Multiple Myeloma Research Consortium

Norwalk, CT, United States

Multiple Myeloma Research Consortium

Norwalk, CT, United States
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Tiedemann R.E.,Mayo Medical School | Zhu Y.X.,Mayo Medical School | Schmidt J.,Mayo Medical School | Yin H.,Translational Genomics Institute | And 10 more authors.
Blood | Year: 2010

A paucity of validated kinase targets in human multiple myeloma has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in myeloma tumor lines bearing common t(4;14), t(14;16), and t(11;14) translocations to identify critically vulnerable kinases in myeloma tumor cells without regard to preconceived mechanistic notions. Fifteen kinases were repeatedly vulnerable in myeloma cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6, HK1, PKN1, PLK1, SMG1, and TNK2. Whereas several kinases (PLK1, HK1) were equally vulnerable in epithelial cells, others and particularly G protein - coupled receptor kinase, GRK6, appeared selectively vulnerable in myeloma. GRK6 inhibition was lethal to 6 of 7 myeloma tumor lines but was tolerated in 7 of 7 human cell lines. GRK6 exhibits lymphoid-restricted expression, and from coimmunoprecipitation studies we demonstrate that expression in myeloma cells is regulated via direct association with the heat shock protein 90 (HSP90) chaperone. GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in multiple myeloma (MM) tumor cells. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma. © 2010 by The American Society of Hematology.


Jakubowiak A.J.,University of Chicago | Siegel D.S.,Hackensack University | Martin T.,University of California at San Francisco | Wang M.,University of Texas M. D. Anderson Cancer Center | And 18 more authors.
Leukemia | Year: 2013

Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics-del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics-and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high-vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7-7.8) vs 8.3 months (95% CI 5.6-12.3)) and overall survival (9.3 (95% CI 6.5-13.0) vs 19.0 months (95% CI 15.4-NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM. © 2013 Macmillan Publishers Limited.


Siegel D.S.,Hackensack University Medical Center | Martin T.,University of California at San Francisco | Wang M.,University of Texas M. D. Anderson Cancer Center | Vij R.,University of Washington | And 18 more authors.
Blood | Year: 2012

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003- A1), patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirtythree patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238. © 2012 by The American Society of Hematology.


News Article | February 15, 2017
Site: www.PR.com

The 2017 Women in Oncology Award Winners Honored by PRIMO Education The winners of the 2017 Women in Oncology Award were announced this morning at the 2nd Annual Practical Recommendations in Immuno and Molecular Oncology (PRIMO) Meeting. The Women in Oncology Awards are presented annually to three outstanding women in academia, industry, and advocacy, and seeks to recognize women who have made outstanding contributions to the lives of those fighting cancer. Wailea, HI, February 13, 2017 --( The Women in Oncology Awards are presented annually to three outstanding women in academia, industry, and advocacy, and seeks to recognize women who have made outstanding contributions to the lives of those fighting cancer. The 2017 the Women in Oncology Award Winners are: Academic Nancy Davidson, MD, is the Executive Director of the Fred Hutchinson and University of Washington Cancer Consortium, located in Seattle, WA. She is a world-renowned breast cancer researcher, who has dedicated her career to the study of cancer biology and treatment. In addition to her role at Fred Hutchinson, she is the President of the American Association for Cancer Research, and the Past-President of the American Society of Clinical Oncology. Advocacy Kathy Giusti is a Founder and Executive Chairman of the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC), as well as the Faculty Co-Chair of the Harvard Business School Kraft Precision Medicine Accelerator. As Executive Chairman of the MMRF, she established innovative research models to accelerate the pace of development for lifesaving treatments, earning her recognition not only as a pioneer of precision medicine, but also as a strong advocate for patient engagement. Due to her and her foundation’s success, Ms. Giusti has earned numerous career accolades, including a #19 ranking in Fortune Magazine’s “World’s 50 Greatest Leaders”, and an appointment to President Obama’s 2015 Precision Medicine Initiative Working Group. Industry Jill DeSimone is the Head of US Oncology at Merck. Under her leadership, pembrolizumab received FDA approval in metastatic melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma, positively impacting a large number of patients across the US. Prior to her time at Merck, Ms. DeSimone was a Senior Vice President at Teva Pharmaceuticals, where she established the Global Women’s Health Unit, as well as a Senior Vice President at Bristol-Meyers Squibb. The organizers of this award, PRIMO Education and Cancer Expert Now, thank these three outstanding women for their commitment to the advancement of cancer care and advocacy, and look forward to their continuing contributions to oncology in the future. Wailea, HI, February 13, 2017 --( PR.com )-- The winners of the 2017 Women in Oncology Award were announced this weekend at the 2nd Annual Practical Recommendations in Immuno and Molecular Oncology (PRIMO) Meeting. The awards were Introduced by Charles Balch, MD, PhD(hc), of the MD Anderson Cancer Center, and presented by meeting Co-chairs Julie Brahmer, MD, MSc, of Johns Hopkins School of Medicine and Julie Vose, MD, MBA, of the University of Nebraska Medical Center.The Women in Oncology Awards are presented annually to three outstanding women in academia, industry, and advocacy, and seeks to recognize women who have made outstanding contributions to the lives of those fighting cancer. The 2017 the Women in Oncology Award Winners are:AcademicNancy Davidson, MD, is the Executive Director of the Fred Hutchinson and University of Washington Cancer Consortium, located in Seattle, WA. She is a world-renowned breast cancer researcher, who has dedicated her career to the study of cancer biology and treatment. In addition to her role at Fred Hutchinson, she is the President of the American Association for Cancer Research, and the Past-President of the American Society of Clinical Oncology.AdvocacyKathy Giusti is a Founder and Executive Chairman of the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC), as well as the Faculty Co-Chair of the Harvard Business School Kraft Precision Medicine Accelerator. As Executive Chairman of the MMRF, she established innovative research models to accelerate the pace of development for lifesaving treatments, earning her recognition not only as a pioneer of precision medicine, but also as a strong advocate for patient engagement. Due to her and her foundation’s success, Ms. Giusti has earned numerous career accolades, including a #19 ranking in Fortune Magazine’s “World’s 50 Greatest Leaders”, and an appointment to President Obama’s 2015 Precision Medicine Initiative Working Group.IndustryJill DeSimone is the Head of US Oncology at Merck. Under her leadership, pembrolizumab received FDA approval in metastatic melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma, positively impacting a large number of patients across the US. Prior to her time at Merck, Ms. DeSimone was a Senior Vice President at Teva Pharmaceuticals, where she established the Global Women’s Health Unit, as well as a Senior Vice President at Bristol-Meyers Squibb.The organizers of this award, PRIMO Education and Cancer Expert Now, thank these three outstanding women for their commitment to the advancement of cancer care and advocacy, and look forward to their continuing contributions to oncology in the future.


Vij R.,University of Washington | Wang M.,University of Texas M. D. Anderson Cancer Center | Kaufman J.L.,Emory University | Lonial S.,Emory University | And 21 more authors.
Blood | Year: 2012

Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomibnaive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy - 17.1% overall (1 grade 3; no grade 4) - in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816. © 2012 by The American Society of Hematology.


Jakubowiak A.J.,University of Michigan | Griffith K.A.,University of Michigan | Reece D.E.,Princess Margaret Hospital | Hofmeister C.C.,Ohio State University | And 17 more authors.
Blood | Year: 2011

This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m2, pegylated liposomal doxorubicin 30 mg/m2, and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatmentrelated mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65%≥ VGPR, and 29% and 35% complete or nearcomplete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568. © 2011 by The American Society of Hematology.


PubMed | Washington University in St. Louis, Mayo Medical School, Multiple Myeloma Research Consortium, University of Chicago and City of Hope
Type: Clinical Trial, Phase I | Journal: American journal of hematology | Year: 2016

Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than four lines of prior therapy and with measurable disease were enrolled. Bendamustine 75 mg/m(2) given on days 1 and 2, lenalidomide 25 mg given days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, was the recommended Phase 2 dose. Seventy-one patients were accrued: 21 on Phase 1 and 50 on Phase 2. The median age was 62.3 years; patients had a median of three prior lines of therapy (range 1-4), with over 70% of the patients having received prior lenalidomide, bortezomib, and/or peripheral blood stem cell transplant. Thirty-four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with grade 3 hematologic in 94% and nonhematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide, and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses


Vij R.,University of Washington | Siegel D.S.,John Theurer Cancer Center at Hackensack University | Jagannath S.,Mount Sinai Medical Center | Jakubowiak A.J.,University of Michigan | And 10 more authors.
British Journal of Haematology | Year: 2012

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m2 in a twice-weekly, consecutive-day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents. © 2012 Blackwell Publishing Ltd.


Van Wier S.,Mayo Medical School | Braggio E.,Mayo Medical School | Baker A.,Translational Genomics Research Institute | Ahmann G.,Mayo Medical School | And 3 more authors.
Haematologica | Year: 2013

Multiple myeloma can be categorized into hyperdiploid or non-hyperdiploid myeloma based on the number of chromosomes found in the tumor clone. Among the non-hyperdiploid myelomas, the hypodiploid subtype has the most aggressive clinical phenotype, but the genetic differences between groups are not completely defined. In order to understand the genetic background of hypodiploid multiple myeloma better, we compared the genomic (array-based comparative genomic hybridization) and transcriptomic (gene expression profiling) background of 49 patients with hypodiploid myeloma with 50 other non-hyperdiploid and 125 hyperdiploid myeloma patients. There were significant chromosomal and gene expression differences between hyperdiploid patients and nonhyperdiploid and hypodiploid patients. Non-hyperdiploid and hypodiploid patients shared most of the chromosomal abnormalities; nevertheless a subset of these abnormalities, such as monosomies 13, 14 and 22, was markedly increased in hypodiploid patients. Furthermore, deletions of 1p, 12p, 16q and 17p, all associated with poor outcome or progression in multiple myeloma, were significantly enriched in hypodiploid patients. Molecular risk-stratification indices reinforce the worse prognosis associated with hypodiploid multiple myeloma compared with non-hyperdiploid multiple myeloma. Gene expression profiling clustered hypodiploid and non-hyperdiploid subgroups closer than hyperdiploid myeloma but also highlighted the up-regulation of CCND2, WHSC1/MMSET and FGFR3 in the hypodiploid subtype. In summary, hypodiploid multiple myeloma is genetically similar to nonhyperdiploid multiple myeloma but characterized by a higher prevalence of genetic alterations associated with poor outcome and disease progression. It is provocative to hypothesize that hypodiploid multiple myeloma is an advanced stage of non-hyperdiploid multiple myeloma. © 2013 Ferrata Storti Foundation.


Salhia B.,Translational Genomics Research Institute | Baker A.,Translational Genomics Research Institute | Ahmann G.,Mayo Medical School | Auclair D.,Multiple Myeloma Research Consortium | And 2 more authors.
Cancer Research | Year: 2010

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow, which evolves from a premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). In some patients, an intermediate stage referred to as smoldering multiple myeloma (SMM) is clinically recognized, with the full-bore malignancy termed MM. We conducted a study to assess differential CpG methylation at 1,500 genic loci during MM progression and profiled CD138 + plasma cells from MGUS, SMM, and MM specimens; human myeloma cell lines; and normal plasma cell (NPC) samples. We showed that the number of differentially methylated loci (DML) increased with tumor grade, and the vast majority were due to hypomethylation. Hierarchical clustering analysis revealed samples that coclustered tightly with NPC. These cases, referred to as "normal-like," contained significantly fewer DML when compared with their non-normal-like counterparts and displayed overall methylation levels resembling NPC. This study represents one of the first methylome interrogation studies in MM and points toward global hypomethylation at genic CpG loci as an important and early mechanism driving myelomagenesis. Determining the set of critical genes and pathways based on the myeloma methylome is expected to lead to an improved understanding of biological mechanisms involved in myelomagenesis. ©2010 AACR.

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