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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
  • Valid for credit through: 9/6/2019
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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


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


  • Joseph Mikhael, MD, MEd, FRCPC

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


    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


    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


    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.


  • Sara Fagerlie, PhD, CHCP

    Scientific Director, Medscape, LLC


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

CME Reviewer

  • Esther Nyarko, PharmD

    Associate CME Clinical Director, Medscape, LLC


    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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    For Physicians

  • Medscape, LLC designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Master Class: Proteasome Inhibitor-Based Therapy


Newly Diagnosed Multiple Myeloma

  • Master Class: Proteasome Inhibitor-Based Therapy: Newly Diagnosed Multiple Myeloma

    • Rafat Abonour, MD

  • Slide 1.

    Slide 1.

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  • Initial Evaluation: Investigative Workup[3]

    • Serum protein electrophoresis, immnofixations, and quantitative immunoglobulins are important to test, especially in patients with immunoglobulin A (IgA) MM
    • Bone marrow biopsy with aspirate should be collected for flow cytometry and cytogenetic analysis
    • Fluorescent in situ hybridization (FISH) should be done on CD138 sorted cells
    • Lactate dehydrogenase (LDH), B2 microglobulin, and cytogenetic analysis are critical for disease staging
    • A skeletal survey is needed at minimum, but a positron emission tomography (PET) scan is preferred because of its higher sensitivity
    • Magnetic resonance imaging [MRI] does not replace a skeletal survey but is becoming widely used, especially in patients with small brain myeloma

  • Slide 3.

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  • Diagnostic Criteria: MM Requiring Therapy[12]

    • Diagnostic criteria include evidence of end organ damage (hypercalcemia, renal failure, anemia, and bone lesions [CRAB] criteria)
    • There are now added biomarkers to identify a subset of asymptomatic patients who require therapy

  • Slide 4.

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  • Staging MM: Revised ISS[13-15]

    • The Revised International Staging System (R-ISS) is intended to improve our ability to provide a better prognosis
    • R-ISS incorporated B2 microglobulin, LDH, and cytogenetic status
    • The presence of high-risk cytogenetics includes deletion of chromosome 17p and translocations of chromosomes 4 and 14 or 14 and 16

  • Slide 5.

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  • Case: Daniel (cont)

    • LDH is required to accurately stage Daniel

  • Slide 6.

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  • Components of MM Therapy[3]

    • Every patient will undergo induction therapy, preferably followed by ASCT and maintenance therapy
    • A significant number of patients eventually will relapse and require treatment
    • Throughout the course of the treatment, it is important to pay attention to supportive care
    • It is important to consider ASCT early in the course of the disease and make a referral to a transplant center by the second cycle

  • Slide 7.

    Slide 7.

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  • VRd vs Rd: SWOG S0777 Data: 3-Drug Regimen as Initial Induction[16]

    • The Southwest Oncology Group S0777 study showed that a 3-drug regimen of bortezomib, lenalidomide, and dexamethasone (VRd, RVd) was superior to lenalidomide and dexamethasone alone for patients not undergoing immediate ASCT
    • High-risk patients had outcomes similar to those of standard-risk patients
    • Patients treated with VRd had better outcomes than patients treated with Rd whether they were standard or high risk
    • Elderly patients did well on the triplet regimen

  • Slide 8.

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  • IFM 2009 Study: ASCT vs No ASCT[17]

    • The IFM2009 study compared VRd induction followed by ASCT or consolidation with VRd and 1 year of lenalidomide maintenance
    •  ASCT resulted in superior progression-free survival (PFS)
    • Transplant-related mortality was 1.7%
    •  4-year overall survival (OS) was similar between the arms; the reason for this is unclear

  • Slide 9.

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  • Case: Daniel (cont)

    • How would you approach change if Daniel was older?

  • Slide 10.

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  • ASCT Eligibility: Age and Fitness[18,19]

    • Fitness is dynamic and should be assessed throughout the course of the disease, not at presentation
    • Use assessment tools to determine fitness
    • All patients should be referred to a tertiary care center to determine eligibility

  • Slide 11.

    Slide 11.

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  • Components of Myeloma Therapy: Transplant-Ineligible Patients[3]

    • If a patient is truly ineligible, they still require an active induction treatment, which usually will include a triplet regimen followed by maintenance or continuation of therapy to prolong PFS and OS
    • Attention should also be paid to supportive care throughout the course of the disease

  • Slide 12.

    Slide 12.

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  • Maintenance Lenalidomide: Meta-Analysis[20]

    • Maintenance lenalidomide has been shown to improve PFS and OS

  • Slide 13.

    Slide 13.

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  • High Risk Cytogenetics[20-22]

    • The benefit of maintenance lenalidomide monotherapy is less clear in patients with high-risk myeloma
    • Adding a proteasome inhibitor in the maintenance setting may provide a benefit for high-risk patients

  • Slide 15.

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  • Implementing Maintenance Therapy[20-24]

    • Most patients, regardless of treatment response, should receive maintenance therapy
    • Currently, the recommendation for lenalidomide monotherapy is to use it until progression but modify for toxicity

  • Slide 16.

    Slide 16.

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  • Other Options in the Frontline Setting[3,24,25]

    • The bortezomib, cyclophosphamide, and dexamethasone regimen may be used for select patients such as patients with advanced renal failure who are on dialysis
    • Monoclonal antibody-based therapy is now approved as frontline treatment, although the approved regimen is not commonly used in United States

  • Slide 17.

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  • Select Adverse Events and Prophylaxis by Drug Class[3,26-28]

    • Pay attention to the side effects of the class of drugs used and use prophylaxis or additional therapies to help prevent them

  • Slide 18.

    Slide 18.

    (Enlarge Slide)
  • Antiviral Prophylaxis[29-32]

    • Patients on proteasome inhibitors and monoclonal antibodies require antiviral prophylaxis
    • Acyclovir is most commonly used

  • Slide 19.

    Slide 19.

    (Enlarge Slide)
  • Thromboembolism Prophylaxis: IMWG Recommendations[28-33]

    • Patients on immunomodulatory agents require prophylaxis

  • Slide 20.

    Slide 20.

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  • Bone-Modifying Agents[34]

    • Bone disease is a hallmark of MM
    • Patients with MM are at increased risk of pathologic fractures and skeletal-related events
    • Patients should be started on a bone-modifying agent
    • Most patients will undergo treatment with a bisphosphonate
    • Denosumab was recently found to be noninferior to zoledronic acid and may be an option in select patients such as those with renal impairment
    • There are no data to support the use of bisphosphonates in patients with solitary plasmacytoma, smoldering myeloma, or indolent myeloma
    • All bone-modifying agents are associated with an increased risk of osteonecrosis of the jaw (ONJ), and patients should have appropriate dental care
    • All patients should receive calcium and vitamin D

  • Slide 21.

    Slide 21.

    (Enlarge Slide)
  • Managing Infections[3,35,36]

    • Patients with MM are at increased risk of infection
    • If prophylactic antibiotics are used, pay careful attention to the side effects, and intravenous immunoglobulins for patients with severe hyperglobulinemia and recurrent infection should be considered

  • Slide 22.

    Slide 22.

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  • Managing Peripheral Neuropathy[9-11,28]

    • Peripheral neuropathy should be addressed early
    • Communication between patients, nurses, and physicians is critical so medications can be adjusted as needed

  • Slide 23.

    Slide 23.

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  • Key Takeaways: Frontline Therapy

  • Slide 24.

    Slide 24.

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