Population Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody, Siltuximab (CNTO 328), in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1365-1365 ◽  
Author(s):  
Lanyi Xie ◽  
Lilian Y Li ◽  
Razelle Kurzrock ◽  
Frits van Rhee ◽  
Xiang Qin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
B Cell ◽  
Treatment Period ◽  
Research Funding ◽  
Castleman’S Disease ◽  
Hodgkin's Lymphoma ◽  
Employment Equity ◽  
Dosing Regimens ◽  
Equity Ownership

Abstract Abstract 1365 Introduction Siltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. Methods PK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. Results The mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. Conclusion The population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures: Xie: Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.

scholarly journals Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1900-1900 ◽  
Author(s):  
Katja Weisel ◽  
Thomas G Hopkins ◽  
Doug Fecteau ◽  
Weichao Bao ◽  
Corinne Quigley ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Research Funding ◽  
Standard Of Care ◽  
Efficacy And Safety ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Correlation Between Serum Ofatumumab Concentrations, Baseline Patient Characteristics and Clinical Outcomes in Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ofatumumab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3433-3433 ◽  
Author(s):  
Anders Österborg ◽  
Birgitte Biilmann Ronn ◽  
Roxanne C Jewell ◽  
Thomas J Kipps ◽  
Jiri Mayer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Pivotal Trial ◽  
Employment Equity ◽  
Baseline Factors ◽  
Equity Ownership ◽  
Univariate Analyses

Abstract Abstract 3433 Poster Board III-321 Introduction Monoclonal antibody (mAb) therapies represent an important clinical advance for patients (pts) with CLL, yet little is known about the pharmacokinetics (PK) and pharmacodynamics of mAb therapy in these pts. Ofatumumab is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity in vitro. Ofatumumab is being evaluated in a pivotal trial for pts with fludarabine-refractory CLL also refractory to alemtuzumab (FA-ref; n=59) or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy (BF-ref; n=79). Overall response rate (ORR; primary endpoint) was 58% in FA-ref and 47% in BF-ref pts at an interim analysis; median progression-free survival (PFS) was 5.7 and 5.9 months, respectively. We evaluated relationships between baseline factors and ofatumumab PK and between PK parameters and treatment outcomes from the pivotal trial. Patients and Methods Pts received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee over 24 weeks of therapy. Blood samples for PK analysis were collected at Dose 1, Dose 8 (last weekly dose), and Dose 12 (last monthly dose). A population PK model was employed that included data from a previous study (Coiffier et al, Blood 2008;111:1094). For Dose 1, Cmax was determined; for Doses 8 and 12, Cmax, Cmin, AUC, clearance (CL), volume of distribution (Vss) and t½ were determined. The relationships between baseline pt characteristics and disease factors and PK parameters were evaluated by multivariate regression analysis. Associations between PK and ORR or PFS were explored using univariate and multivariate logistic regression or Cox regression analyses. Results 90% of the 154 pts received 8 weekly infusions of ofatumumab and 55% received all 12 infusions. PK parameters were similar between FA-ref and BF-ref pts. In multivariate analysis, higher Cmax at Dose 1 was significantly associated with lower % of bone marrow infiltration (p<0.001), lower Rai stage (p=0.002), lower lymphocyte count (p=0.006), smaller BSA (p<0.001) and lower total bilirubin (p=0.013). The majority of responders and non-responders were still receiving treatment at Dose 8; thus, this dose represents an informative time point for analysis. Baseline factors that influenced PK parameters at Dose 8 are shown in the table. Based on univariate analyses, higher Cmax and Cmin at Dose 8 were associated with increased likelihood of response (Table); in addition, significantly higher Cmax, Cmin and AUC were observed in responders versus non-responders (p<0.05 for each; data not shown). Higher Cmax, AUC and Cmin and lower CL at both Doses 8 and 12 were significantly correlated with longer PFS (p<0.05 for each). Based on exploratory multivariate analyses, PK parameters were not independent predictors of ORR or PFS. Conclusions These data demonstrate that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. The pivotal study is ongoing, and further analyses of associations between disease-related factors, PK and treatment response will be performed at study completion. Such analyses will help us to better understand the response kinetics of biological therapy and to optimize the dose. Disclosures Österborg: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Biilmann Ronn:Genmab: Employment. Jewell:GlaxoSmithKline: Employment, Equity Ownership. Kipps:Physicians' Educational Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Mayer:GlaxoSmithKline: Consultancy. Stilgenbauer:GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Hellmann:Novartis, BMS: Consultancy, Honoraria. Robak:GlaxoSmithKline, Roche: Advisory Board, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau. Hillmen:GlaxoSmithKline: Consultancy, Honoraria for Advisory Boards. Trneny:GlaxoSmithKline: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Kozak:GlaxoSmithKline, Amgen: Consultancy. Chan:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Losic:Genmab: Employment, Stock Ownership. Davis:GlaxoSmithKline: Employment, Stock ownership. Wilms:Genmab: Employment, Equity Ownership. Russell:Genmab: Employment, Equity Ownership. Wierda:Genmab, GlaxoSmithKline: Honoraria, Research Funding.

scholarly journals Duohexabody-CD37, a Novel Bispecific Antibody with a Hexamerization-Enhancing Mutation Targeting CD37, Demonstrates Superior Complement-Dependent Cytotoxicity in Preclinical B-Cell Malignancy Models

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4170-4170
Author(s):  
Simone C. Oostindie ◽  
Hilma J. Van Der Horst ◽  
Marije B. Overdijk ◽  
Kristin Strumane ◽  
Sandra Verploegen ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Bispecific Antibody ◽  
Lymphocytic Leukemia ◽  
Single Point Mutation ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Healthy Human ◽  
Complement Dependent Cytotoxicity ◽  
Equity Ownership

Abstract CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a promising therapeutic target for the treatment of B-cell malignancies. Although complement-dependent cytotoxicity (CDC) has proven to be a powerful Fc-mediated effector function for killing hematological cancer cells, CD37 antibody-based therapeutics currently in clinical development are poor inducers of CDC. Here we present DuoHexaBody-CD37, a novel humanized IgG1 bispecific antibody targeting two different CD37 epitopes, with an E430G hexamerization-enhancing mutation, for the potential treatment of B-cell malignancies. The natural process of antibody hexamer formation through intermolecular Fc-Fc interactions between IgG molecules after cell surface antigen binding can be improved by introducing a single point mutation such as E430G in the IgG Fc domain, thereby facilitating more efficient C1q binding and complement activation (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). The hexamerization-enhancing mutation E430G was introduced into two humanized CD37 monoclonal antibodies (mAbs) that bind non-overlapping CD37 epitopes. Different antibody formats and combinations, including the single antibodies, combinations of the mAbs and bispecific mAbs were tested for their capacity to induce CDC and antibody-dependent cellular cytotoxicity (ADCC). The bispecific hexamerization-enhanced antibody variant DuoHexaBody-CD37, showed superior CDC activity compared to the single hexamerization-enhanced mAbs and the combination thereof, both in vitro over a range of different B-cell lines, and ex vivo in tumor cell samples obtained from patients with chronic lymphocytic leukemia (CLL). In a CDC assay using tumor cells obtained from a relapsed/refractory CLL patient who received prior treatment with rituximab, ibrutinib and idelalisib, DuoHexaBody-CD37 induced almost complete lysis (84% lysis at a concentration 100 µg/mL), thereby outperforming the single HexaBody molecules (15% and 23% lysis) and the combination (57%) (Figure 1). In addition to its potent CDC activity, DuoHexaBody-CD37 was also capable of inducing potent ADCC of Daudi cells (EC50 = 12.3 ± 9.5 ng/mL), as assessed using peripheral blood mononuclear cells from 8 healthy human donors in a standard chromium release assay. In assays using whole blood from 6 healthy human donors, DuoHexaBody-CD37 showed efficient B-cell binding and potent and specific depletion of the B-cell population (98% ± 1.3% depletion at 10 µg/mL, EC50 = 0.85 ± 0.284 µg/mL). Furthermore, DuoHexaBody-CD37 induced significant inhibition of tumor growth in vivo in Daudi-luc Burkitt's lymphoma and JVM-3 CLL mouse xenograft models, at doses as low as 0.1 and 1 mg/kg (p<0.05), respectively. In summary, we present a novel therapeutic antibody that, for the first time, combines proprietary DuoBody® and HexaBody® platforms. DuoHexaBody-CD37 induced highly potent CDC and efficient ADCC in preclinical models, suggesting that DuoHexaBody-CD37 may serve as a potential therapeutic mAb for the treatment of human B-cell malignancies. Disclosures Oostindie: Genmab: Employment, Equity Ownership. Van Der Horst:Genmab: Research Funding. Overdijk:Genmab: Employment, Equity Ownership. Strumane:Genmab: Employment, Equity Ownership. Verploegen:Genmab: Employment, Equity Ownership. Lindorfer:Genmab: Research Funding. Cook:Genmab: Research Funding. Chamuleau:Gilead: Research Funding; BMS: Research Funding; celgene: Research Funding; Genmab: Research Funding. Mutis:Gilead: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding; Novartis: Research Funding; OnkImmune: Research Funding. Schuurman:Genmab: Employment, Other: Warrants. Sasser:Genmab: Employment, Equity Ownership. Taylor:Genmab: Research Funding. Parren:Genmab: Equity Ownership; Lava Therapeutics: Employment. Beurskens:Genmab: Employment, Equity Ownership. Breij:Genmab: Employment, Equity Ownership.

scholarly journals Focal Adhesion Kinase Inhibitors Reverse the Stromal Adhesion Phenotype of Ikaros-Mutant B-ALL, Induce Apopotosis, and Synergize with ABL1 Tyrosine Kinase Inhibitors: A New Paradigm for Pathogenesis and Therapy of High-Risk B-ALL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 285-285 ◽  
Author(s):  
Ila Joshi ◽  
Nilamani Jena ◽  
Toshimi Yoshida ◽  
Leto Paraskevopoulou ◽  
Zhihong Zhang ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Focal Adhesion ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Dominant Negative ◽  
Employment Equity ◽  
Equity Ownership ◽  
B Lymphoid ◽  
Inhibitor Treatment

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is a malignancy of precursor B-lymphocytes affecting both children and adults. Deletions and dominant-negative mutations in IKZF1, the gene encoding the Ikaros transcription factor, are found in ~85% of Ph+ B-ALL and in some cases of Ph– B-ALL, and are associated with poor prognosis. Genomic studies of high-risk Ph– or “Ph-like” B-ALLs have revealed frequent mutation and activation of TK genes and signaling pathways. While ABL1 tyrosine kinase inhibitors (TKIs) such as dasatinib and imatinib have been added to chemotherapy regimens for Ph+ B-ALL, over half of these patients will still relapse, which correlates with residual disease burden in the bone marrow (BM) following induction therapy. Hence, new therapeutic strategies are needed for patients with Ikaros-mutant, high-risk Ph+ and Ph– B-ALL. Using mice with a conditional Ikzf1 mutation (Ike5fl) where the recombined allele is similar to the dominant-negative Ik6 mutant found in human B-ALL, we demonstrated recently that Ikaros DNA-binding function is required in the B-lymphoid lineage for transition from the large to small pre-B cell stage of differentiation, and that arrest at this stage of development can give rise to B-ALL (Joshi et al., Nat. Immunol. 2014;15:294). The survival and proliferation of Ikaros mutant pre-B cells is dependent on increased integrin-mediated stromal adhesion and activation of focal adhesion kinase (FAK). FAK is a non-receptor TK, downstream of integrins and growth factor receptors, which plays important roles in cancer stem cell biology, the tumor microenvironment and tumorigenesis. VS-4718 and VS-6063 (defactinib) are potent, orally bioavailable FAK inhibitors that inhibit tumor growth and metastasis in preclinical models, and are currently under evaluation in clinical trials in patients with various solid tumors. VS-6063 has demonstrated tolerability and preliminary signs of clinical activity as a single agent and in combination with paclitaxel in phase I trials (ASCO, 2014). Here, we show that BCR-ABL1 cooperates with Ikzf1 mutation to accelerate B-leukemogenesis in mice. BCR-ABL1+ Ikaros-mutant B-ALLs exhibit stroma-mediated resistance to ABL1 TKIs, while the FAK inhibitors VS-4718 and VS-6063 are effective in blocking stromal adhesion and inducing apoptosis in both mouse and human Ikaros-mutant B-ALL samples. To test whether dysregulation of TK signaling cooperates with Ikzf1 mutation in the pathogenesis of high-risk B-ALL, we isolated BM B-lymphoid progenitor cells from wild-type (WT), IkE5fl/+ CD2-Cre, and IkE5fl/fl CD2-Cre donors, transduced them with BCR-ABL1 retrovirus and transplanted the cells into recipient mice. We observed a dramatic acceleration of precursor B-lymphoid leukemia induced by BCR-ABL1 in IkE5Δ/+ and particularly in IkE5Δ/Δ donor cells that correlated with a striking (~30-fold) increase in the frequency of engrafting leukemia-initiating or leukemic stem cells (LSCs). Relative to Ikzf1 WT BCR-ABL1+ leukemic cells, Ikzf1-mutant BCR-ABL1+ blasts showed significant resistance to imatinib and dasatinib that was dependent on the presence of OP9 stroma. The effect of FAK inhibition, using the FAK inhibitors VS-4718, VS-6062, and VS-6063 (Verastem), was first tested on murine B-ALL cells (genotypes Ikzf1 mutant, Ikzf1 mutant BCR-ABL1+, and Ikzf1 WT BCR-ABL1+) grown on OP9 stroma. FAK inhibitor treatment abolished stromal adhesion of Ikzf1-mutant B-ALL and induced apoptosis in non-adherent cells, but had little effect on Ikzf1 WT B-ALL cells. VS-4718 and VS-6063 were each synergistic with dasatinib in reducing the viability of Ikzf1-mutant BCR-ABL1+ B-ALL cells cultured on OP9 stroma. For primary human B-ALL samples grown on OP9 stroma, IKZF1-mutant cells were also more sensitive to FAK inhibitor treatment than WT IKZF1 WT B-ALL, with or without BCR-ABL1 expression. Collectively, these observations suggest a new model to explain the pathogenesis of high-risk B-ALL and its resistance to therapy. B-ALLs with IKZF1 mutations may be resistant to TKIs and to chemotherapy by virtue of their stromal adhesion phenotype, resulting in failure to eliminate BM LSCs. Inhibition of FAK signaling in Ph+ or Ph­–IKZF1-mutant B-ALL may reverse the stromal-mediated resistance to ABL1 TKIs and/or chemotherapy. Therefore, FAK inhibitors warrant further investigation for the treatment of high-risk IKZF1-mutant B-ALL patients. Disclosures Joshi: Verastem: Research Funding. Yoshida:Verastem, Inc.: Research Funding. Paraskevopoulou:Verastem, Inc.: Research Funding. Zhang:Verastem, Inc.: Research Funding. Krause:Glycomimetics. Inc.: Research Funding. Shapiro:Verastem: Employment, Equity Ownership. Weaver:Verastem: Employment, Equity Ownership. Pachter:Verastem Inc.: Employment, Equity Ownership. Georgopoulos:Verastem, Inc.: Research Funding.

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.

Targeting Brouton's Tyrosine Kinase with PCI-32765 Blocks Growth and Survival of Multiple Myeloma and Waldenström Macroglobulinemia Via Potent Inhibition of Osteoclastogenesis, Cytokines/Chemokine Secretion, and Myeloma Stem-Like Cells in the Bone Marrow Microenvironment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 883-883
Author(s):  
Yu-Tzu Tai ◽  
Betty Y Chang ◽  
Sun-Young Kong ◽  
Mariateresa Fulciniti ◽  
Guang Yang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Growth And Survival ◽  
Equity Ownership ◽  
Trap Staining

Abstract Abstract 883 Specific expression of Bruton's tyrosine kinase (Btk) in osteoclasts (OC), but not osteoblasts (OB), suggests its role in regulating osteoclastogenesis. Although Btk is critical in B cell maturation and myeloid function, it has not been characterized in plasma cell malignancies including multiple myeloma (MM) and Waldenström Macroglobulinemia (WM). We here investigate effects of PCI-32765, an oral, potent, and selective Btk inhibitor with promising clinical activity in B-cell malignancies, on OC differentiation and function within MM bone marrow (BM) microenvironment, as well as on MM and WM cancer cells. We further define molecular targets of Btk signaling cascade in OCs and MM in the BM milieu. In CD14+ OC precursor cells, RANKL and M-CSF stimulate phosphorylation of Btk in a time-dependent fashion; conversely, PCI-32765 abrogates RANKL/M-CSF-induced activation of Btk and downstream PLCγ2. Importantly, PCI-32765 decreased number of multinucleated OC (>3 nuclei) by tartrate-resistant acid phosphatase (TRAP) staining and the secretion of TRAP5b (ED50 = 17 nM), a specific mature OC marker. It increased size of OCs and number of nuclei per OC, with significantly defective bone resorption activity as evidenced by diminished pit formation on dentine slices. Moreover, lack of effect of Dexamethasone on OC activity was overcome by combination of Dexamethasone with PCI-32765. PCI-32765 significantly reduced cytokine and chemokine secretion from OC cultures, including MIP1α, MIP1β, IL-8, TGFβ1, RANTES, APRIL, SDF-1, and activin A (ED50 = 0.1–0.48 nM). It potently decreased IL-6, SDF-1, MIP1α, MIP1β, and M-CSF in CD138-negative cell cultures from active MM patients, associated with decreased TRAP staining in a dose-dependent manner. In MM and WM cells, immunoblotting analysis confirmed a higher Btk expression in CD138+ cells from majority of MM patients (4 out of 5 samples) than MM cell lines (5 out of 9 cell lines), whereas microarray analysis demonstrated a higher expression of Btk and its downstream signaling components in WM cells than in CD19+ normal bone marrow cells. PCI-32765 significantly inhibits SDF-1-induced adhesion and migration of MM cells. It further blocked cytokine expression (MIP1a, MIP-1β) at mRNA level in MM and WM tumor cells, correlated with inhibition of Btk-mediated pPLCγ2, pERK and NF-kB activation. Importantly, PCI-32765 inhibited growth and survival triggered by IL-6 and coculture with BM stromal cells (BMSCs) or OCs in IL-6-dependent INA6 and ANBL6 MM cells. Furthermore, myeloma stem-like cells express Btk and PCI-32765 (10–100 nM) blocks their abilities to form colonies from MM patients (n=5). In contrast, PCI-32765 has no adverse effects on Btk-negative BMSCs and OBs, as well as Btk-expressing dendritic cells. Finally, oral administration of PCI-32765 (12 mg/kg) in mice significantly suppresses MM cell growth (p< 0.03) and MM cell-induced osteolysis on implanted human bone chips in a humanized myeloma (SCID-hu) model. Together, these results provide compelling evidence to target Btk in the BM microenvironment against MM and WM., strongly supporting clinical trials of PCI-32765 to improve patient outcome in MM and WM. Disclosures: Chang: Pharmacyclics Inc: Employment. Buggy:Pharmacyclics, Inc.: Employment, Equity Ownership. Elias:Pharmacyclics Inc: Consultancy. Treon:Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: 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. Munshi:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Actelion: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

An Open-Label, Phase 1 Study of R-CVP in Combination with Inotuzumab Ozogamicin in Patients with CD22-Positive B-Cell Non-Hodgkin's Lymphoma: Preliminary Safety and Efficacy Data

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1633-1633
Author(s):  
Michinori Ogura ◽  
Kiyohiko Hatake ◽  
Andrew Davies ◽  
Michael Crump ◽  
Kensei Tobinai ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Efficacy Data ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Common Grade ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of <33% in Cycle 1 and fewer than 1/3 of patients discontinuing prior to Cycle 3 due to an adverse event (AE). In Part 3 (n = 22), additional patients were enrolled to explore preliminary signs of activity of INO when given in combination with R-CVP. Results: In Parts 2 and 3, a total of 32 patients with follicular lymphoma (FL; n = 15), diffuse large B-cell lymphoma (DLBCL; n = 16), or mantle cell lymphoma (n = 1) were enrolled. CD22 expression was confirmed by immunohistochemistry or flow cytometry prior to enrollment. The median age was 65 years (range, 44–81 years); 34% of patients had 1 prior anti-lymphoma regimen, 34% had 2, 28% had ≥3, and 3% (n = 1) had no previous therapy (median, 2; range, 0–6). The median number of cycles received was 5 (range, 1–6). In Part 2, the MTD was confirmed as standard-dose R-CVP plus INO 0.8 mg/m2, with 2 of 10 patients presenting with a DLT (grade 3 increase in alanine/aspartate aminotransferases [ALT/AST] and grade 4 neutropenia requiring granulocyte-colony stimulating factor). Four patients discontinued due to AEs after 2 cycles (n = 1), 3 cycles (n = 2), and 5 cycles (n = 1), respectively. Across Parts 2 and 3, the most common treatment-related AEs (all grades) were thrombocytopenia (78%), neutropenia (66%), fatigue (53%), constipation (50%), leukopenia (50%), and nausea (41%); the most common grade 3/4 AEs included neutropenia (63%), thrombocytopenia (53%), leukopenia (38%), lymphopenia (31%), increased ALT (9%), increased AST (6%), and febrile neutropenia (6%). There was 1 case of treatment-related fatal pneumonia associated with grade 4 neutropenia. Ten patients discontinued study treatment due to AEs, with thrombocytopenia or delayed recovery from thrombocytopenia being the leading AE causing study drug discontinuation (n = 9 [grade 1/2, n = 6; grade 3/4, n = 3]). The best overall response (ORR; partial + complete response [CR]) from Part 2 and 3 (31 evaluable patients) was 77% (n = 24/31), including 29% (n = 9/31) with CR. Of patients with FL, the ORR was 100% (n = 15/15), including 53% (n = 8/15) with CR. Of patients with DLBCL, the ORR was 60% (n = 9/16), including 7% (n = 1/16) with CR. Conclusions: Results from this phase I study showed that R-CVP in combination with INO 0.8 mg/m2 may have acceptable toxicity and promising activity in patients with relapsed or refractory CD22+ B-cell NHL, based on the response rates in FL and DLBCL. The most common grade 3/4 AEs were hematological toxicities, notably thrombocytopenia and neutropenia. Follow-up for progression-free survival and overall survival is currently ongoing; however, the observed results warrant additional study in both indolent and aggressive B-cell NHL. Disclosures: Ogura: Pfizer Inc: Research Funding. Hatake:Pfizer Inc: Research Funding. Davies:Pfizer Inc: Research Funding. Crump:Pfizer, Celgene, Roche, Millennium, Seattle Genetic: Membership on an entity's Board of Directors or advisory committees. Tobinai:Merck, Zenyaku, Symbio, Biomedics, Pfizer, GSK, Chugai/Roche: Research Funding. Smith:Pfizer Inc: Research Funding. Offner:Pfizer Inc: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. MacDonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Interim Results of an International, Multicenter, Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 904-904 ◽  
Author(s):  
Michael Wang ◽  
Simon A. Rule ◽  
Peter Martin ◽  
Andre Goy ◽  
Rebecca Auer ◽  
...  
Keyword(s):  
B Cell ◽  
Median Time ◽  
Research Funding ◽  
Tumor Response ◽  
Single Agent ◽  
Safety Data ◽  
Phase 2 ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 904 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling which is essential for normal B-cell development. Ibrutinib is an orally administered inhibitor of BTK that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. MCL is an aggressive subtype of NHL, and despite high response rates to initial therapy, patients often relapse with acquired chemotherapy resistance and short response durations to conventional therapy. Preliminary results in 51 evaluable patients from the Phase 2 PCYC-1104 study demonstrated ibrutinib could achieve rapid nodal responses (including complete responses) in relapsed and refractory MCL patients (Wang et al, ASH 2011). Treatment with ibrutinib was associated with a transient increase in peripheral lymphocyte count representing a compartmental shift of cells with the CD19+/CD5+ phenotype from nodal tissues to peripheral blood (Chang et al, ASH 2011). Reported here are interim results of an international study of single-agent ibrutinib in previously treated MCL. Methods Subjects with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were enrolled. Ibrutinib was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was assessed every 2 cycles according to the revised International Working Group for NHL criteria. The primary endpoint of the study is overall response rate (ORR). Secondary endpoints include: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subjects A total of 115 subjects (65 bortezomib-naïve and 50 bortezomib-exposed) were enrolled between February 15, 2011 and July 3, 2012. Of the 111 subjects treated, 109 subjects were evaluable for efficacy (received at least one dose of ibrutinib and underwent ≥ 1 tumor response assessment). Baseline characteristics include median age 68 years (40–84), median time since diagnosis 42 months, median number of prior treatments 3 (1–6), bulky disease (≥ 10 cm) 13%, Ann Arbor stage IV at screening 77.4%, prior stem cell transplant 9.6%, high risk by MIPI score at baseline assessment 48.7%, and refractory disease 44.3%. Results Safety data are available for 111 subjects. Treatment-emergent AEs occurring in ≥ 15% of subjects: diarrhea (35%), fatigue (32%), upper respiratory tract infections (23%), nausea (21%), rash (21%), dyspnea (20%), and oedema peripheral (15%). Grade 3 or higher AEs occurring in ≥ 5% of subjects were neutropenia (11%), anemia (5%), diarrhea (5%), dyspnea (5%), pneumonia (5%), and thrombocytopenia (5%). Grade 4 treatment-related AEs were neutropenia (5%), hyperuricaemia (2%), and pancytopenia (1%). One grade 5 AE, pneumonia, was thought to be treatment-related. In the efficacy evaluable subjects, the ORR (complete + partial responses) is reported in Table 1. The median time on treatment was 6.0 months (0.7-16.6 months); 53% of subjects remain on treatment. Median DOR, PFS and OS have not been reached: 9 month DOR 65%, 12 month estimation of PFS 53% and OS 67%. Responses to ibrutinib increase with longer time on study treatment. Time to PR ranged from 1.4 – 8.3 months (median 1.9) and CR ranged from 1.7 – 11.2 months (median 3.9). This is seen with longer follow-up on the initial 51 subjects reported at ASH 2011: median time on study treatment was 3.8 months and is now 11.3 months; ORR was 69% and is now 74.5%; CR rate was 16% and is now 35.3%. Conclusions Longer follow up demonstrates the durability of responses and confirms the unprecedented single agent activity of ibrutinib in relapsed or refractory MCL in terms of ORR. The treatment- emergent AEs were consistent with safety data previously reported. A pivotal study in relapsed and refractory MCL patients following bortezomib treatment has been initiated. Disclosures: Wang: Pharmacyclic: Research Funding. Off Label Use: Ibrutinib is a novel agent being studied in a clinical trial. Rule:Pharmacyclics: Research Funding. Martin:Pharmacyclics: Research Funding. Goy:Pharmacyclics: Research Funding. Auer:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Jurczak:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. McGreivy:pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. Stevens-Brogan:Pharmacyclics: Employment, Equity Ownership. Kunkel:Pharmacyclics: Employment, Equity Ownership. Blum:Pharmacyclics: Research Funding.

Relationship Between Lenalidomide Dose Modification and Duration Of Treatment In Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2944-2944
Author(s):  
Kathy Lang ◽  
Gary Binder ◽  
Iris Lin ◽  
Dejan Milentijevic ◽  
Huan Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Reduction ◽  
Research Funding ◽  
Duration Of Treatment ◽  
Employment Equity ◽  
Medical Claims ◽  
Dose Modification ◽  
Equity Ownership ◽  
Dose Change ◽  
Dose Reductions

Abstract Introduction A number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. Objective Medical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. Methods A retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. Results Among the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p<0.01). Of the 69 pts with dose reductions, DOT before dose reduction was 5.18 months ± 4.82 compared with 9.46 months ± 10.26 after dose reduction (p<0.01, paired). The subset of pts who were still on LEN therapy at the end of the data window (N=27) showed a similar association between dose reduction and DOT, with DOT of 20.29 months ± 11.62 and 11.99 months ± 9.29 in dose reduction and non-dose reduction subgroups (p<0.01), respectively. Conclusion NDMM pts who had dose reductions of LEN had twice the duration of therapy compared with pts without dose reductions. This analysis suggests that dose modification of MM treatment may be an effective tool to help pts achieve the benefits associated with longer time on therapy. Future clinical studies are needed to determine the best approaches to dose adjustment to improve disease control. Disclosures: Lang: Celgene: Research Funding. Off Label Use: Lenalidomide is a thalidomide analog indicated for the treatment of multiple myeloma, in combination with dexamethasone, in patients who have received at least one prior therapy. Binder:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding. Milentijevic:Celgene: Consultancy. Huang:Celgene: Research Funding. Nagarwala:Celgene: Employment, Equity Ownership. Harwin:Celgene: Honoraria.

Deep Sequencing Reveals Oligoclonality At The Immunoglobulin Locus In Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 401-401 ◽  
Author(s):  
Joaquin Martinez-Lopez ◽  
Mariateresa Fulciniti ◽  
Santiago Barrio ◽  
Victoria Carlton ◽  
Martin Moorhead ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
High Frequency ◽  
Genomic Dna ◽  
Gene Rearrangement ◽  
Common Ancestor ◽  
B Cell Development ◽  
Employment Equity ◽  
A Cell ◽  
Equity Ownership

Abstract Introduction Immunoglobulin (Ig) gene rearrangement is a hallmark of early B-cell development. Multiple myeloma (MM) is a malignancy of the plasma cells, which are at the terminal stage of B cell development. MM is a clonal disease originating from the transformation process of a single plasma cell and, thus, myeloma cells are traditionally thought to have one clonal Ig gene sequence that remains stable throughout the course of the disease. Based on preliminary evidence of oligoclonality, we utilized the LymphoSIGHT™ platform, a high-throughput sequencing method, to detect evidence of oligoclonality at the Ig heavy and kappa chain (IGH and IGK) loci. The sequencing approach can be used to examine two general models for oligoclonality. In the first model, two unrelated clonal Ig sequences are observed indicating the presence of two independent myelomas. Alternatively, in the second model, two related myeloma clonal Ig sequences are observed indicating that both myeloma clones are derived from a common ancestor that arose after the pro B cell stage when VDJ recombination is completed. The common ancestor can be a cell with premalignant lesion or after the MM has developed. Using the sequencing platform, we looked for evidence of these two models of oligoclonality in 193 MM patients. Methods Two cohorts of newly diagnosed MM patients were included in this analysis (N=125, N=68). Using universal primer sets, we amplified IGH and IGK variable, diversity, and joining gene segments from genomic DNA or RNA from bone marrow collected at initial diagnosis. Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination (Faham et al, Blood 2012). In the first cohort (N=125), we assessed gene rearrangement at the IGH-VDJ and IGK loci in 120 patients using RNA only and in 5 patients, we used both DNA and RNA to assess the IGH-VDJ, IGH-DJ and IGK loci. In the second cohort (N=68), we analyzed gene rearrangement at the IGH-VDJ, IGH-DJ and IGK loci using genomic DNA. Myeloma-specific clonotypes were identified for each patient based on their high frequency (5%) within the B-cell repertoire in the diagnostic sample. To identify clonotypes that are present in more than one cell we looked for patterns that are not consistent with having a maximum of one functional and one non-functional clonotype in a cell. Results We observed oligoclonality in 23 of 193 (12%) MM patients. Unrelated Ig sequences, which are consistent with the first model of oligoclonality, were present in 8 of the 193 (4%) patients. Fifteen of 193 (8%) patients exhibited related Ig clones, which is consistent with the second model of oligoclonality. In 4 of the 15 patients clones were related to each other via a somatic hypermutation process and differed by only a few bases (Figure 1), while in other 11 patients, the same VDJ sequence was associated with two distinct isotypes (IgA and IgG). Interestingly, in cases with both RNA and DNA sequencing and oligoclonality, we observed differential expression levels compared to clonal content at the DNA level, suggesting that a low frequency clone could be contributing as a predominant secretory clone. Conclusions This study demonstrates frequent oligoclonality in MM patients and suggests that this phenomenon does occur due to two distinct processes, either as unrelated sequences consistent with independent clones or as related sequences consistent with evolution after the MM malignant lesions occur. These findings shed light on the biology and pathogenesis of MM and may provide prognostic information. Currently, this analysis was limited to high frequency clones, using a threshold of 5% for identification of the myeloma-specific clones. Additional analysis is being performed to assess the presence of lower frequency clones, and data will be presented. Disclosures: Carlton: Sequenta, Inc. : Employment, Equity Ownership. Moorhead:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc. : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

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