(Filanesib) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low Α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study

Total Page:16

File Type:pdf, Size:1020Kb

(Filanesib) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low Α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study Prolonged Survival and Improved Response Rates with ARRY‐520 (Filanesib) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study S Lonial1, J Shah2, JA Zonder3, W Bensinger4, A Cohen5, JL Kaufman1,A Nooka1, D Weber2, B Hilder6, S Rush6, M Ptaszynski6, D Walker6, R Orlowski2 1Winship Cancer Institute, Emory University, Atlanta GA; 2MD Anderson Cancer Center, Houston TX; 3Karmanos Cancer Institute, Wayne State University, Detroit MI; 4Fred Hutchison Cancer Center, Seattle WA; 5Fox Chase Cancer Center, Philadelphia PA; 6Array BioPharma Inc., Boulder CO 1 Disclosures • Consultant: Millenium; Novartis; Onyx; Janssen • Research Support: Merck; Celgene; Novartis 2 Background: Targeting KSP with ARRY‐520 (Filanesib) • Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor – KSP is a microtubule motor protein critical to the function of proliferating cells • KSP inhibition induces aberrant mitotic arrest and rapid cell death – Novel mechanism of action for MM – Preferentially acts on MCL‐1 dependent cells including MM – Not expected to be cross‐resistant with other drugs 3 ARRAY‐520‐212 –Phase 2 Study Design Cohort 1: Filanesib Single-agent Filanesib 1.5 mg/m2 q 2 weeks 1 2 1 2 G‐CSF G‐CSF Cohort 2: Filanesib + Dexamethasone Combination Filanesib 1.5 mg/m2 q 2 weeks 1 2 1 2 G‐CSF G‐CSF Dexamethasone 40 mg PO weekly 4 Key Eligibility Criteria • Measurable disease (serum, urine or free light chain) • ECOG performance status 0‐1 • Adequate hematology labs without transfusion support within 2 weeks • Adequate renal and hepatic function Cohort 1: Phase 2 Filanesib Single‐agent • ≥ 2 prior treatment regimens, including BTZ and an IMiD • Disease should have progressed during or after last regimen Cohort 2: Phase 2 FIlanesib + Dexamethasone • ≥ 2 prior treatment regimens • Refractory to last regimen (progression during or w/in 60 days) • ≥ 2 consecutive cycles of prior treatment that included Len and BTZ – Refractory to Len, BTZ, and dex (40 mg per week) • Patients intolerant to Len or BTZ not included – Adequate prior alkylator therapy 5 Demographics and Disease History Filanesib Filanesib + Dex N = 32 N = 55 Gender Male 18 (56%) 27 (49%) Age at Enrollment (years) Median (Range) 65 (51, 82) 63 (33, 82) ECOG PS 0 5 (16%) 6 (11%) 1 26 (81%) 49 (89%) 2 1 (3%) 0 (0%) High Risk Cytogenetics 3 (9%) 17 (31%) Years Since Diagnosis Median (Range) 3 (1, 11) 5 (1, 18) 6 Prior Therapies Filanesib Filanesib + Dex N = 32 N = 55 Median Prior Regimens 6 8 Prior Proteasome Inhibitor 29 (91%) 55 (100%) Prior BTZ 29 (91%) 55 (100%) BTZ‐refractory 17 (53%) 54 (98%) Prior IMiD 32 (100%) 55 (100%) Prior Len 31 (97%) 55 (100%) Len‐refractory 24 (75%) 55 (100%) Prior Corticosteroid 32 (100%) 55 (100%) Triple‐Refractory (Len, BTZ, Dex) 13 (41%) 53 (96%) Prior Alkylator 32 (100%) 55 (100%) Prior Anthracycline 16 (50%) 38 (69%) Prior Transplant 26 (81%) 49 (89%) 7 Non‐Hematologic Grade 3/4 AEs Regardless of Causality (≥ 5% Incidence) Filanesib Single‐agent Filanesib + Dex N=32 N=55 Pneumonia Hypokalemia Back Pain Fatigue 0 2550751000 255075100 Grade 3 Grade 4 % Incidence % Incidence • Filanesib is not associated with peripheral neuropathy • No cumulative toxicity with long‐term administration 8 Hematologic Toxicity Worst Grade On‐Study Filanesib Single‐agent Filanesib + Dex N=32 N=55 Neutrophils Platelets Hemoglobin Bleeding Febrile Neutropenia Grade 3 Grade 4 0 2550751000255075100 Hematological toxicity predicted based on mechanism of action • Managed with supportive care • Low incidence of febrile neutropenia or bleeding events 9 SAEs and Discontinuations SAEs Filanesib Filanesib + Dex (≥ 5% Incidence, Regardless of Causality) N = 32 N = 55 Any SAE 10 (31%) 25 (45%) Pneumonia 1 (3%) 6 (11%) Non‐neutropenic Fever 1 (3%) 4 (7%) Discontinuations Filanesib Filanesib + Dex N = 32 N = 55 Off Treatment 30 (94%) 48 (87%) Progressive Disease 23 (72%) 41 (75%) AEs 3 (9%) 4 (7%) Death 1 (3%) 3 (5%) Withdrawal Of Consent 2 (6%) 0 (0%) Investigator Decision 1 (3%) 0 (0%) 10 Filanesib Activity Filanesib Filanesib + Single‐agent Dex All Pts All Pts n3255 ORR (≥ PR) 5 (16%) 8 (15%) CBR (≥ MR) 7 (22%) 11 (20%) Duration of Response (months) 8.6 5.1 Time to Next Treatment (Months) 3.7 3.4 OS (months) 19.0 10.5 11 1‐acid glycoprotein (AAG) is a Potential Selection Marker for Filanesib • Background – 1‐acid glycoprotein (AAG) is an acute‐phase serum protein used to diagnose and monitor inflammatory disorders – AAG binds to filanesib – Increasing [AAG] results in increased IC50 for filanesib in vitro – No correlation between [AAG] and common MM prognostic markers • Hypothesis: High pre‐dose [AAG] correlates with lack of ORR and shorter time on study for patients treated with filanesib 12 1‐Acid Glycoprotein (AAG) Is A Potential Selection Marker For Filanesib • AAG is an acute-phase serum protein • AAG binds to filanesib 40 3‐day cell viability assay RPMI‐8226 MM cell line (nM) 30 50 ARRY‐520 IC of Bortezomib 20 Carfilzomib Melphalan Change ‐ 10 Fold 0 00.511.522.53 [AAG] (g/L) Increasing [AAG] attenuates filanesib activity in vitro 13 Low AAG is Associated with Higher ORR Filanesib Single‐agent Filanesib + Dex All Pts1 AAG‐High AAG‐Low All Pts2 AAG‐High AAG‐Low n32621 55 15 36 ORR (≥ PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR (≥ MR) 7 (22%) 0 (0%) 7 (33%) 11 (20%) 0 (0%) 10 (28%) Duration of Response 8.6 ‐ 8.6 5.1 ‐ 5.1 (months) Time to Next 3.7 2.6 5.3 3.4 2.0 5.1 Treatment (months) OS (months) 19.0 4.5 23.3 10.5 2.9 10.8 1 5 patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement, including 1 responder 14 Pre‐Dose AAG Levels Correlate with Clinical Outcome 2.8 2.4 “High” [AAG] Partial Response Minimal Response 2 No response/PD (g/L) 1.6 [AAG] 1.2 0.8 0.4 0 5 10 15 20 25 30 35 Time on Treatment (months) • AAG Cutoff ≥ 1.1 g/L in Array ELISA was qualitatively assigned • Absolute value of cutoff is likely to change in final assay 15 Filanesib is Active in Patients Previously Treated with New MM Drugs (Filanesib + Dex Cohort) Prior Pomalidomide and/or Carfilzomib and/or MLN9708 AAG All High Low N195 13 ≥ PR (n) 4 0 4 ≥ PR (%) 21% 0 31% Data suggest filanesib maintains activity in myelomas resistant to multiple PI and IMiD drugs 16 Low AAG is Associated with Longer Survival Filanesib Single-agent Filanesib + Dex Median 6 prior therapies Median 8 prior therapies 100 100 Low High 75 75 All 50 50 25 25 Percent survival Percent survival 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Overall Survival (months) Overall Survival (months) 17 Conclusions • Filanesib is a first‐in‐class KSP inhibitor – A novel treatment approach in MM, distinct from IMiDs or PIs • AAG may identify patients who do not benefit from filanesib – Patients with high serum AAG may not achieve therapeutic exposure • Demonstrated single‐agent activity in heavily pretreated RRMM – Activity in patients previously treated with novel IMiD/PI – Patients with low serum AAG have improved response and survival • Well‐tolerated safety profile with supportive care – Low incidence of non‐hematological AEs – Hematologic events are generally reversible and not cumulative 18 Future Directions • Data in combination with carfilzomib or bortezomib also presented at this meeting – Abstracts 1938; 1982 • Broad development plan – Ongoing Phase 2 study in combination with carfilzomib in RRMM – Planned studies • Phase 3 study in combination with carfilzomib in RRMM • Phase 2 single‐agent trial in heavily pretreated RRMM 19 Acknowledgements Thank you to all of the patients and families who contributed to this study We would like to thank the co‐investigators, research nurses, study coordinators, and support staff This study was sponsored by Array BioPharma, Inc. Boulder CO 20 21.
Recommended publications
  • Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma
    Pharmaceuticals 2015, 8, 1-20; doi:10.3390/ph8010001 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma Noah M. Merin and Kevin R. Kelly * Internal Medicine, Jane Anne Nohl Division of Hematology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-323-865-3823; Fax: +1-323-865-0060. Academic Editor: Jennifer Carew Received: 29 July 2014 / Accepted: 4 December 2014 / Published: 24 December 2014 Abstract: Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. Keywords: multiple myeloma; proteasome inhibitors; toxicity 1. Introduction Multiple myeloma (MM) is a malignant neoplasm characterized by clonal proliferation of plasma cells in the bone marrow that produce monoclonal protein (M-protein) that may be detected in the serum or urine. It is the second most common hematologic cancer in the United States (after Non-Hodgkin Lymphoma); an estimated 24,050 new cases and 11,090 deaths will occur due to MM in the USA in 2014 [1].
    [Show full text]
  • A Phase 1 Dose-Escalation Study of Filanesib Plus
    A Phase 1 Dose-Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients With Recurrent/ Refractory Multiple Myeloma Ajai Chari, Icahn School of Medicine at Mount Sinai Myo Htut, City Hope National Medical Center Jeffrey A. Zonder, Wayne State University Joseph W. Fay, Baylor Research Institute Andrzej Jakubowiak, University of Chicago Joan B. Levy, Multiple Myeloma Research Consortium Kenneth Lau, Icahn School of Medicine at Mount Sinai Steven M. Burt, Wayne State University Brian J. Tunquist, Array BioPharma Inc Brandi W. Hilder, Array BioPharma Inc Only first 10 authors above; see publication for full author list. Journal Title: Cancer Volume: Volume 122, Number 21 Publisher: Wiley | 2016-11-01, Pages 3327-3335 Type of Work: Article | Post-print: After Peer Review Publisher DOI: 10.1002/cncr.30174 Permanent URL: https://pid.emory.edu/ark:/25593/vj1mj Final published version: http://dx.doi.org/10.1002/cncr.30174 Copyright information: © 2016 American Cancer Society Accessed October 1, 2021 7:46 AM EDT HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Cancer. Manuscript Author Author manuscript; Manuscript Author available in PMC 2019 November 15. Published in final edited form as: Cancer. 2016 November 15; 122(21): 3327–3335. doi:10.1002/cncr.30174. A Phase 1 Dose-Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients With Recurrent/Refractory Multiple Myeloma Ajai Chari, MD1, Myo Htut, MD2, Jeffrey A. Zonder, MD3, Joseph W. Fay, MD4, Andrzej J. Jakubowiak, MD5, Joan B. Levy, PhD6, Kenneth Lau, BA1, Steven M. Burt, MSN, NP-C3, Brian J. Tunquist, PhD7, Brandi W. Hilder, PhD7, Selena A.
    [Show full text]
  • Pomalidomide Enhanced Gemcitabine and Nab-Paclitaxel on Pancreatic Cancer Both in Vitro and in Vivo
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 21), pp: 15780-15791 Research Paper Pomalidomide enhanced gemcitabine and nab-paclitaxel on pancreatic cancer both in vitro and in vivo Nobuhiro Saito1,2, Yoshihiro Shirai1,2,*, Tadashi Uwagawa1,3, Takashi Horiuchi1,2, Hiroshi Sugano1,2, Koichiro Haruki1, Hiroaki Shiba1, Toya Ohashi2 and Katsuhiko Yanaga1 1Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan 2Division of Gene Therapy, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan 3Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan *This author contributed equally to this work Correspondence to: Nobuhiro Saito, email: [email protected] Keywords: IMiDs; pancreatic cancer; gemcitabine/nab-paclitaxel; NF-κB; p53 Received: December 29, 2017 Accepted: February 25, 2018 Epub: March 02, 2018 Published: March 20, 2018 Copyright: Saito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/ nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is attenuated by the antitumor agent-induced activation of nuclear factor-κB (NF-κB). Thalidomide inhibits NF-κB activation, therefore, we hypothesized that pomalidomide, a third-generation IMiD, would also inhibit NF-κB activation and enhance the antitumor effects of gemcitabine/nab-paclitaxel. Methods: In vitro, we assessed NF-κB activity and apoptosis in response to pomalidomide alone, gemcitabine/nab-paclitaxel, or combination of pomalidomide and gemcitabine/nab-paclitaxel in human pancreatic cancer cell lines (PANC-1 and MIA PaCa-2).
    [Show full text]
  • Daratumumab (Darzalex)
    Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Clinical Advances in Immunotherapy in Myeloma Webinar 1, June 14, 2017 Monoclonal Antibodies Speakers Moderator: Mary DeRome Multiple Myeloma Research Foundation Norwalk, Connecticut Faculty: Tom Martin, MD University of California, San Francisco San Francisco, California Amy Marsala, MPH, MSN, NP University of California, San Francisco San Francisco, California Gary Rudman, CSP Myeloma Patient Advocate 1 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Topics for Discussion • Current and future monoclonal antibodies (what they are, how they work) • Management of side effects in the era of monoclonal antibodies • Patient experience on phase 2 clinical trial of Empliciti (elotuzumab) Tom Martin, MD 2 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Current Overall Survival for Newly Diagnosed Myeloma 1.0 89% vs 81% 0.9 Still losing 25% patients in first 3 years 75% vs 62% 0.8 0.7 2007–2011 0.6 0.5 0.4 0.3 Proportion Surviving 2001–2006 0.2 0.1 0.0 012345678910 Years From Diagnosis A good trend but we always need to improve!! Myeloma Treatment: It’s an Art 3 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug New Agents in Myeloma Therapy Oral Kinase HDAC Immuno- New IMiDs proteasomes inhibitors Novel MOA inhibitors therapies • Lenalidomide
    [Show full text]
  • Novel Targets in Multiple Myeloma
    · MULTIPLE MYELOMA · Novel Targets in Multiple Myeloma Douglas Tremblay, MD, and Ajai Chari, MD Abstract also being increasingly approved by the FDA as a part of combination Despite the availability of 6 classes of drugs for the therapy based on PFS extension of 3 to 6 months achieved in random- treatment of multiple myeloma (MM), the disease re- ized phase III studies. The goal of this review is to discuss the targets, mains incurable in most cases, with patients eventually mechanisms of action (MOA), safety, and efficacy of the novel agents relapsing on each of these agents. The benchmark for in MM that are currently have recently met or have the best chance of drug approval in heavily pretreated and multidrug-re- meeting these benchmarks. fractory patients is an overall response rate (ORR) of approximately 25% to 30% and progression-free Targets of Immunomodulatory Drugs survival (PFS) of approximately 4 months, but more Of note, there also have been developments in our understanding of recently in less heavily pretreated patients with relapsed the targets of immunomodulatory drugs (IMiDs). Until recently, it has disease after 1 to 3 lines of therapy, based primarily on been unclear how these oral medications achieve antimyeloma ben- an improvement in PFS of 3 to 6 months in random- efits without significant toxicity at the site of drug absorption in the ized phase III studies. This article reviews the targets, gut or other off-target organ toxicities. Recently, cereblon, a member mechanisms of action (MOA), safety, and efficacy of the of the E3 ubiquitin ligase family, was identified as the likely mediator recently approved agents in MM that have met one of of teratogenicity of IMiDs.
    [Show full text]
  • Salvage Therapies in Relapsed And/Or Refractory Myeloma: What Is Current and What Is the Future?
    Journal name: OncoTargets and Therapy Article Designation: Review Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Thumallapally et al Running head recto: Salvage therapies in relapsed and/or refractory myeloma open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S110189 Open Access Full Text Article REVIEW Salvage therapies in relapsed and/or refractory myeloma: what is current and what is the future? Nishitha Thumallapally1 Abstract: The treatment landscape for multiple myeloma (MM) is evolving with our Hana Yu1 understanding of its pathophysiology. However, given the inevitable cohort heterogeneity Divya Asti1 in salvage therapy, response to treatment and overall prognoses tend to vary widely, making Adarsh Vennepureddy1 meaningful conclusions about treatment efficacy difficult to derive. Despite the hurdles in Terenig Terjanian2 current research, progress is underway toward more targeted therapeutic approaches. Several new drugs with novel mechanism of action and less toxic profile have been developed in the past 1Department of Internal Medicine, decade, with the potential for use as single agents or in synergy with other treatment modalities 2Division of Hematology and Oncology, Staten Island University in MM therapy. As our discovery of these emerging therapies progresses, so too does our need Hospital, New York, NY, USA to reshape our knowledge on knowing how to apply them. This review highlights some of the recent landmark changes in MM management with specific emphasis on salvage drugs available for relapsed and refractory MM and also discusses some of the upcoming cutting-edge therapies For personal use only. that are currently in various stages of clinical development.
    [Show full text]
  • Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients with Recurrent/Refractory Multiple Myeloma
    Original Article A Phase 1 Dose-Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients With Recurrent/Refractory Multiple Myeloma Ajai Chari, MD1; Myo Htut, MD2; Jeffrey A. Zonder, MD3; Joseph W. Fay, MD4; Andrzej J. Jakubowiak, MD5; Joan B. Levy, PhD6; Kenneth Lau, BA1; Steven M. Burt, MSN, NP-C3; Brian J. Tunquist, PhD7; Brandi W. Hilder, PhD7; Selena A. Rush, BS7; Duncan H. Walker, PhD7; Mieke Ptaszynski, MD7; and Jonathan L. Kaufman, MD8 BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/ refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The cur- rent study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of pro- phylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively.
    [Show full text]
  • Belantamab Mafodotin to Treat Multiple Myeloma: a Comprehensive Review of Disease, Drug Efficacy and Side Effects
    Review Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects Grace Lassiter 1,*, Cole Bergeron 2, Ryan Guedry 2, Julia Cucarola 2, Adam M. Kaye 3 , Elyse M. Cornett 4, Alan D. Kaye 4 , Giustino Varrassi 5, Omar Viswanath 4,6,7,8 and Ivan Urits 4,9 1 School of Medicine, Georgetown University, Washington, DC 20007, USA 2 School of Medicine, Louisiana State University Shreveport, Shreveport, LA 71103, USA; [email protected] (C.B.); [email protected] (R.G.); [email protected] (J.C.) 3 Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA; akaye@pacific.edu 4 Department of Anesthesiology, Louisiana State University Shreveport, Shreveport, LA 71103, USA; [email protected] (E.M.C.); [email protected] (A.D.K.); [email protected] (O.V.); [email protected] (I.U.) 5 Paolo Procacci Foundation, Via Tacito 7, 00193 Roma, Italy; [email protected] 6 College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85724, USA 7 Department of Anesthesiology, School of Medicine, Creighton University, Omaha, NE 68124, USA 8 Valley Anesthesiology and Pain Consultants—Envision Physician Services, Phoenix, AZ 85004, USA 9 Southcoast Health, Southcoast Physicians Group Pain Medicine, Wareham, MA 02571, USA * Correspondence: [email protected] Received: 14 December 2020; Accepted: 18 January 2021; Published: 21 January 2021 Abstract: Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time.
    [Show full text]
  • Patient Case and Question
    MMRF Patient Summit West Palm Beach, FL 2/11/2017 Management of Multiple Myeloma: The Changing Paradigm Relapsed/Refractory Disease Kenneth H. Shain, MD, PhD Assistant Member H. Lee Moffitt Cancer Center Assistant Professor University of South Florida College of Medicine Tampa, Florida Patient Case and Question A 65-year-old violinist is diagnosed with myeloma and receives Revlimid, Velcade, and dexamethasone (RVD) followed by high-dose melphalan and stem cell transplantation and Revlimid maintenance. 2½ years later, her myeloma markers are increased and, in light of persistent left leg pain, a PET-CT is performed and reveals a new lesion there and in a few other areas. Which of the following factors is NOT a consideration for her treatment at this point? A. The amount of neuropathy she has or could develop B. Her travel schedule C. The genetics of her myeloma at the time of her diagnosis D. The presence of bone disease E. None of the above 1 MMRF Patient Summit West Palm Beach, FL 2/11/2017 What is relapsed/refractory disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy Options for Relapsed/Refractory Disease Continue to Increase When did you relapse from your initial therapy? ≤6 months >6 months Repeat initial therapy Different therapy Different therapy Stem cell transplant Stem cell transplant Clinical trial 2 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Factors to Consider in Treatment Selection DISEASE-RELATED • Amount of disease – CRAB symptoms, rate of progression • Duration of response to initial therapy • FISH/cytogenetics/genomics profile PRIOR TREATMENT–RELATED • Prior drug exposure • Toxicity of regimen • Mode of administration • Previous SCT PATIENT-RELATED • Pre-existing toxicity • Presence of other medical conditions • Age/frailty • General health • Personal lifestyle and preferences FISH, fluorescence in situ hybridization; SCT, stem cell transplant Lonial S.
    [Show full text]
  • (Filanesib) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low Α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study
    Prolonged Survival and Improved Response Rates with ARRY‐520 (Filanesib) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study S Lonial1, J Shah2, JA Zonder3, W Bensinger4, A Cohen5, JL Kaufman1,A Nooka1, D Weber2, B Hilder6, S Rush6, M Ptaszynski6, D Walker6, R Orlowski2 1Winship Cancer Institute, Emory University, Atlanta GA; 2MD Anderson Cancer Center, Houston TX; 3Karmanos Cancer Institute, Wayne State University, Detroit MI; 4Fred Hutchison Cancer Center, Seattle WA; 5Fox Chase Cancer Center, Philadelphia PA; 6Array BioPharma Inc., Boulder CO 1 Disclosures • Consultant: Millenium; Novartis; Onyx; Janssen • Research Support: Merck; Celgene; Novartis 2 Background: Targeting KSP with ARRY‐520 (Filanesib) • Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor – KSP is a microtubule motor protein critical to the function of proliferating cells • KSP inhibition induces aberrant mitotic arrest and rapid cell death – Novel mechanism of action for MM – Preferentially acts on MCL‐1 dependent cells including MM – Not expected to be cross‐resistant with other drugs 3 ARRAY‐520‐212 –Phase 2 Study Design Cohort 1: Filanesib Single-agent Filanesib 1.5 mg/m2 q 2 weeks 1 2 1 2 G‐CSF G‐CSF Cohort 2: Filanesib + Dexamethasone Combination Filanesib 1.5 mg/m2 q 2 weeks 1 2 1 2 G‐CSF G‐CSF Dexamethasone 40 mg PO weekly 4 Key Eligibility Criteria • Measurable disease (serum, urine or free light chain) • ECOG performance status 0‐1 • Adequate hematology labs without transfusion
    [Show full text]
  • Experimental Therapies for Relapsed Myeloma
    New Therapies for Relapsed Myeloma Abramson Cancer Center Update in Hematologic Cancers Dan Vogl, MD MSCE Assistant Professor of Medicine Hematology/Oncology Division Abramson Cancer Center January 22, 2016 Disclosures Consulting: • Celgene Corporation • Onyx/Amgen • Millennium/Takeda Pharmaceuticals • Karyopharm Research support: • Millennium/Takeda Pharmaceuticals • Acetylon • GSK • Constellation • Calithera Topics Proteasome Inhibitors • Carfilzomib • Ixazomib Histone Deacetylase Inhibitors • Panobinostat • Ricolinostat Monoclonal antibodies • Daratumumab • Isatuximab • Elotuzumab Other drugs • Ibrutinib, vemurafenib, filanesib, selinexor Proteasome Inhibitors carfilzomib, ixazomib Carfilzomib: ASPIRE Planned interim analysis of a randomized, open-label phase III trial Pts with relapsed or KRd progressive MM, Carfilzomib Days 1, 2, 8, 9, 15, 16/cycles 1-12, Days 1, 2, 15, 16/cycles 13-18 1-3 prior treatments Lenalidomide Days 1-21 + with ≥ PR in Dexamethasone Days 1, 8, 15, 22 ≥ 1 prior regimen, 28-day cycle ECOG PS 0-2, and (n = 396) Until PD or CrCl ≥ 50 mL/min unacceptable (N = 792) toxicity Rd Lenalidomide Days 1-21 + Stratified by β2- microglobulin, prior Dexamethasone Days 1, 8, 15, 22 bortezomib, and prior 28-day cycle lenalidomide (n = 396) Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter. Lenalidomide: 25 mg. Dexamethasone: 40 mg. Stewart AK, et al. N Engl J Med. 2015;372:142-152. Carfilzomib: ASPIRE Better responses Toxicity • CR 32 vs 9% • More diarrhea, cough, fever, • ORR 87 vs 67% URI, hypokalemia,
    [Show full text]
  • Management of Multiple Myeloma: the Changing Paradigm
    MMRF Patient Summit West Palm Beach, FL 2/11/2017 Management of Multiple Myeloma: The Changing Paradigm Promising Clinical Trials in Multiple Myeloma Ajay Nooka, MD Assistant Professor Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University Atlanta, Georgia Impact of Clinical Trials in Myeloma: Dramatic Improvements in Survival in <10 Years Bortezomib Lenalidomide Thalidomide Pomalidomide Elotuzumab Daratumumab Melphalan Carfilzomib Panobinostat ASCT Ixazomib Corticosteroids 1958 1962 1983 1999 2002 2012 2013 2015 Median OS 72 mo 64 mo 29.9 mo <12 mo ? 1958 1971–1998 2001–2005 2006–2011 2015– Kumar SK et al. Leukemia. 2014;28:1122. Kumar SK et al. Blood. 2008;111:2516. 1 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Targets in Myeloma Plasma Cell Ocio EM et al. Leukemia .2014;28:525. Goal of Clinical Trials: Making Progress Against Myeloma • Increase understanding of the disease – Improve the way we use currently available drugs – Identify new treatments • Develop new medications that improve, and potentially lengthen, the lives of patients with cancer • Reduce toxicities/side effects • No placebos! 2 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Pertinent Research Questions • How can treatments be matched to patients’ subtypes/genomics (personalized medicine)? Venetoclax Monotherapy for Relapsed/ Refractory Multiple Myeloma: Safety and Efficacy Results From a Phase 1 Study Venetoclax Pro-apoptotic BCL-2 protein BCL-2 Apoptosis initiation Pro-apoptotic BIM protein BAX BAK Cancer Cell Cancer Cell Death BAX Survival Activation of caspases Cytochrome c BCL-2 overexpression allows cancer Venetoclax binds selectively to BCL-2, freeing cells to evade apoptosis by pro-apoptotic proteins that initiate programmed sequestering pro-apoptotic proteins.3-5 cell death (apoptosis).6-8 1.
    [Show full text]