽

Yoshimasa Kamei ◽

Hiroyuki Kamiguchi ◽

Eric V. Wong ◽

Iris Rapoport ◽

...

Keyword(s):

Surface Expression ◽

Cell Surface Expression ◽

Cross Linking ◽

Cell Contact ◽

Homophilic Binding ◽

Dynamic Regulation ◽

Nonreceptor Tyrosine Kinase ◽

Neuronal Growth Cone

Dynamic regulation of the cell surface expression of adhesion molecules is an important mechanism for controlling neuronal growth cone motility and guidance. Clathrin-mediated vesicular internalization of L1 via the tyrosine-based endocytosis motif YRSL regulates adhesion and signaling by this Ig superfamily molecule. Here, we present evidence that tyrosine-1176 (Y1176) of the YRSL motif is phosphorylated in vivo. The nonreceptor tyrosine kinase (p60src) is implicated in L1-mediated neurite outgrowth, and we find that p60src phosphorylates Y1176 in vitro. Phosphorylation of Y1176 prevents L1 binding to AP-2, an adaptor required for clathrin-mediated internalization of L1. mAb 74-5H7 recognizes the sequence immediately NH2-terminal to the tyrosine-based motif and binds L1 only when Y1176 is dephosphorylated. 74-5H7 identifies a subset of L1 present at points of cell–cell contact and in vesicle-like structures that colocalize with an endocytosis marker. L1–L1 binding or L1 cross-linking induces a rapid increase in 74-5H7 immunoreactivity. Our data suggest a model in which homophilic binding or L1 cross-linking triggers transient dephosphorylation of the YRSL motif that makes L1 available for endocytosis. Thus, the regulation of L1 endocytosis through dephosphorylation of Y1176 is a critical regulatory point of L1-mediated adhesion and signaling.

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GS-9219 - A Novel Prodrug of the Acyclic Nucleotide PMEG Has Antitumor Activity Against Naive and Melphalan-Refractory Spontaneous Myeloma in Pet Dogs.

Blood ◽

10.1182/blood.v110.11.1508.1508 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1508-1508

Author(s):

Douglas H. Thamm ◽

Daniel B. Tumas ◽

Hans Reiser ◽

Grushenka H.I. Wolfgang ◽

Ilene D. Kurzman ◽

...

Keyword(s):

Multiple Myeloma ◽

Complete Remission ◽

Plasma Cells ◽

Safety Data ◽

Leukemia Cell ◽

Pet Dogs ◽

Naturally Occurring ◽

Treatment Naïve

Abstract Multiple myeloma is an important hematopoietic cancer in humans and pet dogs. While clinical remission can be achieved using currently available antineoplastic agents, eventual drug resistant relapse is common. GS-9219, a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), has been shown to have potent cytotoxic activity in vitro in human lymphoblasts and leukemia cell lines and in vivo in naturally occurring non-Hodgkin’s lymphoma in dogs (naive and refractory). We hypothesized that malignant plasma cells in multiple myeloma similarly would possess the intracellular enzymatic machinery necessary for the activation of GS-9219. To generate proof-of-concept, activity and safety data in multiple myeloma, a pilot study with GS-9219 monotherapy was initiated in pet dogs with naturally occurring chemotherapy-naive or refractory multiple myeloma. Three dogs with spontaneously occurring IgA myeloma (1 naive, 2 melphalan-refractory) have been treated with GS-9219 as a 30-minute intravenous infusion weekly for 2 weeks at 1 mg/kg, then every 3 weeks for another 3 treatments at 0.8 mg/kg (total of five GS-9219 doses). To date, major anti-tumor responses have been observed in all 3 multiple myeloma dogs treated with GS-9219. Two dogs are in complete remission as indicated by normalization of serum paraprotein and complete resolution of hypercalcemia, peripheral cytopenias and bone marrow plasmacytosis. The third currently has a strong partial response (normal marrow and >95% reduction in serum paraprotein). The only significant toxicity noted throughout the study was a single episode of transient neutropenia in one dog which resolved and, after a one week delay, treatment was continued without issue. Assessment of durability of response is currently ongoing, with all dogs remaining in remission to date; one dog has remained in complete remission for more than 5 months following completion of the treatment regimen. In conclusion, GS-9219 has significant anti-tumor activity in spontaneous melphalan-refractory or treatment-naive canine multiple myeloma.

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