Multiple Myeloma, Version 1.2013

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

Abstract

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is approved for 1.0 contact hour. Approval as a provider refers to recognition of educational activities only and does not imply ANCC Commission on Accreditation approval or endorsement of any product. Accredited status does not imply endorsement by the provider of the education activity (NCCN). Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-13-006-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/8799; and 4) view/print certificate.

Release date: January 11, 2013; Expiration date: January 11, 2014

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to NCCN Guidelines for Multiple Myeloma

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Multiple Myeloma

F1NCCN Guidelines Insights: Multiple Myeloma, Version 1.2013

Version 1.2013 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0004

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. The American Cancer Society has estimated that 21,700 new cancer cases of MM will be diagnosed in the United States in 2012, and an estimated 10,710 deaths from the disease will occur.1 The mean age of affected individuals is 62 years for men (75% >70 years) and 61 years for women (79% >70 years).

Understanding of the key pathways responsible for MM has led to the development of novel agents. The availability of many novel evidence-based options for the treatment of MM has led to significant improvements in response and survival.

Most patients with MM experience relapse or become refractory to treatment, partly because of the changing tumor biology. The agents and regimens used as initial therapy have shown significant activity and improved outcomes in patients with relapsed or refractory MM. These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MM. These include the addition of new agents and regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of MM.

Treatment of Progressive or Relapsed Myeloma

Salvage therapy is considered for progressive or relapsed MM in patients with relapsed disease after autologous or allogeneic stem cell transplant (SCT); primary progressive disease after initial autologous or allogeneic SCT; and those ineligible for SCT with progressive or relapsing disease after initial primary therapy.

A variety of therapies are available as options for salvage therapy. The choice of therapy for relapsed/refractory MM is influenced by patient characteristics, comorbidities (eg, presence of significant peripheral neuropathy), and response to and time to relapse with previous therapies. If the relapse occurs more than 6 months after completion of the initial primary therapy, patients may be re-treated with the same primary regimen.

The NCCN Multiple Myeloma Panel members have classified the salvage regimens options either as “preferred regimens” or “other regimens” (see MYEL-D 2 of 2, on page 13) based on evidence and a balance of efficacy and toxicity.

Preferred Salvage Therapy Regimens

Carfilzomib: In patients who have become resistant to bortezomib, the use of a new proteosome inhibitor, such as carfilzomib, with a different chemical backbone has been shown to overcome this resistance.2,3

Carfilzomib is a second-generation proteosome inhibitor that binds highly selectively and irreversibly to the proteasome. It is administered intravenously. Preclinical studies with carfilzomib show lack of neurodegeneration in vitro4 and less neurotoxicity in animal studies.5 The FDA granted accelerated approval of carfilzomib for the treatment of patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have shown disease progression on or within 60 days of completion of the last therapy. The FDA approval was based on the results of the open-label, single-arm phase II study in which 266 patients received single-agent carfilzomib intravenously twice weekly for 3 of 4 weeks.6 Of the evaluable patients in this study, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. Patients had a median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. The primary end point of this trial was overall response rate (ORR), and secondary end points included duration of response, clinical benefit response rate (≥minimal response), progression-free survival (PFS), overall survival (OS), and safety. The ORR seen in the trial was 23.7%, median duration of response was 7.8 months, and median OS was 15.6 months.6 No cumulative toxicities were reported. Common adverse events reported were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Treatment-related peripheral neuropathy occurred in 12.4% of patients overall. This is substantially lower than the incidence of peripheral neuropathy seen in the study evaluating subcutaneous bortezomib.7,8 The rate of cardiac events observed in this study was within the expected range for this population and also was not greater than previously reported with bortezomib.9,10 The safety and efficacy data of carfilzomib seen in this trial are comparable to those reported by other phase II trials.11,12 The available data indicate that carfilzomib produces durable responses with an acceptable tolerability profile in heavily pretreated patients with myeloma.

The results of the ongoing phase III studies should provide insight into the optimal use of carfilzomib in all patients with MM. The international, randomized, multicenter phase III trial known as ASPIRE has completed enrollment and is comparing lenalidomide plus low-dose dexamethasone with or without carfilzomib in patients who have received 1 to 3 prior therapies for relapsed MM (ClinicalTrials.gov identifier: NCT01080391). Other phase III trials currently recruiting patients include an international phase III trial, known as the ENDEAVOR trial, which will evaluate the combination of carfilzomib and low-dose dexamethasone versus the combination of bortezomib and low-dose dexamethasone (ClinicalTrials.gov identifier: NCT01568866). A phase III clinical trial, known as the FOCUS trial, will evaluate single-agent carfilzomib versus best supportive care in patients with relapsed and refractory MM who have received 3 or more prior therapies (ClinicalTrials.gov identifier: NCT01302392).

In the recently updated version of the NCCN Guidelines for MM, the panel included single-agent carfilzomib as a salvage therapy option in patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have shown disease progression on or within 60 days of completion of the last therapy (category 2A).

Bortezomib in Combination With Thalidomide and Dexamethasone: An international open-label study randomized 269 patients with progressive or relapsed MM after at least 1 autologous SCT to receive bortezomib with thalidomide and dexamethasone or thalidomide and dexamethasone.13 Patients receiving the triple-drug combination of bortezomib with thalidomide and dexamethasone had significantly better outcomes. Median time to progression was longer (19.5 vs. 13.8 months) and PFS was also significantly longer (18.3 vs. 13.6 months) compared with thalidomide and dexamethasone. The complete response (CR) and near-CR rate was higher in patients receiving bortezomib, thalidomide, and dexamethasone compared to thalidomide and dexamethasone (45% vs. 25%; P=.001). No significant difference was observed in OS between the arms over a median follow-up of 30 months. The most clinically significant adverse event seen was grade 3 peripheral neuropathy in 29% of patients on the triple-drug combination versus 12% of those on thalidomide and dexamethasone.13

The panel included bortezomib in combination with thalidomide and dexamethasone as an option for relapsed/refractory myeloma (category 2A).

Other Salvage Therapy Regimens

Lenalidomide in Combination With Bendamustine and Dexamethasone: A multicenter phase I/II trial investigated treatment with the combination of bendamustine, lenalidomide, and dexamethasone for patients (n=29) with relapsed refractory MM.14 A partial response was seen in 52% (n=13) of patients, and a very good partial response was seen in 24% (n=6). The median PFS was 6.1 months (95% CI, 3.7-9.4 months), and the 1-year PFS rate was 20% (95% CI, 6%-41%).14

The panel included lenalidomide in combination with bendamustine and dexamethasone as an option for relapsed/refractory myeloma (category 2A).

Vorinostat in Combination With Bortezomib: Vorinostat is an oral inhibitor of histone deacetylase (HDAC) class I and II proteins. It regulates genes and proteins involved in tumor growth and survival. It is FDA approved for the treatment of patients with cutaneous T-cell lymphoma. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and were confirmed in independent phase I trials in patients with relapsed/refractory MM, showing an ORR of up to 42%.15 An international, multicentered, open-label, single-arm phase IIB trial called Vantage 095 studied combination vorinostat and bortezomib in patients who were bortezomib-refractory and in those considered refractory, intolerant, or ineligible for immunomodulatory drug-based regimens. The combination of vorinostat and bortezomib was active and well tolerated in these patients. The ORR in the Vantage 095 study was 17%.16 The median OS observed was 11.2 months, with a 2-year OS rate of 32%.19 Another international multicenter, randomized, double-blind phase II trial compared vorinostat and bortezomib with bortezomib and placebo in patients with relapsed/refractory MM.17 The ORR in patients treated with vorinostat and bortezomib was 56% versus 41% in those treated with bortezomib and placebo.17 The median PFS was 7.63 for vorinostat and bortezomib versus 6.83 months for bortezomib and placebo-treated patients.

Based on these data, the panel has included vorinostat in combination with bortezomib as a treatment option for relapsed/refractory myeloma (category 2A).

Management of Peripheral Neuropathy in MM

Peripheral neuropathy is a common complication seen in patients with MM. It can be caused by MM itself or by certain therapies, such as bortezomib, thalidomide, vinca alkaloids, and cisplatin. Bortezomib-induced neuropathy occurs in nearly 70% of patients.18-20 Although the neuropathy does improve with time in most patients, it has a significant impact on quality of life, especially in the elderly population.

Effective management of treatment-emergent peripheral neuropathy is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. A randomized trial, MMY-3021, compared single-agent bortezomib administered through the conventional intravenous route versus the subcutaneous route in 222 patients.7 The findings from the phase III MMY-3021 study show noninferior efficacy with subcutaneous versus intravenous bortezomib with regard to the primary end point (ORR after 4 cycles of single-agent bortezomib). Consistent results were shown with regard to secondary end points.7 The results showed no significant differences between the groups in terms of time to progression or 1-year OS.7,8 However, patients receiving bortezomib subcutaneously had a significant reduction in peripheral neuropathy, and significantly less grade 3/4 neuropathy (6% vs. 16%).7 Based on these data, the updated US Prescribing Information notes that “starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy.” The FDA-recommended dose of bortezmib is 1.3 mg/m2 administered as either a 3- to 5-second bolus intravenous injection or a subcutaneous injection.

The panel has noted in a footnote that subcutaneous bortezomib may be considered for patients with preexisting or high-risk peripheral neuropathy (see MYEL-D 2 of 2, on page 13).

Conclusions

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of recurrent or progressive disease in the most recent version of the NCCN Guidelines for MM. The NCCN Guidelines are in continuous evolution. They are updated annually, or sometimes more often if new high-quality clinical data become available in the interim. The recommendations in the NCCN Guidelines, with few exceptions, are based on evidence from clinical trials. Expert medical clinical judgment is required when applying these guidelines in the context of individual clinical circumstances to provide optimal care. The physician and patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials.

EDITOR: Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network, has disclosed that she has no relevant financial relationships.

CE AUTHORS: Nicole B. Fair, BS, Manager, Continuing Education and Grants, has disclosed that she has no relevant financial relationships. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships. James Prazak, RPh, Director, Continuing Education and Grants, has disclosed the following relationships with commercial interests: Bristol-Myers Squibb Company: Pension; Pfizer, Inc: Stockholder; United Healthcare Group: Stockholder; Johnson & Johnson: Stockholder. Dorothy Shead, MS, Director, Patient and Clinical Information Operations, has disclosed that the has no relevant financial relationships. Rashmi Kumar, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

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    NCCN Guidelines Insights: Multiple Myeloma, Version 1.2013

    Version 1.2013 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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