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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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  • 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.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.75 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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Master Class: Proteasome Inhibitor-Based Therapy


Relapsed/Refractory Multiple Myeloma

  • Master Class: Proteasome Inhibitor-Based Therapy: Relapsed/Refractory Multiple Myeloma

    • Thomas Martin, MD

  • Slide 1.

    Slide 1.

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  • Monitoring Patients After Initial Therapy: Asymptomatic, Non-Progressing[3]

    • Appropriate monitoring for disease progression is critical
    • Patients in remission after initial therapy are followed with routine blood tests every 4 to 12 weeks, depending on the depth of response and prior disease characteristics
    • Thomas Martin, MD: If they are getting active treatment, I follow it every 4 weeks. If not, every 12 weeks is fine
    • The tests include a complete blood cell count (CBC) and routine chemistries and myeloma-specific tests
      • Protein electrophoresis, serum-free light chains, and quantitative immunoglobulins 
    • Imaging studies and repeat bone marrow biopsies are not routinely recommended during remission but can be performed at relapse

  • Slide 2.

    Slide 2.

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  • Don't Miss Disease Progression[37]

    • International Myeloma Working Group (IMWG) criteria define progression as a 25% or greater increase in M-protein from its lowest value
    • 2 consecutive measurements are required to officially confirm disease progression

  • Slide 3.

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  • Evaluation at Relapse[3]

    • Light-chain escape is a more common way of progression, so it is imperative to check serial serum-free light chain evaluations even if the original disease was predominantly characterized by a serum or urine M-protein
    • Upon relapse, perform a repeat 24-hour test to assess urine M-component but also to assess creatinine clearance
    • Dr Martin: I usually repeat imaging for symptomatic bone disease. I frequently repeat a bone marrow biopsy to reassess cytogenetics and FISH testing 

  • Slide 4.

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  • When to Initiate Therapy at Relapse[3]

    • Patients can be asymptomatic at relapse
    • Biochemical progression is noted from blood tests of asymptomatic patients
    • Patients may not need immediate treatment, especially if the proteins are rising slowly
    • In contrast, some asymptomatic patients may have a history of high-risk disease or have a rapid doubling time with their myeloma proteins
      • Consider starting treatment immediately in these patients, even in the absence of symptoms, with the goal of preventing symptomatic disease
    • In patients with symptomatic disease or end-organ disease such as anemia, new bone lesions, or renal insufficiency, treatment must be initiated immediately 

  • Slide 5.

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  • Therapy Selection Considerations[38]

    • There are a number of active therapies available for the treatment of relapsed disease
    • Many factors should be considered when selecting therapy, including disease-related, therapy-related, and patient-related factors
    • Dr Martin: If a patient has evidence of high-risk disease, we may favor using a proteasome inhibitor as part of the relapse regimen
      • If prior therapy resulted in significant toxicity, we would want to avoid similar agents to prevent that toxicity from happening again
      • If a patient now has renal insufficiency or other new comorbidities, we may favor proteasome inhibitors or immunomodulatory drugs depending on the comorbidity
      • We should strive to provide truly personalized care for patients with relapsed MM

  • Slide 6.

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  • Therapy at First Relapse[3,38]

    • The goals of therapy will vary from patient to patient
    • Dr Martin: For most patients with first relapse or early relapse, I tend to be more aggressive in trying to induce the deepest response possible
    • Recent randomized trials have demonstrated that triplet regimens are superior to doublets, with higher overall response rates, improved PFS, and, in a few studies, improved OS
    • In frail patients, treatment with a triplet may still be possible using modified doses

  • Slide 7.

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  • Recent Phase 3 Trials: Relapsed/Refractory MM[6,39-45]

    • The experimental arm in all these studies yielded prolonged PFS and benefits in patients with adverse FISH cytogenetics 

  • Slide 9.

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  • ASPIRE: Lenalidomide/Dex ± Carfilzomib[39]

    • The investigators have subsequently reported on a subset analysis of patients with high-risk disease that the PFS advantage with carfilzomib, lenalidomide, and dexamethasone (KRd) vs len/dex was approximately 9 months

  • Slide 10.

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  • ENDEAVOR: Carfilzomib/Dex vs Bortezomib/Dex[40,46]

    • There was an increased incidence of severe hypertension, cardiac toxicity, and renal insufficiency in the carfilzomib-containing arm and an increased risk of neuropathy in the bortezomib-containing arm
    • Patients with deletion 17p, or high-risk patients, did better with carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd)
    • Dr Martin: In general, when I think about a high-risk patient, I would consider choosing a triplet over a doublet

  • Slide 11.

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  • TOURMALINE-MM1: Ixazomib + Len/Dex vs Placebo + Len/Dex[41]

    • The triplet regimen of ixazomib, lenalidomide, and dexamethasone (IRd) resulted in improved PFS of approximately 21 months vs the control arm
    • This improvement was maintained in the subset of 17p-deleted patients
    • This study was done in patients who were sensitive to prior proteasome inhibitor therapy
    • In a patient who may have been resistant to prior bortezomib or carfilzomib, this may not be the best regimen
    • Oral ixazomib appears to be associated with a lower incidence of peripheral neuropathy than standard bortezomib-based therapy

  • Slide 12.

    Slide 12.

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  • CASTOR: Bortezomib/Dex ± Daratumumab[43]

    • Median PFS has been reported to be approximately 17 months for triplet therapy vs 7 months for the doublet regimen
    • Subgroup analysis found an even longer PFS benefit in patients receiving daratumumab/bortezomib/dexamethasone as the first treatment in relapse
    • Patients with high-risk disease appeared to do well on this regimen
    • Dr Martin: Overall, the data are emerging to suggest that antibody therapy can be combined nicely with proteasome inhibitors, both bortezomib and carfilzomib, as well as with immunomodulatory drugs such as lenalidomide and pomalidomide

  • Slide 13.

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  • Antibody-Based Therapies[47]

    • Infusion-related reactions are a common side effect of antibody-based therapy
    • Daratumumab causes a uniform false positive Indirect Antiglobulin Test
      • Every patient should have a typing screen performed prior to receiving daratumumab
    • Both elotuzumab and daratumumab can cause a false positive immunofixation electrophoresis
      • In general, this may cause an underestimation of the number of patients who have achieved complete remission
      • This may be increasingly significant as antibodies move to frontline treatment

  • Slide 14.

    Slide 14.

    (Enlarge Slide)
  • Ask The Expert: Fit Patient, High Risk[3]

    • A panel of 18 myeloma experts were surveyed, and carfilzomib, lenalidomide, and dexamethasone was the most commonly selected regimen for a patient like Daniel

  • Slide 15.

    Slide 15.

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  • Case: Daniel (cont)

    • Daniel had evidence of high-risk disease at relapse and was treated with carfilzomib, lenalidomide, and dexamethasone

  • Slide 16.

    Slide 16.

    (Enlarge Slide)
  • Cardiopulmonary Issues[48]

    • Dr Martin: Specifically, with KRd, the things I watch closely for are hypertension, renal insufficiency, volume overload, and congestive heart failure
    • Cardiac signals have occurred with all proteasome inhibitors, and they are more pronounced with carfilzomib
    • Patients may have predisposing factors like older age, other comorbidities, or something in their prior treatment history
    • Identify patients before starting therapy who may have uncontrolled blood pressure problems or congestive heart failure and control these before beginning proteasome inhibitor or carfilzomib-based therapy
    • It is very important to do a history and physical exam as screening tools prior to proteasome inhibitor therapy 

  • Slide 17.

    Slide 17.

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  • Incidence of Cardiac Issues With Carfilzomib[39,40,48]

    • Dr Martin: Patients should be watched very closely, and you should take an active role in managing potential adverse events. You need to follow fluid status and follow weights. You need to evaluate patients if they are having shortness of breath

  • Slide 18.

    Slide 18.

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  • Managing Cardiac Issues for Patients on Carfilzomib[49]

    • Dr Martin: I typically follow labs weekly for cycle 1. I look for tumor lysis. I look for renal insufficiency. I look for electrolyte abnormalities, so we do not have any arrhythmias. You need to treat tumor lysis if it occurs. You need to treat hypertension aggressively if it occurs. You need to consider dose reductions or diuretics if they are having volume overload

  • Slide 19.

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  • Second ASCT[50]

    • A second ASCT is an option in patients with relapsed disease, especially if they have good performance status
    • Dr Martin: The general rule is that a second ASCT will result in a PFS benefit of approximately 40% to 50% compared with transplant number 1. In general, I think the minimum PFS benefit from transplant 1 should be at least 24 months. I really prefer if it is more than 36 months to take patients to a second ASCT

  • Slide 20.

    Slide 20.

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  • Case: Daniel (cont)

    • Daniel has now progressed on some of our best myeloma drugs: pomalidomide, ixazomib, and daratumumab
    • As expected with each subsequent therapy, PFS is shorter and shorter and continued relapse occurs

  • Slide 21.

    Slide 21.

    (Enlarge Slide)
  • Other Considerations

    • Dr Martin: In some patients, it may be appropriate to consider palliative or hospice care. However, there are additional options. In young patients, I always consider salvage combination chemotherapy, especially if they have not had any significant alkylator or anthracycline chemotherapy in the past
      • Another option is to mix up multiple agents, so do triplet or 4-drug therapy, especially when some of the individual agents perhaps failed and were not combined
      • For instance, I often will combine carfilzomib with pomalidomide and dexamethasone. I may see responses 10% of the time even though the patient was refractory to the individual agent
      • One also can consider other agents, perhaps, agents that are approved in other cancers. A great example is the drug venetoclax, which is approved for use in chronic lymphocytic leukemia (CLL).  This drug works especially well in patients with myeloma who have the 11;14 translocations. This drug is currently in phase 3 trials in relapsed MM
      • We have an amazing portfolio of novel therapies that are currently being tested in clinical trials

  • Slide 22.

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This content has been condensed for improved clarity.