Molecular Analysis of RAS-RAF Tyrosine-Kinase Signaling Pathway Alterations in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2876-2876
Author(s):  
Valentina Artusi ◽  
Claudia Haferlach ◽  
Alexander Kohlmann ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Mutation Rate ◽  
Plasma Cell ◽  
Deep Sequencing ◽  
Response To Therapy ◽  
Braf V600e ◽  
Employment Equity ◽  
Available N ◽  
Equity Ownership

Abstract Abstract 2876 Multiple myeloma (MM) is a malignancy of abnormal plasma cells and a correlation with poor outcome has been described for immunoglobulin heavy-chain (IgH) translocations, deletions of 13q or 17p. Thus far, a convincing relationship between specific mutations, disease onset and progression has not been fully established. Aberrant impairment of important signaling pathways can drive oncogenesis and contribute to MM development. We therefore chose to study NRAS, KRAS and BRAF, three members of the RAS-RAF signaling pathway, as well as TP53 and CCND1, two fundamental genes in cell cycle control. We here investigated 41 MM cases to further elucidate molecular mechanisms underlying this disease. Bone marrow (n=35) or, in case of plasma cell leukemia, peripheral blood (n=6) specimens were collected between 12/2006 and 6/2011 and molecular analyses using a deep-sequencing assay (454, Branford, CT) in combination with the 48.48 Access Array technology (Fluidigm, South San Francisco, CA) were performed on mononuclear cells after Ficoll enrichment or magnetic activated plasma cell sorting using anti-CD138 beads (RoboSep, STEMCELL Technologies SARL, France). The cohort included 16 female and 25 male patients at first diagnosis, with a median age of 63 years (range: 33–84 years). Based on fluorescence in situ hybridization (FISH), the cohort was characterized as follows: IgH rearrangements were detected in 54.3% of patients (19/35: n=6 with t(4;14), n=9 with t(11;14), n=3 with t(14;16), n=1 other; data not available: n=5). A deletion 13q14 was present in 64.9% of patients (24/37; data not available: n=4). Trisomy 3 was detected in 48.0% of patients (12/25; data not available: n=16), trisomy 9 was detected in 50.0% of patients (12/24; data not available: n=17), trisomy 11 was detected in 46.4% of patients (13/28; data not available: n=13), and trisomy 15 was detected in 56.2% of patients (9/16; data not available: n=25), respectively. Interestingly, in all cases where FISH data was available (n=36), at least 1 aberration was detectable. Further, we studied the occurrence of somatic mutations in NRAS, KRAS, BRAF, TP53 and CCND1. In our cohort, we detected an overall mutation rate within the RAS pathway of 41.4% (17/41), in line with a recent report (Chapman et al., Nature, 2011). KRAS was the most frequently mutated gene with 21.9% of cases with mutations (9/41 patients), followed by NRAS (19.5%; 8/41 patients). Recently, BRAF V600E mutations have gained clinical interest since they became manageable by targeted treatment in melanoma. Interestingly, Chapman et al. discovered a mutational rate of 4% by sequencing of 161 MM patients (Nature, 2011). Even if BRAF is not a frequently mutated gene in MM, it justifies upfront diagnostic screening since these patients may benefit from new treatments. In our cohort, 2/41 patients harbored BRAF V600E mutations. Moreover, because of their involvement in the same signaling pathway, we also noticed that mutations affecting NRAS, KRAS or BRAF were predominantly mutually exclusive, except for one patient who concomitantly harbored a BRAF and a NRAS mutation. Additionally, we observed an overall molecular TP53 mutation rate of 12.2% (5/41 patients). In these 5 patients, in total 7 mutations (5 missense substitutions; 2 frame-shift mutations) were detected. 1/4 cases concomitantly harbored a deletion of the TP53 gene, as detected by FISH. Finally, we were interested in the analysis of CCND1, which is located on 11q13, a region frequently involved in chromosomal translocations (9/20 IgH translocated cases in our cohort). Here, we were able to detect 2/41 (4.8%) CCND1 mutated cases. Concerning the correlation between IgH rearrangements and molecular aberrations we observed that 21.9% (9/35; n=5 IgH status not available) of patients that were IgH rearranged, concomitantly carried a TP53 or RAS-RAF mutation. In more detail, 2/5 TP53 mutated patients and 50.0% (8/16) RAS-RAF mutated cases concomitantly harbored an IgH rearrangement. Taken together, MM patients are currently stratified in part based on cytogenetic/FISH classification. We demonstrated that deep-sequencing analyses support an additional molecular characterization. In our cohort, all patients carried mutations detected by FISH and 23/41 (56.1%) carried a molecular mutation. Future clinical studies need to confirm the frequencies of these mutations as well as their association with response to therapy and outcome. Disclosures: Artusi: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Grossmann:MLL Munich Leukemia Laboratory: Employment.

scholarly journals Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Proteasome Inhibitor Based Therapy at First Relapse in Routine Clinical Practice in Germany

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1953-1953 ◽  
Author(s):  
H. Tilman Steinmetz ◽  
Moushmi Singh ◽  
Andrea Lebioda ◽  
Aurelien Mantonnier ◽  
Leah Fink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Treatment Duration ◽  
Employment Equity ◽  
Available N ◽  
Median Treatment ◽  
Median Treatment Duration ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership ◽  
Patient Profiles

Abstract Background: Proteasome inhibitors (PI) represent an important therapeutic advance in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). In 2017, three distinct PIs (bortezomib [BTZ], carfilzomib [CFZ] and ixazomib [IXA]) were available in Germany but real-world data describing their usage was scarce. Aim: To describe characteristics and treatment experience of PI-treated patients with RRMM in Germany. Methods: A national retrospective medical chart review included consecutive patients treated with at least one dose of PI-based regimen in participating hospitals/centers across Germany between January and June 2017. The following data were extracted until April 2018 or death of patient, whichever occurred first: patient demographics, disease characteristics and treatment history at diagnosis and at initiation of PI-based therapy. Physician assessed treatment response were also collected. Results: Physicians from 44 participating centers extracted 302 patient charts, including 219 patients in 2nd line (2L) and 83 in 3rd line treatment (3L), as shown in Figure 1. Results for 2L patients are described below (Table 1, Figure 2): BTZ-treated patients represented 42% of patients (n=92) with a PI-based therapy in 2L. BTZ was often combined with dexamethasone (dex) alone (77%). Median age was 74 years and 56.5% had an ECOG status ≥2 at 2L initiation. Most patients (86%) did not receive a prior transplant. Median treatment duration was 6 months among 40 patients who completed 2L; based on 38 narratives, 2L was ended as planned (47.4%). Where response was available (n=83), 25% of patients achieved a complete response/very good partial response [CR/VGPR]. Median time to next treatment (TTnT) was 7.5 months for 12 patients who moved to 3L. Patient profiles differed in terms of prior treatment exposure: 22% of patients had been treated with a BTZ-based therapy in both 1L and 2L and 62% switched therapies from 1L lenalidomide (len) to BTZ. None of the patients receiving len in 1L were transplanted. A CR/VGPR was achieved by 65% of prior BTZ-treated patients (13/20) and 30% of patients with prior len therapy (17/57). CFZ-treated patients: 48% (n=106) of patients received CFZ-based therapy in 2L. Of those, 56% (n=59) received CFZ in combination with len/dex (KRd) and 44% (n=47) with dex alone (Kd). Median age was 68 years, 60.4% had an ECOG status of 0-1 at 2L initiation and 49% had received a transplant. In 1L, 82% had received a BTZ-based regimen. Where response was mentioned (n=89), a CR/VGPR was reached in 53% of CFZ-treated patients. Median treatment duration was 6.5 months (24/106). Based on 21 narratives, the main reason for discontinuing CFZ in 2L was disease progression (47.6%). Median TTnT was 9.5 months for 10 patients who moved to 3L. The patient profiles by KRd or Kd combination were as follows: at KRd initiation, median age was 65 years, 10.2% of patients had an ECOG status ≥2 and 72.9% were transplanted. At Kd initiation, median age was 71 years, 76.6% of patients had an ECOG ≥2 and 19.1% were transplanted. IXA-treated patients (n=21) represented only 10% of PI-treated patients in 2L. Median age was 66 years, 71.4% had an ECOG status of 0-1 at 2L initiation, 33% were transplanted, and 72% had received a BTZ combination in 1L. Information on response was premature as it was only available for 13 patients with no CR reached (VGPR 77%). Median treatment duration was 4 months (n=9) and median TTnT was 10 months for 4 patients who moved into 3L. Limitation: The main limitation of the study was the sample size of IXA-treated patients due to open inclusion criteria to select patient charts. This analysis was not powered to compare between PIs. Hence, results are descriptive of the clinical experience with PI-based therapy to date and reflect current treatment practices in Germany in 2017. Conclusion: In Germany, distinct patient characteristics are observed in clinical practice by selected PI-based therapy. Patients treated with novel PI agents in 2L are generally younger and more transplanted than bortezomib-treated patients; these appear to be important considerations when tailoring therapy in RRMM. In addition, the choice between triplet or doublet therapy for CFZ-based combinations seems to reflect prior transplant status and patients' overall functional performance. Evidence suggests that use of novel PI agents such as CFZ can translate into deeper response in 2L. Disclosures Steinmetz: Amgen, Celgene, Novartis, Vifor: Research Funding; Amgen; BMS, Celgene, Hexal-Sandoz, Medice, Novartis; Janssen-Cilag; Pharmacosmos; Pfizer, Vifor; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, Amgen, Bayer, Celgene, Janssen-Cilag, Novartis: Other: Travel grants. Singh:Amgen: Employment, Equity Ownership. Lebioda:Amgen: Employment, Equity Ownership. Mantonnier:Kantar Health: Employment, Other: Received funding to conduct this research. Fink:Kantar Health: Employment, Other: Received funding to conduct this research. Rieth:Amgen: Employment, Equity Ownership. Suzan:Amgen: Employment, Equity Ownership. Gonzalez-McQuire:Amgen: Employment, Equity Ownership.

scholarly journals Real-Time Genomic Profiling Identifies Novel Mutations and Improved Therapy for Histiocytoses

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2723-2723
Author(s):  
Lynn Lee ◽  
Anjelika Gasilina ◽  
Jayeeta Roychoudhury ◽  
Jason Clark ◽  
Francis X McCormack ◽  
...  
Keyword(s):  
Real Time ◽  
Response To Therapy ◽  
Braf V600e ◽  
Biological Behavior ◽  
Inadequate Response ◽  
Genomic Profiling ◽  
Employment Equity ◽  
Mek Inhibitors ◽  
Equity Ownership ◽  
Mutant Forms

Abstract BACKGROUND: The histiocytic disorders include several heterogeneous diseases including Langerhans cell histiocytosis (LCH,) juvenile xanthogranuloma, Erdheim-Chester disease (ECD,) and Rosai-Dorfman disease. These conditions have variable clinical courses and can be refractory to contemporary therapy, resulting in end-organ damage or even death. The etiopathogenesis of LCH and the other histiocytoses remained unclear for decades, until the identification of recurring BRAF V600E mutations, and more recently mutations in the downstream gene MAP2K1 (encoding the enzyme MEK) in LCH and ECD. Given the high risk of recurrence and the unpredictable response to therapy in some patients, we sought to characterize the genomic landscape of histiocytic lesions in patients in real-time. Our principal goal was to select alternative treatments for patients with inadequate response to standard therapies. As a secondary goal, we aimed to further characterize the biological effects of MAP2K1 mutations found in LCH and ECD, and determine their susceptibility to targeted therapies. METHODS AND RESULTS: We used a hybrid capture-based sequencing platform to molecularly profile eighty-five patient samples from patients with one of the above diagnoses. Fifteen patient samples (18%) harbored the BRAF V600E point mutation, and four LCH patients carried a novel 5 or 6 amino-acid in-frame deletion (indel) in BRAF (N486_P490del or N486_T491>K.) Eleven patient samples (13%) harbored activating mutations in MAP2K1. Additional recurrently altered genes included NRAS, KRAS and CDKN2A/B. Transcriptomic profiling also identified several patients with recurrent ALK gene fusions, previously described in other malignancies and recently also identified in histiocytosis not-otherwise-specified. One patient with multisystem LCH with CNS involvement was found to have a BRAF indel. She declined systemic chemotherapy, but agreed to treatment with a targeted agent. Based on the likelihood of resistance to BRAF V600E-specific inhibitors, we started treatment with the MEK inhibitor Trametinib resulting in resolution of disease-associated lymphadenopathy within days, and improvement of CNS symptoms as well. She remains in remission 4 months after the initiation of treatment. In two children, multi-system refractory LCH progressed to secondary HLH (hemophagocytic lymphohistiocytosis). Both demonstrated the presence of BRAF-V600E and their disease promptly responded to the BRAF inhibitor Dabrafenib. We then characterized the biological behavior of the MAP2K1 mutations using retroviral transduction in order to stably express these mutations in NIH/3T3 and BaF/3 cells. We demonstrate that these mutations all result in constitutive activation at baseline, as evidenced by increased phosphorylation of the target ERK. These mutant forms of MAP2K1 also express sustained activation of ERK in response to EGF stimulation. Additionally, we tested clinically available MEK inhibitors against mutant forms of MAP2K1, and show that all result in a dose-dependent decrease in phospho-ERK levels in vitro, supporting our hypothesis that MEK inhibition is a valid therapeutic approach in the histiocytic neoplasms. Finally, we demonstrate with an animal model that MAP2K1 is sufficient to induce disease. Using the cre-lox recombinase system in transgenic mice, we selectively express an activated form of MEK in CD11c-positive cells, which is largely restricted to the dendritic cell/macrophage lineage. These mice developed normally, but by a median of 17 weeks of age, mice became moribund and on necropsy exhibited hepatosplenomegaly with extensive infiltration of spleen, liver and lungs with CD68+ macrophages. DISCUSSION: Genomic profiling identified mutations in majority of patients, including a novel BRAF indel. We further show that these mutations result in activation of the MAP kinase pathway, and that activated MAP2K1 is capable of transforming hematopoietic cells resulting in a multisystem histiocytic disorder in mice. Finally, we demonstrate that available MEK inhibitors efficiently block disease-associated mutations. We propose that all patients with histiocytic neoplasms undergo comprehensive genomic profiling in order to identify potential causal mutations, and clinical trials for histiocytoses include MEK inhibitors in relapsed/refractory disease or even as upfront therapy. Disclosures Ali: Foundation Medicine: Employment, Equity Ownership. Bailey:Foundation Medicine, Inc: Employment, Equity Ownership. Stevens:Foundation Medicine Inc.: Employment, Equity Ownership. Ross:Foundation Medicine: Employment, Equity Ownership. Miller:Foundation Medicine: Employment, Equity Ownership.

scholarly journals Comparative Analysis of sSLAMF7, sBCMA, and M-Protein As Prognostic, Predictive, and Pharmacodynamic Biomarkers in Relapsed/Refractory Multiple Myeloma Treated with Pomalidomide and Dexamethasone +/- Elotuzumab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1853-1853
Author(s):  
Ann Forslund ◽  
Hao Tang ◽  
Chunzhe Duan ◽  
Mihaela Popa-McKiver ◽  
James R. Berenson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Comparative Analysis ◽  
Research Funding ◽  
Tumor Burden ◽  
Response To Therapy ◽  
Risk Category ◽  
Employment Equity ◽  
Mixed Effect ◽  
Equity Ownership ◽  
Monitoring Response

Despite advances in therapy, multiple myeloma (MM) remains largely incurable, and therefore identification of predictive or prognostic biomarkers is important for optimal treatment (tx) selection and detection of early progression. Elotuzumab (Elo) is an IgG1 monoclonal antibody that targets SLAMF7 on MM cells and is approved for relapsed and/or refractory (RR) MM in combination with lenalidomide or pomalidomide and dexamethasone (Pd). BCMA, a cell surface protein with expression fairly restricted to MM cells, is being investigated in clinical studies for multiple targeting strategies. Soluble forms of SLAMF7 (sSLAMF7) and BCMA (sBCMA) are elevated in serum from patients (pts) with MM and are proposed surrogate markers of tumor burden. Serum monoclonal protein (M-prt) is the standard marker to assess tumor burden and monitor response and progression in pts with MM. However, the variable and slow rate of M-prt turnover may complicate early detection of relapse or response to therapy. Previously, we demonstrated that Elo-containing regimens show a more pronounced decrease in free sSLAMF7 compared with non-Elo regimens (Postelnek J et al. Blood 2015). Changes in sBCMA have not been reported for pts receiving Elo-based regimens in clinical trials, but high levels of sBCMA have been associated with poor outcomes for pts with MM receiving a variety of tx. This is the first comparative analysis of these serum markers in a randomized trial to assess their potential utility for predicting and monitoring response to Elo-containing regimens. Methods: Of the 117 pts randomized in ELOQUENT-3 (NCT02654132), serum samples were available for 106 (sSLAMF7) and 51 (sBCMA) pts (further data on sBCMA will be generated). Concentrations of sSLAMF7 and sBCMA were measured by ELISA at Cycle [C] 1, Day [D] 1, 8, 15, and 22; C2D1, and C3D1. Serum M-prt was measured by standardized SPEP at C1D1, C2D1, and C3D1 at a central laboratory and was available for all pts. Associations between baseline (BL) sSLAMF7/sBCMA and prognostic factors at study entry (ISS, number of prior therapies, MM risk category; assessed using Kruskal-Wallis rank sum tests) or efficacy in each study arm (responder vs non; median PFS) were assessed. Hazard ratios (HR) for PFS were calculated using univariate Cox models and p-values were calculated using log-rank tests. Linear mixed effect models were used to explore dynamics of sSLAMF7 and sBCMA relative to serum M-prt over time for responders and non-responders within each tx arm. Results: At BL, higher sSLAMF7 and sBCMA levels were associated with high-risk disease; higher BL sBCMA levels were also associated with ISS stage III disease. Among pts treated with Pd who had higher BL sSLAMF7 or sBCMA levels there was a trend towards non-response and poorer PFS. No association between BL sSLAMF7 and EPd tx efficacy was observed; however, EPd treated pts with higher BL sBCMA tended to have poorer PFS. Regardless of BL levels of sSLAMF7, PFS was longer with EPd than Pd; this difference was even more substantive in pts with elevated sSLAMF7 (≥median; HR=0.415, p=0.006). Concentration of M-prt at BL did not appear to be associated with response to either tx, but high levels did show a trend for poorer PFS in the Pd arm with no difference observed in the EPd arm. Reduction of both free sSLAMF7 and sBCMA from BL was observed as early as C1D8 in both EPd and Pd arms; the reduction in free sSLAMF7 was more pronounced in the EPd arm than the Pd arm. Greater reductions of sSLAMF7 and sBCMA distinguished responders from non-responders no later than the beginning of the second cycle. Decreases in M-prt did not distinguish responders from non-responders in either arm until Cycle 3, and the reduction was smaller than either sSLAMF7 or sBCMA. Summary: Data from pts enrolled in ELOQUENT-3 show that high BL levels of sBCMA were associated with a trend to poorer PFS in both the Pd and EPd arm. High BL sSLAMF7 levels were also associated with poorer PFS in Pd arm, but not in the EPd arm. A trend toward lower response rate in pts with high BL levels of sSLAMF7 or sBCMA was identified in the Pd arm, but no association was seen in pts receiving EPd. The dynamics of sBCMA and sSLAMF7 revealed an earlier decrease than for serum M-prt, separating responders from non-responders as soon as C1D22. sSLAMF7 and sBCMA may therefore represent a more sensitive parameter for monitoring response to tx in MM, however additional studies are needed to better understand this application. Disclosures Forslund: Gilead Sciences: Equity Ownership; Bristol-Myers Squibb: Employment, Equity Ownership. Tang:Bristol-Myers Squibb: Employment, Equity Ownership. Duan:Bristol-Myers Squibb: Employment. Popa-McKiver:Bristol-Myers Squibb: Employment. Berenson:Incyte Corporation.: Consultancy, Research Funding; Amag: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau. Robbins:Bristol-Myers Squibb: Employment, Equity Ownership.

scholarly journals Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1848-1848
Author(s):  
Maria Karvouni ◽  
Heyue Zhou ◽  
Arnika Kathleen Wagner ◽  
Qiangzhong Ma ◽  
Alamdar H. Baloch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Phase 1 ◽  
Employment Equity ◽  
Multiple Myeloma Patient ◽  
Myeloma Cells ◽  
Car T ◽  
Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5768-5768
Author(s):  
Adekemi Taylor ◽  
Martine Allard ◽  
Cecile Kresja ◽  
Dana Lee ◽  
Greg Slatter
Keyword(s):  
Multiple Myeloma ◽  
Steady State ◽  
Solid Tumors ◽  
Upper Bound ◽  
Myeloid Leukemia ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Mean ◽  
The Relationship ◽  
Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

Impact of Baseline Free Light Chain Ratio (rFLC) On Clinical Outcomes and Change in rFLC During Treatment in Patients with Relapsed/Refractory Multiple Myeloma Treated with Pegylated Liposomal Doxorubicin Plus Bortezomib or Bortezomib Alone.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4778-4778
Author(s):  
Valeria Magarotto ◽  
Anil Londhe ◽  
Keith C. Lantz ◽  
Colin Lowery ◽  
Pieter Sonneveld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Outcomes ◽  
Light Chain ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Free Light Chain ◽  
Controlled Study ◽  
Employment Equity ◽  
Ortho Biotech ◽  
Equity Ownership

Abstract Abstract 4778 Background The serum immunoglobulin-free light chain (sFLC) assay measures levels of free κ and » immunoglobulin light chains. In multiple myeloma (MM), similar to other plasma cell dyscrasias, a secretory dysfunction causes an abnormal sFLC (κ/») ratio (rFLC). The rFLC (normal range: 0.26-1.65) is a requirement for documenting stringent complete remission (sCR) and can be a prognostic indicator in newly diagnosed multiple myeloma (Dispenzieri et al. for the International Myeloma Working Group, Leukemia, 2009). As part of a randomized controlled study in MM (Orlowski et al., JCO 2007), we previously have shown that the normalization of rFLC after the first 2 cycles of pegylated liposomal doxorubicin (PLD) + bortezomib (B) or B alone is associated with a prolonged time to progression (TTP) and higher response rate (RR) among patients with relapsed/refractory MM (Orlowski et al., Blood 2007, abstract #2735). In this analysis, we examined how baseline ratios of sFLC impacted clinical outcomes (TTP and RR), and if sFLC ratios changed over the course of treatment in patients receiving PLD + B or B alone. Methods Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 with B at 1.3 mg/m2 on Days 1, 4, 8, and 11, or B alone on this same dose and schedule, for up to eight 21-day cycles, or at least 2 cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred. Serial serum κ/» measurements were made prior to the start of therapy and at the end of each cycle throughout the entire study using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Results Sera from 491 patients were available for these analyses: 31 patients (6.3%) had a normal baseline rFLC, while 460 patients (93.6%) had an abnormal baseline rFLC (<0.26 or >1.65). Among patients with a normal baseline rFLC, 14 received B and 17 received PLD + B. The RR (≥partial remission) was 5/14 (35.7%) and 5/17 (29.4%), respectively (P=0.73). Mean TTP was 297 days for B vs. not reached for PLD + B (P=0.93, HR 0.92, CI 95%). In patients with an abnormal baseline rFLC, 232 received B and 228 received PLD + B. The RR was 95/232 (40.9%) and 107/228 (46.9%), respectively (P=0.19). TTP was longer and statistically significant for patients who received PLD + B (282 days) vs. B alone (180 days; P=0.001, HR 1.76, CI 95%). For the overall population, TTP was 297 vs. 218 days (P=0.11, HR 0.51, CI 95%) and RR was 10/31 (32.3%) vs 202/460 (43.9%) for normal vs abnormal baseline rFLC groups, respectively. During the course of therapy, there was a trend for an increase in the percentage of patients in whom the baseline rFLC changed from abnormal to normal (Table). This trend occurred in earlier treatment cycles and reached a plateau in later cycles. When only patients who had completed at least 4 cycles of therapy were examined, the same trend was observed (not shown). Conclusion This study showed a correlation between the baseline rFLC and outcomes (TTP and RR) in patients with relapsed/refractory MM treated with PLD + B or B alone. Similar to the overall study results, combination therapy demonstrated better outcomes over B alone in patients with abnormal rFLC at baseline. Regardless of treatment, patients with normal rFLC at baseline had longer TTP but lower RR than patients with abnormal rFLC at baseline, which was possibly due to the small number of patients with normal rFLC at baseline. Disclosures: Londhe: Centocor Ortho Biotech Services, LLC: Employment, Equity Ownership. Lantz:Centocor Ortho Biotech Services, LLC: Employment. Lowery:Centocor Ortho Biotech Services, LLC: Employment, Equity Ownership. Sonneveld:Johnson & Johnson: Consultancy. Bladé:Johnson & Johnson / Janssen-Cilag: Honoraria; Schering-Plough: Honoraria.

The Epitope Targeted by Apoptosis-Inducing ICAM-1 Antibody B11 Is Highly Expressed in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4897-4897
Author(s):  
Markus Hansson ◽  
Niina Veitonmäki ◽  
Anders Lindblom ◽  
Björn Frendéus
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Disease Progression ◽  
Plasma Cells ◽  
Human Tumor ◽  
University Hospital ◽  
Employment Equity ◽  
New Drug ◽  
Equity Ownership

Abstract Abstract 4897 Complex adhesive and non-cognate interactions participate in multiple myeloma disease progression, resistance to apoptosis, and development of drug resistance. In spite of significant recent attempts to develop new drug classes targeting both myeloma and its microenvironment, multiple myeloma remains an incurable disease warranting development of more effective therapies. Applying novel combined target and drug discovery methodology we isolated a human tumor cell apoptosis-inducing antibody (IgG B11) targeting ICAM-1, as previously described. ICAM-1 is a cell adhesion molecule strongly implicated in myeloma pathophysiology, both regarding bone marrow stromal cell mediated disease progression and cell adhesion mediated drug resistance. We here characterize B11 epitope expression by multicolor FACS analysis in 25 patients investigated for multiple myeloma referred to Department of Hematology, Lund University Hospital, Lund, Sweden and 5 healthy controls. The B11 epitope was highly expressed in plasma cells in 5 of 5 patients with myeloma and in 1 of 1 patient with AL (light chain) amyloidosis. A comprehensive preclinical program assessing IgG B11 anti-myeloma activity and evaluating IgG B11 safety has been conducted. Based on these studies, and having received an investigational new drug (IND) approval from the U.S. Food and Drug Administration (FDA), clinical phase I trials with IgG B11 will soon commence. Disclosures Veitonmäki: BioInvent International: Employment. Lindblom:BioInvent International: Employment, Equity Ownership. Frendéus:BioInvent International AB: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Ultra-Deep Next-Generation Sequencing Detects RUNX1 Mutations with Unprecedented Sensitivity and Allows to Monitor Minimal Residual Disease In 116 Samples From MDS and AML Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1691-1691 ◽  
Author(s):  
Alexander Kohlmann ◽  
Vera Grossmann ◽  
Sonja Schindela ◽  
Wolfgang Kern ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Disease Progression ◽  
Deep Sequencing ◽  
Residual Disease ◽  
Initial Diagnosis ◽  
Employment Equity ◽  
Clone Size ◽  
Low Level ◽  
Mutational Burden ◽  
Equity Ownership ◽  
Conventional Methods

Abstract Abstract 1691 RUNX1 (runt-related transcription factor 1) mutations constitute a disease-defining molecular aberration in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Mechanistically, deregulations occur either through balanced translocations or molecular mutations. Importantly, patient-specific RUNX1 mutations have been proposed to represent clinically useful biomarkers to follow disease progression from MDS to s-AML, as well as to monitor minimal residual disease (MRD) during AML treatment. As such, unbiased methodologies are warranted to provide necessary diagnostic sensitivity and throughput. Here, we investigated 116 samples from 25 patients (18 AML and 7 MDS) using next-generation amplicon deep-sequencing. For a longitudinal analysis starting at diagnosis and following the course of treatment peripheral blood (n=20) or bone marrow specimens (n=96) were obtained between 11/2005 and 6/2010. PCR assays targeting the RUNX1 beta isoform were performed with 60 ng of genomic DNA, obtained from mononuclear cells. In median, 5 time points per patient were analyzed with a median time span of 14 months (range: 5 – 34 months). The median sampling interval was 3.2 months. For each patient, one or more molecular mutations were known from standard testing at diagnosis using a combination of denaturing high-performance liquid chromatography and direct Sanger sequencing. In 166 amplicons covering the full spectrum of RUNX1 mutations we applied the 454 small volume Titanium chemistry assay to perform ultra-deep sequencing of specific PCR products (454 Life Sciences, Branford, CT). In median, 3346 reads per amplicon were generated, thereby allowing a highly sensitive assessment of RUNX1 mutational burden in these patients. As such, at 5% diagnostic sensitivity, 167 reads would cover a certain molecular mutation. At a cut-off of 0.5% sensitivity in median 17 reads were remaining for evaluation. First, we evaluated the concordance of NGS and conventional methods for the samples being taken at initial diagnosis. In all 25 patients deep-sequencing analyses concordantly detected the mutations known from conventional methods, i.e. in total 9 missense mutations, 1 nonsense mutation, 2 in-frame alterations, and 13 frameshift alterations. At initial diagnosis, deep-sequencing detected in AML cases the mutations with a median burden of 44% sequencing reads, whereas in MDS cases in median 35% sequencing reads harbored the mutations, respectively. In 2/25 (8%) cases, deep-sequencing detected additional low-level mutations (0.9% and 3.2%) that were not observed by standard techniques. Secondly, we investigated whether the technique of ultra-deep sequencing would be superior to current routine testing methods during follow-up and in detecting MRD. In 7/25 (28%) patients, an increasing clone size was detectable earlier than by conventional methods. Clone sizes with mutations as low as 0.2% - 7.0% of reads were detectable by NGS up to 9 months earlier during course of disease than by conventional methods. In no case did NGS miss mutations known by conventional methods. Overall, in 12/25 (48%) patients, ultra-deep sequencing revealed additional subclones and enabled the quantitative assessment of their respective clone size. In 6/25 (24%) cases this ultra-deep sequencing approach allowed to then quantitatively monitor the changing composition of parallel subclones per patient during treatment and disease progression. In particular, in two MDS patients dominant clones were proven to disappear during course of the disease and existing low-level or novel clones were emerging at s-AML stage. Similarly, in two AML patients dominant clones were suppressed during chemotherapy. Previously existing low-level mutations, already observed at the stage of initial diagnosis, were then detected at relapse with much greater mutational burden. Finally, in 2/25 cases with mutations concomitantly occurring in the same amplicon deep-sequencing was able to delineate monoallelic or biallelic status of the mutation. In conclusion, RUNX1 mutations are useful biomarkers with clinical utility for the detection of MRD in patients with hematological malignancies. We here demonstrated that amplicon-based NGS is a suitable method to accurately detect and quantify the variety of RUNX1 aberrations with high sensitivity and enables an individualized monitoring of disease progression and treatment efficacy. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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