Bruno B, Rotta M, Giaccone L, et al. New drugs for treatment of multiple myeloma. Lancet Oncol. 2004;5:430-442.
Anderson KC. Progress and Paradigms in Multiple Myeloma. Clin Canc Res. 2016;22:5419-5427.
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Chari A, Mazumder A, Jagannath S. Proteasome inhibition and its therapeutic potential in multiple myeloma. Biologics: Targets & Therapy. 2010;4:273–287.
Shi Q, Chen L. Cereblon: a protein crucial to the multiple functions of immunomodulatory drugs as well as cell metabolism and disease generation. J Immunol Res. 2017. doi: 10.1155/2017/9130608. [Epub ahead of print].
Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-631.
Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62:1841-1849.
Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108:618-621
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Ninlaro® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2016.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548
Greipp PR, San Miguel J, Durie BG, et al. International Staging System for Multiple Myeloma. J Clin Oncol. 2005;23:3412-3420.
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863-2869.
Chng WJ, Dispenzieri A, Chim C-S, et al. IMWG consensus on risk stratification in multiple myeloma Leukemia. 2014;28:269-277.
Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519-527.
Attal M, Lauwers-Cances , Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-1320.
Palumbo A, Bringhen S, Mateos M-V, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-2074.
Larocca A, Palumbo A. How I treat fragile myeloma patients. Blood. 2015;126:2179-2185.
McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279-3289.
Sonneveld P, Avet-Loiseah H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955-2562.
Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955.
Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patientsLeukemia. 2013;28:690-693.
Darzalex® [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2017.
Mateos B-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528.
Kurtin SE, Bilotti E. Novel agents for the treatment of multiple myeloma: proteasome inhibitors and immunomodulatory agents. J Adv Pract Oncol. 2013;4:307-321.
Raje NS, Yee AJ, Roodman GD. Advances in supportive care for multiple myeloma.J Natl Compr Canc Netw. 2014;12:502-511.
IMWG website. Publications. Available at: http://imwg.myeloma.org/category/imwg-publications/. Accessed July 4, 2018.
Hansson E, Forbes HJ, Langan SM, Smeeth L, Bhasharan K. Herpes zoster risk after 21 specific cancers: population-based case–control study. Br J Cancer. 2017;116:1643-1651.
Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784-4790.
Kamber C, Zimmerli Suter-Riniker F, et al. Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients. Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients. Bone Marrow Transplant. 2015;50:573-578.
Fukushima T, Sato T, Nakamura T, et al. Daily 500 mg valacyclovir is effective for prevention of Varicella zoster virus reactivation in patients with multiple myeloma treated with bortezomib. Anticancer Res. 2012;32:5437-5440.
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.
Anderson K, Ismaila N, Flynn PJ, et al Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol. 2018;36:812-818.
Colson K. Treatment-related symptom management in patients with multiple myeloma: a review. Support Care Cancer. 2015;23:1431-1445.
Drayson M, et al. Tackling early morbidity and mortality in myeloma (TEAMM): assessing the benefit of antibiotic prophylaxis and its effect on healthcare associated infections in 977 patients [ASH abstract 903]. Blood. 2017;130.
Kumar S, Anderson KC, Durie B, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-e346.
Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017;130:963-973.
Stewart AK, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27-38.
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634.
Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
San Miguel JF, Hungreia VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trialLancet Oncol. 2014;15:1195-1206.
Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:728-734.
Dimopoulos MA, Goldschmidt H, Niesviszky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:1327-1337.
van de Donk NWCJ, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13-29.
Mateos MV, Moreau P, Berenson JR, et al. Once-weekly versus twice-weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma: results of the randomized phase 3 study A.R.R.O.W. Presented at: 2018 American Society of Clinical Oncology meeting. Chicago, IL. Abstract 8000.
Mikhael J. Management of carfilzomib-associated cardiac adverse events. Clin Lymphoma Myeloma Leuk. 2016;16:241-245.
Giralt S, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on salvage hematopoietic cell transplantation in patients with relapsed multiple myeloma. Biol Blood Marrow Transplant. 2015;21:2039-2051.

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Faculty

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer
International Myeloma Foundation
Professor
City of Hope Cancer Center
Los Angeles, California

Disclosures

Disclosure: Joseph Mikhael, MD, MEd, FRCPC, FACP, has disclosed the following relevant financial relationships:
Received grants for clinical research from: AbbVie Inc.; Celgene Corporation; Sanofi

Dr Mikhael does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Mikhael does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Rafat Abonour, MD

Professor of Pathology & Laboratory Medicine
Medical Director, Bone Marrow Transplant Program
Medical Director, Stem Cell Laboratory
Indiana University School of Medicine
Indianapolis, Indiana

Disclosures

Disclosure: Rafat Abonour, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Amgen Inc.; Bristol-Myers Squibb Company; Celgene Corporation; Janssen Pharmaceuticals; Takeda Pharmaceuticals North America, Inc.
Received grants for clinical research from: Celgene Corporation; Takeda Pharmaceuticals North America, Inc.

Dr Abonour does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Abonour does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Thomas Martin, MD

Professor of Clinical Medicine
UCSF Medical Center
San Francisco, California

Disclosures

Disclosure: Thomas Martin, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Roche
Received grants for clinical research from: Amgen Inc.; Sanofi

Dr Martin does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Martin does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor

Sara Fagerlie, PhD, CHCP

Scientific Director, Medscape, LLC

Disclosures

Disclosure: Sara Fagerlie, PhD, CHCP, has disclosed no relevant financial relationships.

CME Reviewer

Esther Nyarko, PharmD

Associate CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

CME / ABIM MOC

Master Class: Proteasome Inhibitor-Based Therapy

Authors: Rafat Abonour, MD; Thomas Martin, MD; Joseph Mikhael, MD, MEd, FRCPC
CME / ABIM MOC Released: 9/6/2018
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 9/6/2019, 11:59 PM EST

Start Activity

Target Audience and Goal Statement

This activity is intended for hematologists, oncologists, and other healthcare professionals caring for patients with multiple myeloma.

The goal of this activity is to increase knowledge and competence for healthcare professionals managing care of patients undergoing treatment with proteasome inhibitor (PI)-based combination therapy for the treatment of multiple myeloma (MM).

Upon completion of this activity, participants will:

Have increased knowledge regarding
- Differentiating PI-based combination treatments for MM
Demonstrate greater confidence in their ability to
- Select optimal PI-based regimens for appropriate patients with MM

Disclosures

Faculty

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer
International Myeloma Foundation
Professor
City of Hope Cancer Center
Los Angeles, California

Disclosures

Disclosure: Joseph Mikhael, MD, MEd, FRCPC, FACP, has disclosed the following relevant financial relationships:
Received grants for clinical research from: AbbVie Inc.; Celgene Corporation; Sanofi

Dr Mikhael does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Mikhael does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Rafat Abonour, MD

Professor of Pathology & Laboratory Medicine
Medical Director, Bone Marrow Transplant Program
Medical Director, Stem Cell Laboratory
Indiana University School of Medicine
Indianapolis, Indiana

Disclosures

Disclosure: Rafat Abonour, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Amgen Inc.; Bristol-Myers Squibb Company; Celgene Corporation; Janssen Pharmaceuticals; Takeda Pharmaceuticals North America, Inc.
Received grants for clinical research from: Celgene Corporation; Takeda Pharmaceuticals North America, Inc.

Dr Abonour does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Abonour does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Thomas Martin, MD

Professor of Clinical Medicine
UCSF Medical Center
San Francisco, California

Disclosures

Disclosure: Thomas Martin, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Roche
Received grants for clinical research from: Amgen Inc.; Sanofi

Dr Martin does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Martin does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor

Sara Fagerlie, PhD, CHCP

Scientific Director, Medscape, LLC

Disclosures

Disclosure: Sara Fagerlie, PhD, CHCP, has disclosed no relevant financial relationships.

CME Reviewer

Esther Nyarko, PharmD

Associate CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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The Role of Proteasome Inhibition in Multiple Myeloma

International Myeloma Working Group Publications

Black Swan Research Initiatives

International Myeloma Foundation Website

Dr. Durie Blogs

Connect with Dr. Durie

Continue »

Master Class: Proteasome Inhibitor-Based Therapy: The Role of Proteasome Inhibition in MM
- Joseph Mikhael, MD, MEd, FRCPC, FACP
[ CLOSE WINDOW ]

Slide 1.

Overview
[ CLOSE WINDOW ]

Slide 2.

Steering Committee and Working Group
[ CLOSE WINDOW ]

Slide 3.

The Myeloma Microenvironment Is Key to Disease Pathophysiology^[1]
- The pathophysiology of multiple myeloma (MM) is complex
- Interaction with the microenvironment is critical for MM cell function
- Understanding of how the disease proliferates has provided information to identify therapeutic targets
[ CLOSE WINDOW ]

Slide 4.

FDA-Approved Therapy for Multiple Myeloma Since 2000^[2]
- MM has undergone a transformation in the last decade due largely due to novel agents and autologous stem cell transplant (ASCT)
[ CLOSE WINDOW ]

Slide 5.

Proteasome Inhibitors and MM Treatment^[3]
- Proteasome inhibitors are critical components of MM treatment
- 3 proteasome inhibitors are US Food and Drug Administration (FDA) approved: bortezomib, carfilzomib, and ixazomib
- Proteasome inhibitors are used routinely in frontline therapy and relapse therapy
- Evidence is now emerging for some use in maintenance therapy
[ CLOSE WINDOW ]

Slide 6.

Inhibition of Proteasomes Impacts Cellular Processes^[2-4]
- The mechanism of proteasome inhibition is complex
- Originally, proteasomes were thought to function mainly through nuclear factor kB (NFkB) but other pathways are impacted as well
- Proteasome inhibitors impact cellular processes including apoptosis, proliferation, migration, and angiogenesis
[ CLOSE WINDOW ]

Slide 7.

Other Pathways: Immunomodulatory Agents^[5]
- Immunomodulatory agents are commonly combined with proteasome inhibitors
[ CLOSE WINDOW ]

Slide 8.

Other Pathways: Monoclonal Antibodies^[2]
- Monoclonal antibodies can be combined with proteasome inhibitors or immunomodulatory agents
- Monoclonal antibodies also work primarily on the cell's surface by targeting antigens such as CD38.
[ CLOSE WINDOW ]

Slide 9.

Immunomodulation by Monoclonal Abs: Elotuzumab^[6-8]
- Monoclonal antibodies can also have an impact in the immune environment in immune modulation, as is seen with elotuzumab, which engages local immune cells and particular natural killer cells
[ CLOSE WINDOW ]

Slide 10.

FDA-Approved Proteasome Inhibitors^[9-11]
- The 3 FDA-approved proteasome inhibitors have different indications and routes of administration
[ CLOSE WINDOW ]

Slide 11.

Key Takeaways
[ CLOSE WINDOW ]

Slide 12.

« Back

Page 2 of 4

Newly Diagnosed Multiple Myeloma

CME / ABIM MOC Information Download Slides

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References

Faculty and Disclosures

Faculty

Joseph Mikhael, MD, MEd, FRCPC

Rafat Abonour, MD

Thomas Martin, MD

Editor

Sara Fagerlie, PhD, CHCP

CME Reviewer

Esther Nyarko, PharmD

Peer Reviewer

CME / ABIM MOC

Master Class: Proteasome Inhibitor-Based Therapy

Target Audience and Goal Statement

Disclosures

Faculty

Joseph Mikhael, MD, MEd, FRCPC

Rafat Abonour, MD

Thomas Martin, MD

Editor

Sara Fagerlie, PhD, CHCP

CME Reviewer

Esther Nyarko, PharmD

Peer Reviewer

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Master Class: Proteasome Inhibitor-Based Therapy

The Role of Proteasome Inhibition in Multiple Myeloma

Master Class: Proteasome Inhibitor-Based Therapy: The Role of Proteasome Inhibition in MM

Slide 1.

Overview

Slide 2.

Steering Committee and Working Group

Slide 3.

The Myeloma Microenvironment Is Key to Disease Pathophysiology[1]

Slide 4.

FDA-Approved Therapy for Multiple Myeloma Since 2000[2]

Slide 5.

Proteasome Inhibitors and MM Treatment[3]

Slide 6.

Inhibition of Proteasomes Impacts Cellular Processes[2-4]

Slide 7.

Other Pathways: Immunomodulatory Agents[5]

Slide 8.

Other Pathways: Monoclonal Antibodies[2]

Slide 9.

Immunomodulation by Monoclonal Abs: Elotuzumab[6-8]

Slide 10.

FDA-Approved Proteasome Inhibitors[9-11]

Slide 11.

Key Takeaways

Slide 12.

PDF Downloads

The Myeloma Microenvironment Is Key to Disease Pathophysiology^[1]

FDA-Approved Therapy for Multiple Myeloma Since 2000^[2]

Proteasome Inhibitors and MM Treatment^[3]

Inhibition of Proteasomes Impacts Cellular Processes^[2-4]

Other Pathways: Immunomodulatory Agents^[5]

Other Pathways: Monoclonal Antibodies^[2]

Immunomodulation by Monoclonal Abs: Elotuzumab^[6-8]

FDA-Approved Proteasome Inhibitors^[9-11]