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APRIL 2010

VOL 3, NO 2, SUPPLEMENT 2

A Supplement to

Highlights from a Symposium

Unifying Practice Patterns Among Academic and Community Clinicians: Focus on Myeloma

This activity is provided by MediCom Worldwide, Inc. This activity is jointly supported through educational grants from Millennium Pharmaceuticals, Inc.; Centocor Ortho Biotech Services, LLC; Ortho Biotech, a division of Janssen-Cilag; Bristol-Myers Squibb; and Genzyme Corporation.

ÂŠ 2010 Green Hill Healthcare Communications, LLC

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Activity Release Date: March 5, 2010 Expiration Date: March 5, 2011 Program Overview Effective, low-risk management of patients with hematologic malignancies, such as multiple myeloma, is rapidly evolving and becoming increasingly complex in nature. Advancements in multiple myeloma manifestation, autologous stem cell transplantation (ASCT), and newly introduced targeted biologic therapeutic agents require a comprehensive, cross-disciplinary understanding on behalf of all oncology healthcare professionals. Early versus late diagnosis, and first-onset versus recurring or refractory disease are all managed by using different therapeutic strategies. Favorable patient outcomes depend on adoption of best-practice guidance and are determined by individual case-by-case assessment of each patient’s disease and risk–benefit ratio. This supplement presents highlights from a December 2009 continuing education symposium and provides an overview of recently released evidence that supports the recommended improvements in patient management. Target Audience This activity is designed for physicians, pharmacists, physician assistants, nurses, nurse practitioners, and other healthcare professionals who have an interest in enhancing their knowledge and understanding of the management of multiple myeloma. Learning Objectives Upon completion of this activity, participants should be able to: • Describe best strategies for tailoring multiple myeloma management according to patientspecific needs • Contrast and compare strategies for treatment of multiple myeloma in patients with newly diagnosed disease compared with those with recurring or refractory disease • Correlate evidence related to efficacy and safety of biologic agents to application of treatment regimens in non-study clinical environments General Information • This activity is eligible for credit through March 5, 2011. After this date, this activity will expire and no further credit will be awarded.

• Expected time to complete this activity as designed: 1.0 hour • There are no fees for participating in this activity. All participants must complete the Activity Evaluation Form. Participants must receive a minimum score of 70% on the self-assessment portion of the form to qualify for CE credit. The certificate will be mailed 4 weeks after receipt of a completed, qualified form. Accreditation CME Credit: Accreditation Statement: MediCom Worldwide, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: MediCom Worldwide, Inc. designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CPE Credit: MediCom Worldwide, Inc. is accredited by the Accreditation ® Council for Pharmacy Education as a provider of continuing pharmacy education. This activity is acceptable for 1.0 contact hour of Continuing Education Credit. Universal Activity Number: 827-0000-10244-H01-P. Knowledge-based CPE activity. Nursing Credit: Accreditation Statement: MediCom Worldwide, Inc., 101 Washington Street, Morrisville, PA 19067, is approved by the California Board of Registered Nursing, Provider Number CEP11380. MediCom designates this CNE activity for 1.0 contact hour. Program Number: 10-244-235. Disclosures In accordance with the Accreditation Council for Continuing Medical Education (ACCME), ACPE, and California Board of Nursing, MediCom Worldwide, Inc. requires that all program planners, faculty, and providers who are in a position to control the content of a CE activity are required to disclose any relevant financial relationships they may have or have had within the past 12 months with the commercial supporter or the manufacturer(s) of any com-

mercial device(s) discussed in this educational activity. Accordingly, the following disclosures were made. Reviewer Disclosure The reviewer reported the following: Dr. Ann F. Mohrbacher has received honoraria related to speakers’ bureau activities from Celgene Corporation and Millennium Pharmaceuticals, Inc. Provider Disclosure The individuals listed below from MediCom Worldwide, Inc. reported the following for this activity: Joan Meyer, executive director; Jacqui Brooks, MBBCH, MRCPsych, VP medical education; Gene Tombler, PhD, medical director; and Lori K. Pender and Marie S. Recine, medical writers, have nothing to disclose. Off-Label/Investigational Disclosures This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the reviewer. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program. Dr. Ann F. Mohrbacher indicated that the material would include the discussion of unlabeled uses of commercial products or investigational/ unapproved products not yet approved by the FDA for certain uses in the United States. Conflict of Interest Resolution To resolve identified conflicts of interest, the educational content was fully peer reviewed by members of the MediCom Content Review Committee. The resulting certified activity was found to provide educational content that is current, evidencebased, and commercially balanced. Supported by educational grants from Millennium Pharmaceuticals, Inc.; BristolMyers Squibb; Centocor Ortho Biotech Services, LLC; Genzyme Corporation; and Ortho Biotech, a division of Janssen-Cilag.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Township, NJ 08831. Email: editorial@greenhillhc.com. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Township, NJ 08831. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Township, NJ 08831. The ideas and opinions expressed in Journal of Multidisciplinary Cancer Care®, The Oncology Nurse®, and The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Multidisciplinary Cancer Care®, The Oncology Nurse®, or The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. Please convey any errors to the Editorial Director. Journal of Multidisciplinary Cancer Care®: ISSN# 1949-0321. The Oncology Nurse®: ISSN# 1944-9798. The Oncology Pharmacist®: ISSN# 1944-9607. Journal of Multidisciplinary Cancer Care®, The Oncology Nurse®, and The Oncology Pharmacist® are published by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Township, NJ 08831. Telephone: 732-656-7935. Fax: 732-656-7938. Copyright ©2010 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Multidisciplinary Cancer Care, The Oncology Nurse, and The Oncology Pharmacist are registered trademarks of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Cover Art: Copyright iStockphotos.com/Sebastian Kaulitzki.

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MULTIPLE MYELOMA CONTENTS Introduction page 3 Treatment of Newly Diagnosed Multiple Myeloma page 5 The Role of Stem Cell Transplantation and Managing Relapsed/Refractory Multiple Myeloma page 14 Self-Assessment Questions page 22

REVIEWER Ann F. Mohrbacher, MD Associate Professor of Clinical Medicine Keck School of Medicine University of Southern California Los Angeles, California

Introduction

ultiple myeloma (MM) is a malignant plasma cell tumor. The cancerous cells typically reside within the bone marrow. In 2006, the prevalence of MM in the United States was an estimated 67,000 individuals.1 The prevalence of MM is twofold higher in the US black population than in whites, and men are more frequently affected, independent of race.2 The disorder affects primarily older individuals (60 years). Fewer than 1% of cases are diagnosed in individuals younger than 35 years.3 The exact etiology of the disease is unknown, although genetics and environment are both considered factors in its development.2 In the United States alone, the disorder claims in excess of 12,000 lives annually.3

Skillful management of MM includes prevention, identification, and treatment of complications and adverse effects. Mortality associated with MM has significantly decreased within the past 2 decades. Prior to 1980, individuals with MM experienced a slow and progressive deterioration in health and related quality of life until their death. As a result of improved diagnostics, novel treatment options, and more aggressive management strategies, patients who are diagnosed with MM today and attain a complete remission have a 50% chance of surviving 5 years and a 20% chance of surviving 10 years or more.4 The initial diagnosis of MM is often a clinical challenge. Signs and symptoms of the disease are slow to manifest, diffuse, and often nonspecific. The patient may present with fatigue and pain, both of which are associated with a host of more common and familiar ailments, resulting in missed or delayed diagnosis.3 A biomarker, 2-microglobulin, was validated in the early 1980s. Its use has enabled clinicians to better identify MM earlier in the

course of the patient’s workup by means of a blood test designed to detect abnormal immunoglobulins.5 Once the diagnosis is made, treatment will be customized, for each individual patient, depending on patient age and physical condition, presence of new or recurring disease, stage of the disease, naïve exposure to first-line treatment, previous treatment response as well as toxicity profile of the therapeutic agent under consideration and results from a comprehensive, individualized risk-benefit analysis.6 Prognosis is improved in patients whose disease is assigned a lower stage and managed appropriately. In the past, treatment options for patients with MM were scarce, and those that were available lacked efficacy and had poor safety profiles. In the new millennium, therapeutic options for patients with MM have advanced tremendously. The mSMART guidelines for MM were published in 2005, and subsequent consensus guidelines include recommendations for evidence-based supportive care; highly effective and welltolerated chemotherapeutic regimens; and (for eligible patients) autologous stem cell transplantation (ASCT).6,7 Skillful management of maintenance therapy has become extremely important in view of increased survivorship resulting from the availability of effective firstline induction therapy. Furthermore, despite improved outcomes, MM remains without cure, which means that patients who initially respond well to induction therapy will ultimately relapse and require additional treatment.7 Interventions using novel biologic agents (eg, immunomodulatory drugs; proteasome inhibitor), alone or in combination, target cellular mechanisms and interact within the bone marrow’s microenvironment. Use of ASCT as a complementary intervention may also improve outcomes for the appropriate subset of patients. A thorough understanding of the empirical data is necessary to provide an evidencebased approach to each individual patient with the goal of achieving effective and low-risk therapeutic management and favorable outcomes.6

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MULTIPLE MYELOMA Skillful management of MM includes prevention, identification, and treatment of complications and adverse effects, such as immunodeficiency, compression fractures of the spine with or without spinal cord compression, pathologic fractures of other bones, osteonecrosis of the jaw (a rare complication to bisphosphonate therapy), loss of renal function resulting in elevated calcium and uric acid levels, anemia, and acute and/or chronic pain.8 Prompt recognition of adverse effects of therapy with an equally prompt dose reduction can greatly reduce the rate of premature treatment discontinuation and significantly improve treatment efficacy.8 It is critical for all healthcare professionals who contribute to the care of patients with MM to understand the interconnectedness of the disease, comorbid conditions, treatment effects, and response to treatment to optimize patient care and clinical outcomes.

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The goal of this supplement is to present the most recent evidence on best practice options for the management of patients with MM, including treatment strategies for individuals who are newly diagnosed and for those who are in remission or who have been refractory to treatment. The use of appropriate treatment may extend the lives of patients, their quality of life, and their ability to function.9 ● References 1. Horner MJ, Ries LAG, Krapcho M, et al; eds. SEER Cancer Statistics Review, 1975-2006, based on November 2008 SEER data submission, posted to the SEER website, 2009. Table 1.21, US prevalence counts, invasive cancers only, January 1, 2006, using different tumor inclusion criteria. http://seer.cancer.gov/csr/1975_2006/ results_single/sect_01_table.21_2pgs.pdf. Accessed February 23, 2010. 2. Bergsagel PL. Epidemiology, etiology, and molecular pathogenesis. In: Richardson P, Anderson K. Multiple Myeloma (State of the Art). Remedica Publishing: London, UK; 2004.

3. American Cancer Society. Detailed guide: multiple myeloma. What are the risk factors for multiple myeloma? May 12, 2009. www.cancer.org/ docroot/CRI/content/CRI_2_4_2X_What_are_ the_risk_factors_for_multiple_myeloma_30.asp. Accessed February 23, 2010. 4. Denz U, Haas P, Wäsch R, et al. State of the art therapy in multiple myeloma and future perspectives. Eur J Cancer. 2006;42:1591-1600. 5. Child JA, Crawford SM, Norfolk DR, et al. Evaluation of serum beta 2-microglobulin as a prognostic indicator in myelomatosis. Br J Cancer. 1983;47:111-114. 6. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110. 7. Gay F, Palumbo A. Multiple myeloma: management of adverse events. Med Oncol. July 7, 2009. Epub ahead of print. 8. Kumar S. Stem cell transplantation for multiple myeloma. Curr Opin Oncol. 2009;21:162-170. 9. Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia. 2009;23:1716-1730.

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MULTIPLE MYELOMA

Treatment of Newly Diagnosed Multiple Myeloma ANN F. MOHRBACHER, MD—REVIEWER Associate Professor of Clinical Medicine, Keck School of Medicine, University of Southern California, Los Angeles

Considerable progress has been made recently in the treatment of patients with multiple myeloma. Thanks to advances including autologous stem cell transplantation (ASCT) and novel therapies such as thalidomide, bortezomib, and lenalidomide, long-term survival rates have significantly improved, although these gains have been largely seen among patients younger than 60 years of age. Today, ASCT is a standard of care following induction chemotherapy for patients younger than 65 years with newly diagnosed disease; tandem transplantation appears most beneficial for patients with a partial response or stable disease after initial ASCT. These data, however, come from studies performed prior to the routine use of novel agents as induction therapy. The efficacy of thalidomide-based induction therapy is well established, and numerous studies are evaluating the safety and efficacy of bortezomib- and lenalidomide-based regimens. Another area of active research involves identifying therapies to prolong or consolidate response after transplantation. Thalidomide-based maintenance after ASCT improves progression-free and overall survival; results from trials of bortezomib- and lenalidomide-based maintenance regimens are expected in the near future. Finally, there is a need to identify new approaches to the treatment of elderly patients with newly diagnosed multiple myeloma. Two combination regimens—melphalan/prednisone/thalidomide (MPT) and bortezomib/melphalan/prednisone (VMP)—are widely used in this setting. A number of other combination regimens are under investigation in this setting, as is the role of maintenance therapy.

he treatment of multiple myeloma (MM) has undergone major changes since the introduction of the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid), and the proteasome inhibitor bortezomib (Velcade), in the past several years. The incorporation of these agents into regimens that include corticosteroids, alkylating agents, and/or anthracyclines improves clinical outcomes for newly diagnosed patients compared with the use of these regimens alone. However, the challenge remains to identify the optimal sequence and combination of agents for use in the transplantation setting and for transplantation-ineligible patients with newly diagnosed disease. This review focuses on the latest research into these issues.

Management of transplantationeligible patients Autologous stem cell transplantation (ASCT) is the standard of care following induction chemotherapy for newly diagnosed MM patients who do not have contraindications to such treatment.1 Randomized clinical trials demonstrate that in patients younger than 65 years, ASCT sig-

nificantly improves response rates, eventfree survival (EFS), and overall survival (OS) compared with conventional chemotherapy.2,3 Subsequent randomized studies that compared a single ASCT with planned double or tandem ASCT produced intriguing results.4,5

Randomized clinical trials demonstrate that in patients younger than 65 years, ASCT significantly improves response rates, eventfree survival, and overall survival compared with conventional chemotherapy. In one study, which enrolled 321 transplantation-eligible patients younger than 60 years, double ASCT significantly increased response rates and EFS, but did not increase OS.5 Another randomized trial, which enrolled 399 patients younger than 60 years, found that double ASCT did sig-

nificantly increase OS but had no effect on response rate relative to single ASCT.4 Although these results appear to conflict, both trials identified a subgroup of patients who derived significant clinical benefit from double transplantation: patients who did not achieve at least a very good partial response (VGPR) after the first transplant4,5 (Figure 1). In the Medical Research Council Adult Leukaemia Working Group VII trial, the probability of survival at 7 years posttransplantation in this patient subgroup was 11% in the single ASCT arm versus 43% in the double-transplant arm (P <.001).4 Currently, the National Comprehensive Cancer Network (NCCN) recommends tandem transplantation, within 6 months of the initial transplantation, only for patients with partial response (PR) or stable disease (SD) after the first ASCT.1 In most of the phase 3 trials conducted in the ASCT setting, superior EFS and OS were associated with high complete response (CR) rates, a conclusion recently corroborated by meta-analysis.6 This finding has implications for clinical research in MM. Because median survival after ASCT is approximately 5 to 6 years, it takes 10 or more years to publish mature survival results

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MULTIPLE MYELOMA

Overall survival (%)

Figure 1A

Months after first transplantation

Event-free survival (%)

Figure 1B

Figure 1. Overall Survival (A) and Event-free Survival (B) with Double vs Single Autologous Stem Cell Transplant in Patients Failing to Achieve Very Good Partial Response or Better After First Transplantation Reprinted with permission from Attal M, Harousseau JL, Facon T, et al; for the Intergroupe Francophone du Myelome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Eng J Med. 2003;349(26):2495-2502. Copyright © 2003 Massachusetts Medical Society. All rights reserved. Reprinted with permission from Cavo M, Tosi P, Zamagni E, et al. Prospective randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007;25:2434-2441. Copyright © 2007 American Society of Clinical Oncology. All rights reserved.

from large prospective studies. The ability to use a valid surrogate marker could hasten the clinical development of promising new 6

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therapies in the ASCT setting. However, achieving CR alone is not sufficient for prognostication; the CR must be durable.

Barlogie and colleagues demonstrated that patients with sustained CR at 3 years had significantly superior survival compared with those who failed to achieve CR at all and to those who attained, but subsequently lost, CR status before 3 years.7 This 3year CR rate is currently an important end point for clinical trials. It is critical to note, however, when evaluating the ASCT literature that all the major prospective, randomized trials of ASCT following induction therapy were designed and conducted before the incorporation of novel agents into the treatment paradigm. Traditionally, a combination of vincristine (Vincasar PFS, Oncovin)/doxorubicin (Adriamycin, Doxil)/dexamethasone (Decadron) (VAD) was used as induction therapy prior to stem cell harvest, ablative therapy, and stem cell infusion.8 Today, there are several induction regimen options, which can be broadly classified into three major groups: thalidomide-based, bortezomib-based, and lenalidomide-based therapies (Figure 2). Note that these groupings do not preclude the use of two novel agents in one regimen, such as bortezomib/thalidomide/dexamethasone (VTD). A combination of thalidomide/dexamethasone (TD) was one of the first novel agent regimens to be evaluated in this setting.9-15 Retrospective data, phase 2 studies, and a randomized phase 3 comparison of TD versus dexamethasone alone were encouraging and supported a direct comparison between TD and VAD as induction regimens in newly diagnosed MM in a phase 3 trial. Compared directly with VAD induction therapy, TD significantly improved the VGPR rate compared with ASCT in this randomized trial (13% vs 35%, respectively; P = .002).14 Among the 204 enrolled patients, there were six deaths in the TD arm versus nine in the VAD arm. The rate of venous thromboembolism/pulmonary embolism was significantly higher with TD (23% vs 8%; P = .004), but the rates of other adverse events were similar. Efforts to improve upon the efficacy of the TD regimen include the evaluation of three-drug regimens, such as thalidomide/doxorubicin/dexamethasone (TAD) and cyclophosphamide (Cytoxan)/thalidomide/ dexamethasone (CTD). Each of these reg-

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MULTIPLE MYELOMA imens improved response rates relative to VAD-based induction in phase 3 trials.16,17 Bortezomib-based induction has also been extensively studied in the ASCT setting (Table 1).18-22 In all of these studies, bortezomib-based induction therapy significantly increased the proportion of patients achieving at least a VGPR prior to transplantation compared with the control arm. It is important to note that these improvements were not limited to patients with favorable disease characteristics. The benefits of bortezomib-based therapy were seen in patients with cytogenetic abnormalities, including del(13),18,20,21 t(4;14),18,21 and del(17).21 Moreover, response rates were further augmented in the bortezomib arms compared with the control after ASCT. As shown in Table 1, CR rates after transplantation were increased in all study arms compared with pretransplantation, and the differences between the bortezomib-based regimens and control arms were statistically significant in the three largest phase 3 trials. These three trials also showed significant increases in the proportion of patients achieving at least a VGPR after transplantation. The fourth study is a preliminary analysis of the Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM) trial; although all point estimates favor the VTD arm, none of the differences were statistically significant in this early analysis conducted in a small number of patients. Updated results from the PETHEMA/GEM trial and other studies shown in Table 1 were presented at the 51st Annual Meeting of the American Society of Hematology (ASH), which was held in December 2009 in New Orleans.23-25 Finally, data are beginning to emerge regarding lenalidomide-based induction regimens.26-31 A combination of lenalidomide/cyclophosphamide/low-dose dexamethasone (RCd) produced a confirmed response rate (at least VGPR) of 32% in a phase 2 trial conducted in 53 patients.26 The incidence of myelosuppression leading to dose reductions and delays was reduced when the cyclophosphamide dose was reduced from 300 mg/m2 to a flat dose of 300 mg, given on days 1, 8, and 15. Another three-drug combination produced an encouraging 74% at-least-VGPR response rate in a phase 1/2 trial.28 Sixty-five patients

Figure 2. Novel Induction Regimens for Transplantation-eligible Myeloma Patients

Lenalidomidebased

Thalidomidebased

TD indicates thalidomide/dexamethasone; TAD, thalidomide/doxorubicin/dexamethasone; CTD, cyclophosphamide/thalidomide/dexamethasone; VD, bortezomib/dexamethasone; VTD, bortezomib/thalidomide/dexamethasone; PAD, bortezomib/doxorubicin/dexamethasone; Ld, lenalidomide/low-dose dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; RVCD, lenalidomide/bortezomib/cyclophosphamide/ dexamethasone.

Table 1. Phase 3 Studies of Bortezomib-based Induction Therapy: Response Rates Before and After ASCT Regimen

VD vs VAD

PAD vs VAD

VTD vs TD

N = 442 4

N = 300 4

N = 460 3

N = 119 6

Sample size No. of cycles

Pre-ASCT CR nCR VGPR

6a 15c 39e

1 7 16

5 n/a 42f

1 n/a 15

21b 32b 62b

6 12 29

30 41d n/a

6 12 n/a

Post-ASCT CR nCR VGPR

18a 37e 57g

10 19 38

23f n/a 80h

9 n/a 50

43b 55b 76b

23 32 58

49 64 n/a

34 53 n/a

ASCT indicates autologous stem cell transplantation; CR, complete response; nCR, near-complete response; PAD, bortezomib/doxorubicin/dexamethasone; TD, thalidomide/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; VD, bortezomib/dexamethasone; VGPR, very good partial response; VTD, bortezomib/thalidomide/dexamethasone. P = .01 P <.001 P = .004 d P = .0006 e P <.0001 f P = .0015 g P = .0003 h P = .0019 a

b c

Sources: References 18-22.

received a lenalidomide/bortezomib/dexamethasone (RVD) induction regimen in this dose-escalation trial. High-quality responses were seen independent of cytogenetics (del[13q] and t[4;14]). At the maximal planned dose, 100% of patients responded to induction therapy. A four-drug regimen also appears promising. EVOLUTION was a phase 1/2 multicenter trial that

evaluated lenalidomide/bortezomib/cyclophosphamide/dexamethasone (RVCD) induction in newly diagnosed MM.27 Five of 25 treated patients experienced a stringent CR, and 68% had at least a VGPR after treatment. These early results require confirmation in a larger group of patients, but taken together, it appears that lenalidomide/ bortezomib-based combinations are

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MULTIPLE MYELOMA Thalidomide maintenance post-ASCT has been evaluated in phase 3 trials (Table 2). N Thalidomide dose CR rates PFS rates OS rates each study, thalidomide In Thalidomide vs control increased CR rates and PFS, Attal M, 597 400 mg daily 67% vs 55% At 4 years: At 4 years: and in two of the trials, OS.32-34 et al until PD or AE 52% vs 36% 87% vs 77% The Intergroupe Francophone Barlogie B, 668 400 mg daily with 62% vs 43% At 5 years: At 5 years: du Myélome (IFM) 99-02 et al taper over time 56% vs 44% No difference evaluated thalidomide study until PD maintenance after tandem Spencer A, 243 200 mg daily for 65% vs 44% At 3 years: At 3 years: transplantation in low-risk et al 1 year 42% vs 23% 86% vs 75% patients (ie, one or no adverse AE indicates adverse event; ASCT, autologous stem cell transplantation; CR, complete response; OS, overall survival; PD, 32 Patients prognostic factors). progressive disease; PFS, progression-free survival. were randomized to no mainteAll comparisons are statistically significant unless otherwise stated. nance, pamidronate mainteFigure 3. Time to Reversal of Abnormal Renal Function in the VISTA Trial nance, or a combination of pamidronate and thalidomide. Thalidomide was started at 400 mg/day but could be reduced to as low as 50 mg/day in the event of toxicity. At the time of randomization, 45%, 47%, and 50% of patients in each group, respectively, had responded to induction (P = NS). However, maintenance therapy with thalidomide significantly increased the best response to treatment after randomization compared with the other arms. Sixty-seven percent of thalidomide maintenance patients ultimately achieved a CR or VGPR compared with 55% in the control arm and 57% in the pamidronate monotherapy arm (P = .03). In addition, Reprinted with permission from Dimopoulos MA, Richardson PG, Schlag R, et al. VMP (bortezomib, melphathalidomide maintenance significantly lan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with improved EFS and OS compared with the moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 2009;27:6086-6093. Copyright © 2009 American Society of Clinical Oncology. All other arms. The EFS benefit was limited to rights reserved. those patients who had not achieved at least highly active and feasible for induction longed period for the purpose of prolong- a VGPR after ASCT and did not have prior to ASCT. Recently, updated results ing remission and reducing the risk of del(13). from the EVOLUTION trial and other relapse, thereby improving progression-free The most recently published study of trials testing three- and four-drug thalidomide-based maintenance therapy lenalidomide/bortezomib combinations The results of these two after ASCT was conducted by the were presented at ASH, providing further studies strongly suggest that Australasian Leukaemia and Lymphoma support for the continued evaluation of Group (ALLG).34 They compared a combimaintenance therapy 29-31 these combinations. nation of daily thalidomide plus alternateprovides additional antiday prednisolone (Omnipred) with predRole of maintenance therapy after nisolone alone after single ASCT. The tumor efficacy rather than transplantation initial dose of thalidomide was 100 mg/day, simply working to maintain Patients who do not achieve a VGPR or with planned escalation to 200 mg/day as better after first transplantation are candi- an already established tolerated. Thalidomide was administered dates for a second ASCT.1,4 The question response to ASCT. for 1 year, whereas prednisolone was adminremains, however, whether additional istered indefinitely. The addition of thalidotherapy is needed for those patients who do mide to the maintenance regimen signifiachieve VGPR or CR after the first ASCT survival (PFS) and OS. Currently, the cantly increased the CR/VGPR rate and as well as those who receive tandem trans- NCCN recommends either thalidomide prolonged PFS and OS compared with plantation. Maintenance therapy can be alone (category 1) or thalidomide plus pred- prednisolone monotherapy.34 As in IFM 99defined as the administration of low-inten- nisone (category 2B) for maintenance ther- 02, response rates (CR/VGPR) were similar sity, well-tolerated treatment over a pro- apy after ASCT.1 after ASCT as well as prior to beginning

Table 2. Phase 3 Studies of Thalidomide Maintenance Post-ASCT

Patients with event (%)

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MULTIPLE MYELOMA maintenance (39% with combination therapy vs 41% with prednisolone monotherapy). A significant improvement in response was not seen until the end of the maintenance phase (63% vs 40%; P <.001). The results of these two studies strongly suggest that maintenance therapy provides additional antitumor efficacy rather than simply working to maintain an already-established response to ASCT. A third study, known as Total Therapy 2 (TT2), evaluated the incorporation of thalidomide into several treatment phases: induction, between-tandem transplants, consolidation, and maintenance.33 Overall, the TT2 regimen significantly improved response rates and EFS, but not OS, compared with a similarly intense treatment protocol that did not include thalidomide. A recent update to this study suggests, however, that thalidomide may particularly benefit patients with high-risk MM.35 With median follow-up of 6 years, the estimated OS rate at 5 years was 56% for patients with cytogenetic abnormalities treated with thalidomide but only 43% for their counterparts in the control group (P = .02). There was no difference in survival for patients without cytogenetic abnormalities (5-year OS, 72% with thalidomide vs 75% with control; P = .02). Moreover, the durability of CR, an important prognostic factor and surrogate for OS, was not improved when thalidomide was used in patients without cytogenetic abnormalities (CR rates at 5 years, 63% with thalidomide vs 61% for control; P = .66) but was improved in those with cytogenetic abnormalities (47% with thalidomide vs 25% for control; P = .05). This discrepancy suggests that not all CRs are created equal. The results of TT2 suggest that patients with unfavorable cytogenetics who achieve a CR are more likely to relapse quickly than those with favorable cytogenetics and that the use of thalidomide from induction through maintenance increases response rates and survival outcomes for these high-risk patients. Taken together, it is reasonable to conclude that thalidomide-based maintenance improves PFS and OS after ASCT and that the mechanism is likely to involve additional tumor cytoreduction

Table 3. Estimated 10-year Survival Rates Over Time Age group

Survival rate during time period

P value

1990-1992

2002-2004

<50 years

25%

41%

<.001

50-59 years

17%

29%

<.001

60-69 years

11%

15%

.03

70-79 years

10%

.09

>80 years

.94

Source: Reference 45; adapted from Table 2.

Table 4. Results of ECOG E4A03: 1-year Survival by Age Subgroup

Survival at 1 year, % (95% CI)

Lenalidomide/high-dose dexamethasone

104

91 (85-97)

Lenalidomide/low-dose dexamethasone

108

98 (92-99)

Lenalidomide/high-dose dexamethasone

119

83 (76-90)

Lenalidomide/low-dose dexamethasone

114

94 (89-99)

P valuea

Age <65 years

.01

Age ď&#x20AC;&#x20AC;65 years

.004

CI indicates confidence interval; ECOG, Eastern Cooperative Oncology Group. a P values reflect the results of a multiple regression analysis of significant predictors of overall survival that were identified in univariate analysis. Source: Reference 49.

rather than eradication or suppression of minimal residual disease. The optimal duration of maintenance remains to be determined, and additional prospective trials are needed to determine whether maintenance improves outcomes for highrisk patients. Several clinical trials are underway to determine the roles of bortezomib and lenalidomide.36-43 Management of elderly transplantation-ineligible patients Before the advent of novel therapies and the widespread use of ASCT, no significant advances were made in the treatment of MM despite three decades of clinical research.44 In the late 1990s, median survival after diagnosis was approximately 2.5 to 3.0 years, and survival rates at 1 year were approximately 75%.44 More recently, survival has improved for younger patients with MM but not for the elderly, who generally are not candidates for ASCT and may not receive new therapies due to

comorbidities, poor performance status, and concerns about toxicity (Table 3).45 Clearly, there is a need to identify more active treatments for elderly patients who are not transplantation candidates. One approach to the management of elderly, transplantation-ineligible patients is the use of dexamethasone; however, this corticosteroid appears to be more toxic than prednisone in this population when used at high doses. The IFM 95-01 trial compared three dexamethasone-based regimens with melphalan (Alkeran)/prednisone (MP) in 488 newly diagnosed, elderly patients (aged 65-75 years) in a randomized trial.46 In all three dexamethasone groups, the drug was administered at a high dose: 40 mg/day on days 1 to 4, 9 to 13, and 17 to 20 for the first two cycles, then as 40 mg/day on days 1 to 4 of all subsequent cycles. The results demonstrated that a combination of melphalan/ dexamethasone significantly improved response rates at 6 months, but there was no improvement in OS compared with MP. It

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MULTIPLE MYELOMA is important to note that morbidity was increased in the dexamethasone arms. Significantly more pyogenic infections and severe nonhematologic toxicities (eg, hemorrhage and gastrointestinal and psychiatric complications) were reported in the dexamethasone arms. A second study also found that MP remains a better treatment option than dexamethasone-based therapy in the elderly. In a randomized study, TD was compared with MP in 289 patients (median age, 72 years).47 Those who achieved SD or better were randomized a second time to interferon maintenance, with or without thalidomide. In this study, dexamethasone was administered as 40 mg/day on days 1 to 4 and 15 to 18 for even-number cycles and on days 1 to 4 only for odd-number cycles. This TD regimen significantly improved response rates compared with MP, but median PFS was not improved, and median OS was actually significantly shorter (41.5 vs 49.4 months, respectively; P = .024). Mortality was associated with age older than 75 years and poor performance status. Note that in both of these studies, dexamethasone was administered in daily pulses of 40 mg, although the exact frequency of each pulse differed. The toxicity of TD is two-sided and strongly depends on age with thalidomide-associated deep venous thrombosis and dose-related peripheral poly-neuropathy occurring, both of which have a direct effect on patient quality of life. Furthermore, these effects may have an even stronger impact in the elderly MM patient. The important lesson from this trial is that TD can result in excess early mortality (usually in the first year) in patients over 75 years of age with poor performance status, in particular from infections that are presumed linked to dexamethasone.48 Based on these studies, high-dose dexamethasone should be avoided in elderly patients with MM. A lower-dose dexamethasone regimen was directly compared with a higher-dose regimen in the E4A03 trial conducted by the Eastern Cooperative Oncology Group (ECOG).49 Although patients of all ages were eligible, a sufficient number of elderly patients were included, which allows a meaningful comparison in this subgroup. All patients received lenalidomide 25 mg/day on days 1 to 21 of each 28-day cycle. The high-dose regimen comprised 10

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dexamethasone 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 of each cycle, whereas the low-dose regimen utilized dexamethasone 40 mg only on days 1, 8, 15, and 22 of each cycle. The trial was stopped after the second planned interim analysis because of significant differences in OS. In both patients younger than 65 years and patients 65 years and older, OS at 1 year was higher with low-dose therapy than with high-dose therapy (Table 4).49 Again, the inferior survival with high-dose dexamethasone appeared to be due to excess toxicity, particularly in elderly patients. Although high-dose dexamethasone should be avoided in elderly patients receiving either thalidomide or lenalidomide, it is not clear that younger patients will not benefit from the increased CR rates observed with these regimens.

A subgroup analysis of VISTA revealed that VMP produced a faster time to reversal of abnormal renal function than did MP in those with moderately impaired renal function at baseline, defined as glomerular filtration rate 50 mL/min or less. Other efforts to improve outcomes for elderly, transplantation-ineligible patients involve the incorporation of novel agents into the MP regimen. IFM 99-06 was a randomized phase 3 trial that compared three arms: MP, MPT, and reduced-intensity ASCT in elderly patients (65 to 75 years of age).50 The MPT regimen significantly reduced the risk of death compared with MP (hazard ratio [HR], 0.59; P = .0006) and ASCT (HR, 0.69; P = .027). Grade 3/4 toxicity was increased with MPT compared with MP, including rates of neutropenia (48% vs 26%; P <.0001), thrombosis or embolism (12% vs 4%; P = .008), constipation (10% vs 0%; P <.0001), somnolence/fatigue/dizziness (8% vs 0%; P <.0001), and peripheral neuropathy (6% vs 0%; P = .001). Nonetheless, these events were generally manageable and did

not diminish the survival benefit seen in this study. Building on this experience, the IFM then conducted a randomized, placebocontrolled trial specifically in patients older than age 75.51 Indeed, 36% of patients who participated in IFM 01/01 were at least 80 years old. Patients were randomized to MP plus placebo or MPT; thalidomide 100 mg/day or placebo was given continuously for 72 weeks as an extended maintenance phase. With a median follow-up of approximately 48 months, median OS was significantly longer in the MPT arm (44.0 vs 29.1 months; P = .028). Rates of grade 2/3/4 peripheral neuropathy (20% vs 5%; P <.001) and grade 3/4 neutropenia (23% vs 9%; P = .003) were significantly increased with MPT, but there was no difference in the number of toxic deaths (one in each group). Other groups have evaluated the incorporation of bortezomib into the MP regimen.52,53 This combination, known as VMP, produced an 89% response rate in a phase 1/2 study of patients 65 years of age and older (N = 60).52 This response rate is more than double that seen among historical controls who received six cycles of MP (42% response rate). The subsequent randomized Velcade as Initial Standard Therapy in multiple myeloma (VISTA) trial compared VMP with MP in 682 transplantation-ineligible patients.53 Approximately 30% of the enrolled patients were 75 years of age or older. Time to progression (TTP), the primary endpoint, was significantly increased in the VMP arm (24.0 vs 16.6 months; HR, 0.48; P <.001). This benefit was seen in younger patients (younger than 75 years; HR, 0.47; 95% confidence interval [CI], 0.34-0.66) and their older counterparts (HR, 0.53; 95% CI, 0.31-0.90). OS was significantly improved with VMP in the population as a whole (HR, 0.61; P = .008); OS results by age subgroup were not reported. A subgroup analysis of VISTA revealed that VMP produced a faster time to reversal of abnormal renal function than did MP in those with moderately impaired renal function at baseline, defined as glomerular filtration rate 50 mL/min or less (Figure 3).54 Overall, 44% of patients with renal impairment treated with VMP experienced reversal of this abnormality versus

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MULTIPLE MYELOMA 34% treated with MP. Receipt of VMP approached statistical significance in multivariate analysis as a factor associated with reversal (P = .07). Currently, the MPT and VMP regimens are reasonable choices for elderly, transplantation-ineligible patients newly diagnosed with MM. Several important questions remain, however, regarding the optimal treatment of these patients. First, is maintenance therapy necessary in this population, and if so, which regimen should be used? The results of ongoing trials will help answer these questions.55-60 Second, is melphalan a necessary component of the treatment regimen? This is an increasingly important question in MM research because of the leukomogenic potential of alkylating agents such as melphalan. As survival increases, so do concerns about the long-term safety of the commonly used regimens. This question is currently being addressed in a randomized clinical trial that substitutes thalidomide for melphalan.55 A total of 246 elderly patients had been randomized to VMP or bortezomib/thalidomide/prednisone (VTP) induction, with a second randomization to bortezomib/thalidomide (VT) or bortezomib/prednisone (VP) maintenance, at the time of first data analysis. With a median follow-up of 16 months, there were no differences in TTP or OS between the groups. However, there was a greater rate of nonhematologic toxicities with VTP, including cardiac events, which resulted in treatment discontinuations. Updated results from this study have recently been presented,56 and full publication of these data is eagerly awaited. Additional insight into the relative safety and efficacy of VTD relative to VMP will come from the Untreated Patients receiving therapy For multiple myeloma in a Randomized trial Of three novel regimens for patients Not intending to receive Transplant therapy (UPFRONT) study, a randomized phase 3b trial being conducted in communitybased practices.57 A second question is whether thalidomide can safely increase the efficacy of VMP in this population. A phase 3 trial conducted in Italy enrolled 511 patients and randomized them to induction with VMP or bortezomib/melphalan/predni-

sone/thalidomide (VMPT).59,60 Patients in the VMPT arm also received maintenance with bortezomib and thalidomide. After enrollment of the first 135 patients, the protocol was amended and bortezomib was administered weekly instead of biweekly, thus providing comparative data on two bortezomib administration schedules. In the primary analysis, rates of VGPR and CR were higher with VMPT (VGPR, 51% vs 42%, P = .06; CR, 35% vs 21%, P <.0001).60 In the subgroup analysis by bortezomib administration schedule, efficacy was maintained but toxicity was reduced with weekly bortezomib dosing. Rates of grade 3/4 peripher-

In the subgroup analysis by bortezomib administration schedule, efficacy was maintained but toxicity was reduced with weekly bortezomib dosing. al neuropathy were significantly reduced from 10% to 12% with biweekly bortezomib to 4% to 5% with weekly administration (P, not reported). This finding is encouraging because if neuropathy could be minimized in the induction setting, researchers could better evaluate novel agents as long-term maintenance. Finally, the question of whether lenalidomide can replace thalidomide is being explored. Results of a phase 1/2 dose-ranging trial found that the maximum tolerated dose of melphalan/prednisone/ lenalidomide (MPR) in elderly patients was melphalan 0.18 mg/kg and prednisone 2 mg/kg, given on days 1 to 4, and lenalidomide 10 mg on days 1 to 21, every 28 days.61 At this dose level, 17 of 21 (81%) patients achieved at least a PR to treatment. Moreover, all 54 treated patients were alive at 1 year. The authors state that 100% survival at 1 year is unprecedented in this population. The most frequent grade 3/4 adverse events were neutropenia (68%), thrombocytopenia (32%), anemia (17%), infections (9%), cutaneous reactions (8%), and thromboembolism (6%). No cases of deep vein thrombosis were reported once

aspirin prophylaxis was administered. Given this highly encouraging activity, results from the MM-015 study, a randomized phase 3 trial of MP versus MPR in elderly patients with newly diagnosed disease, are eagerly awaited.58 Notably, MM015 also evaluates lenalidomide maintenance therapy and should help further elucidate the role of maintenance therapy in the nontransplantation setting. As an update since the ASH 2009 meeting, clinical trials exploring the roles of bortezomib and lenalidomide as part of maintenance therapy regimens, both for transplant and non-transplant eligible patients, are yielding promising early results.36-38,56,58,62,63 As a consequence of the reports from the ASH 2009 meeting, the NCCN recently updated its guidelines to include lenalidomide as a maintenance therapy based on improvements in TTP in three independent, randomized trials that showed a reduction in risk of the disease progressing.1,38,58,62 However, the NCCN panel has also noted that safety and efficacy data are still preliminary and a full peer review is needed. Consequently, the recommendation is currently limited to that of category 2A. Conclusions High-dose therapy followed by ASCT is the standard of care for the treatment of younger patients with newly diagnosed MM, whereas frontline treatment with MPT or VMP is standard for elderly, transplantation-ineligible patients. The efficacy of ASCT can be increased with the use of novel agents in the induction regimen and/or in a maintenance phase, in which these agents may provide additional cytoreduction. The optimal sequence and combination of novel therapies remain to be determined, although three-drug induction regimens appear promising for use prior to ASCT. Thalidomide is the best-studied maintenance agent to date, but results are expected for bortezomibbased and lenalidomide-based maintenance strategies in the near future in both the transplantation and nontransplantation settings. â&#x2014;? Acknowledgement The reviewer thanks Lori K. Pender for medical writing assistance.

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MULTIPLE MYELOMA References

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(MM). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 354. 26. Kumar S, Hayman S, Buadi F, et al. Phase II trial of lenalidomide (Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. Presented at: The American Society for Hematology Annual Meeting; December 6-9, 2008; San Francisco, CA. 27. Kumar S, Flinn IW, Noga SJ, et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma. Initial results from the phase I/II multi-center EVOLUTION study. Presented at: The American Society for Hematology Annual Meeting; December 6-9, 2008; San Francisco, CA. 28. Richardson P, Lonial S, Jakubowiak A, et al. Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a phase I/II study. Presented at: The American Society for Hematology Annual Meeting; December 6-9, 2008; San Francisco, CA. 29. Kumar S, Flinn IW, Hari PN, et al. Novel threeand four-drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: encouraging results from the multi-center, randomized, phase 2 EVOLUTION study. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 127. 30. Jakubowiak AJ, Reece DE, Hofmeister CC, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: updated results of phase I/II MMRC trial. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 132. 31. Richardson PG, Lonial S, Jakubowiak AJ, et al. High response rates and encouraging time-toevent data with lenalidomide, bortezomib, and dexamethasone in newly diagnosed multiple myeloma: final results of a phase I/II study. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 1218. 32. Attal M, Harousseau JL, Leyvraz S, et al; for the InterGroupe Francophone du Myélome. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 33. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 34. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793. 35. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112:3115-3121. 36. Gay F, Falco P, Crippa C, et al. Sequential approach with bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 3419. 37. Lee CK, Kaiser J, Myint H, et al. An outcome study on survival and disease control in patients with high-risk multiple myeloma (MM) for relapse, treated with high-dose melphalan combined with bortezomib for autotransplant followed by posttransplant maintenance with bortezomib and

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MULTIPLE MYELOMA lenalidomide. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 3404. 38. McCarthy PL, Owzar K, Stadtmauer EA, et al. Phase III Intergroup study of lenalidomide (CC5013) versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma (CALGB 100104): initial report of patient accrual and adverse events. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 3416. 39. Comparison of 25 mg versus 5 mg lenalidomide as maintenance therapy in patients with multiple myeloma. ClinicalTrials.gov Identifier: NCT008 91384. http://clinicaltrials.gov/ct2/show/NCT0 0891384?term=myeloma+maintenance+lenalid omide&phase=23&rank=1. Accessed January 21, 2010. 40. Maintenance therapy using lenalidomide in myeloma (IFM 2005-02): ClinicalTrials.gov Identifier: NCT00430365. http://clinicaltrials.gov/ ct2/show/ NCT00430365?term=myeloma+maintenance+lenalidomide&phase=23&rank=2. Accessed January 21, 2010. 41. GEM05 for patients with multiple myeloma under 65 years (GEM05MENOS65). Clinical Trials.gov Identifier: NCT00461747. http:// clinicaltrials.gov/ct2/show/NCT00461747?term =myeloma+maintenance+bortezomib&phase= 23&rank=2. Accessed January 21, 2010. 42. Efficacy of bortezomib consolidation after highdose melphalan with stem cell support in myeloma patients. ClinicalTrials.gov Identifier: NCT00 417911. http://clinicaltrials.gov/ct2/show/NCT00 417911?term=myeloma+maintenance+bor tezomib&phase=23&rank=7. Accessed January 21, 2010. 43. Tandem transplantation in multiple myeloma (MM) patients with <12 months of prior treatment. ClinicalTrials.gov Identifier: NCT00 670631. http://clinicaltrials.gov/ct2/show/NC T00670631?term=myeloma+maintenance+bort ezomib&phase=23&rank=4. Accessed January 21, 2010. 44. Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998;16:3832-3842. 45. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008; 111:2521-2526. 46. Facon T, Mary JY, Pegourie B, et al; for the Intergroupe Francophone du Myelome. Dexamethasone-based regimens versus melphalanprednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292-1298.

47. Ludwig H, Hajek R, Tothova E, et al. Thalidomide-dexamethasone compared with melphalanprednisolone in elderly patients with multiple myeloma. Blood. 2009;113:3435-3442. 48. Sonneveld P. Thalidomide/dexamethasone in myeloma: a double-edged sword. Blood. 2009;113: 3394. 49. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 50. Facon T, Mary JY, Hulin C, et al; for the Intergroupe Francophone du Myelome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem-cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-1218. 51. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:3664-3670. 52. Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006;108:2165-2172. 53. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359:906-917. 54. Dimopoulos MA, Richardson PG, Schlag R, et al. VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 2009;27:6086-6093. 55. Mateos MV, Oriel A, Martinez J, et al. Bortezomib (Velcade) and melphalan-prednisone (VMP) versus velcade-thalidomide-prednisone (VTP) in elderly untreated multiple myeloma patients: which is the best partner for velcade: an alkylating or an immunomodulator agent? Presented at: The American Society for Hematology Annual Meeting; December 6-9, 2008; San Francisco, CA. 56. Mateos M-V, Orial A, Martinez J, et al. A prospective, multicenter, randomized, trial of bortezomib/melphalan/prednisone (VMP) ver-

sus bortezomib/thalidomide/prednisone (VTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide (VT) versus bortezomib/prednisone (VP) in elderly untreated patients with multiple myeloma older than 65 years. Blood (ASH Annual Meeting Abstracts). 2009;14:Abstract 3. 57. Niesvizky R, Reeves J, Flinn IW, et al. Phase 3b UPFRONT study: interim results from a community practice-based prospective randomized trial evaluating three bortezomib-based regimens in elderly, newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts) 2009;14:Abstract 129. 58. Palumbo A, Dimopoulos MA, Delforge M, et al. A phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 613. 59. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide for initial treatment of elderly multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 128. 60. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma patients: a prospective, randomized phase III study. Presented at: 14th Congress of the European Hematology Association; June 4-7, 2009, Berlin, Germany. 61. Palumbo A, Falco P, Corradini P, et al; for the GIMEMA—Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA—Italian Multiple Myeloma Network. J Clin Oncol. 2007;25:4459-4465. 62. Attal M, Harousseau JL, Marit G, et al. Lenalidomide after autologous transplantation for myeloma: first analysis of a prospective, randomized study of the Intergroup Francohone Du Myelome (IFM 2005 02). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 529. 63. Mellqvist U-H, Westin J, Gimsing P, et al. Improved response rate with bortezomib consolidation after high dose melphalan: first results of a Nordic Myeloma Study Group randomized phase III trial. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 530.

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MULTIPLE MYELOMA

The Role of Stem Cell Transplantation and Managing Relapsed/Refractory Multiple Myeloma ANN F. MOHRBACHER, MD—REVIEWER Associate Professor of Clinical Medicine, Keck School of Medicine, University of Southern California, Los Angeles

The introduction of novel drugs with unique mechanisms of action has improved outcomes in patients with relapsed and/or refractory multiple myeloma, and there is evidence that these agents can overcome the negative prognostic risk of certain cytogenetic abnormalities. Questions remain, however, regarding their optimal use in advanced myeloma, including how best to combine and/or sequence them and how prior therapies and stem cell transplantation (SCT) may impact their effectiveness. SCT is used across the spectrum of advanced myeloma, including the treatment of primary refractory myeloma and relapsed disease, as well as salvage therapy for refractory disease. At present, the use of novel agent combinations and transplantation in the treatment of advanced myeloma is empiric, but treatment decisions must take into account previous lines of therapy and degree and duration of response achieved, type of relapse, and patient factors. The current goal of therapy in advanced myeloma is to optimize the efficacy of existing drugs and SCT by using the most effective combinations and/or sequence of treatments.

he introduction of novel drugs, such as the proteasome inhibitor, bortezomib (Velcade), and the immunomodulatory drugs (IMiDs), thalidomide (Thalomid) and lenalidomide (Revlimid), has improved outcomes in patients with relapsed and/or refractory multiple myeloma (MM). The goal of therapy in advanced MM is to optimize the efficacy of existing drugs and SCT by using the most effective combinations and/or sequence of treatments. This article reviews recent data on use of novel therapy combinations in relapsed/refractory MM and updated strategies for use of transplantation as salvage therapy. Novel agents Bortezomib, lenalidomide, and dexamethasone are the building blocks upon which virtually all regimens for advanced MM will be based at the present time. However, there are a number of unanswered questions regarding their optimal use: • The activity of the individual novel agents is relatively low; what agents can be added to them to increase time to progression (TTP) and survival? • How effective are they if one has previously received thalidomide or has cytogenetic abnormalities? (There is already evidence that novel therapies 14

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can overcome the negative prognostic risk of certain cytogenetic abnormalities.) • What is the activity of doublet versus triplet therapy? • How do prior therapies or SCT influence efficacy? Single-agent trials Bortezomib. The first phase 3, singleagent, novel therapy trial was the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial, which compared bortezomib versus dexamethasone.1 This trial, which used standard bortezomib dosing (1.3 mg/m2 on days 1, 8, 15, and 22) for three 5-week cycles, included a total of 669 patients who had received one to three prior therapies. Compared with patients receiving dexamethasone, these heavily-treated patients receiving bortezomib had higher response rates, longer TTP, and longer survival, although complete response (CR) rates with bortezomib monotherapy were quite low by current standards (9%)1-4 (Table 1). TTP was relatively modest with bortezomib (6 months), given that this was second- to fourth-line therapy. Median overall survival (OS) was significantly improved with bortezomib over that seen with dexamethasone (29.8 vs 23.7 months, respectively).5

Lenalidomide. Single-agent lenalidomide has displayed clinical benefit in relapsed or refractory MM in phase 1 and 2 studies.6-8 Lenalidomide monotherapy (30 mg once daily) was recently evaluated in relapsed and refractory MM in a large multicenter, open-label, phase 2 study.2 Patients (N = 222) had received a median of five prior therapies. Single-agent lenalidomide was active, with an overall response rate (ORR, at least partial response [PR]) of 26%; however, the CR rate was low (2%) (Table 1). Overall response rates were similar for patients who had received two or fewer prior lines of treatment versus three or more prior lines of treatment, which included thalidomide, bortezomib, or SCT. Responses were also similar in patients who were refractory, relapsed, or sensitive to prior thalidomide therapy (ORR, 30%, 17%, and 23%, respectively). Double-agent trials US Food and Drug Administration– approved doublet therapies for previously treated MM include lenalidomide/dexamethasone (LD) and bortezomib plus pegylated liposomal doxorubicin (PLD; Doxil). Lenalidomide/dexamethasone. The efficacy of LD in the treatment of patients with relapsed or refractory MM who had received at least one prior therapy was confirmed in

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MULTIPLE MYELOMA Table 1. Summary of Single- and Double-agent Trials in Relapsed and Refractory Myeloma Trial

Regimen

ORR (PR)

Median TTP (months)

Duration of response (months)

Bortezomib (n = 333)

9%a

43%a

7.8

1-year OS: 80%b Median OS: 29.8 months

Dexamethasone (n = 336)

<1%

18%

3.5

5.6

1-year OS: 67% Median OS: 23.7 months

Lenalidomide (N = 222)

26%

5.2

8.4 (MR, n = 98) 12.6 (PR, n = 28)

1-year OS: 67% Median OS: 23.2 months PFS: 4.9 months

Lenalidomide/ dexamethasone (n = 177)

14.1%a

61%a

11.1a

15.8a

Median OS: 29.6 monthsa

Placebo/dexamethasone (n = 176)

0.6%

19.9%

4.7

5.1

Median OS: 20.2 months

Bortezomib + PLD (n = 324)

44%

9.3a

10.2a

15-month OS: 76%c

Bortezomib (n = 322)

41%

6.5

7.0

15-month OS: 65%

Survival

Single-agent trials APEX (Richardson PG, et al5)

Richardson PG, et al2

Double-agent trials MM-009 (Weber DM, et al3)

Orlowski RZ, et al4

APEX indicates Assessment of Proteasome Inhibition for Extending Remissions; CR, complete response; MR, minimal response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PR, partial response; TTP, time to progression. P <.001 vs comparator. P = .027 vs comparator. c P = .03 vs comparator. a

two similar phase 3 trials conducted in North America (MM-009, N = 353)3 and internationally (MM-010, N = 351).9 A total of 61% of patients receiving lenalidomide (25 mg on days 1-21 of a 28day cycle) in combination with dexamethasone in the North American study achieved a PR or better compared with 19.9% of patients receiving placebo plus dexamethasone3 (Table 1). A total of 14.1% of patients receiving LD achieved a CR, and median TTP was 11.1 months. Although direct comparisons between the LD and lenalidomide monotherapy trials cannot be made, the ability of added dexamethasone to increase the quality and duration of response over that achieved with lenalidomide monotherapy is evident. The effect of prior thalidomide exposure on response rate was evaluated in a prospective subgroup analysis of data pooled from

the MM-009 and MM-010 phase 3 trials.10 Of the 704 patients in the studies, 39% had previously received thalidomide. Thalidomide-exposed patients had more prior lines of therapy and a longer duration of MM than thalidomide-naïve patients. Among patients receiving LD, the ORR was higher in thalidomide-naïve patients than those who had previously received thalidomide (64.6 vs 53.5%, respectively). Thalidomidenaïve patients also experienced longer duration of response and progression-free survival (PFS). However, the lower efficacy seen in thalidomide-exposed patients could be due to the fact that these patients were a more heavily pretreated group in general. LD was active in patients who had not previously responded to, or relapsed on, thalidomide. In addition, OS was similar in thalidomide-naïve and thalidomideexposed patients.

The effect of prior thalidomide and number of prior therapies on TTP and long-term OS in the pooled LD phase 3 results was subsequently evaluated.11 At the time of the analysis, 47% of patients who had received placebo/dexamethasone had crossed over to receive LD as per study protocol; these included patients who had progressed on placebo/dexamethasone prior to study unblinding or were receiving placebo/dexamethasone at the time of unblinding. As seen in the prospective analysis, the ORR continued to be higher (65% vs 54%) and TTP longer (13.8 vs 8.3 months) in thalidomide-naïve patients than in thalidomide-exposed patients, respectively. Patients who had not been responsive to prior thalidomide tended to have worse outcomes. When outcomes were compared according to number of prior therapies, TTP was

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MULTIPLE MYELOMA Table 2. Time to Progression and Overall Survival According to Number of Prior Therapies in an Analysis of Pooled MM-009 and MM-010 Data 1 Prior Therapy

2 Prior Therapies

LD (n = 124)

Dexamethasone (n = 124)

LD (n = 229)

Dexamethasone (n = 227)

Median TTP (months)

14.5a

4.7

9.6

4.7

Median OS (months)

39.1

33.6

33.3

27.3

LD indicates lenalidomide/dexamethasone; OS, overall survival; TTP, time to progression. P <.05 compared with patients receiving LD who had received 2 prior therapies.

Source: Reference 11.

found to be significantly longer when LD was used at first relapse than when used later as salvage therapy (Table 2).11 The questions are whether this difference is simply a result of patients becoming progressively more resistant to the individual agents used in these combination therapies over time and, if so, what strategies can be used to overcome this. Although OS was slightly longer in patients receiving LD as second-line therapy than in those receiving it as a subsequent line of therapy, the difference was not significant. These results indicate that LD can be used effectively as second-line therapy for relapsed MM. Bortezomib/PLD. The efficacy and safety of bortezomib/PLD (V-PLD) were compared with those of bortezomib monotherapy in a phase 3 trial that included 613 patients who had received one or more prior therapies12—a patient population similar to that in the phase 3 LD trials. ORRs were similar among the two study arms (44% for V-PLD and 41% for bortezomib monotherapy) (Table 1). However, TTP was significantly increased with the addition of PLD (9.3 months with V-PLD vs 6.5 months with bortezomib monotherapy; P <.001). A post-hoc analysis of data from this trial showed that, in contrast to that seen with LD doublet therapy, VPLD provided a consistent efficacy benefit in terms of response rates and TTP in both thalidomide-exposed and thalidomide-naïve patients.12 Triple-agent trials The use of three-drug regimens built on a backbone of dexamethasone plus either bortezomib or an IMiD (ie, thalidomide or lenalidomide) has generated much interest 16

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in both the frontline and relapsed/refractory setting. A number of agents have been evaluated as the “third drug” in these regimens. Bortezomib/thalidomide/dexamethasone. A regimen combining bortezomib, thalidomide, and dexamethasone (Decadron) (VTD) demonstrated notable clinical activity in heavily pretreated advanced and refractory MM in a phase 1/2 trial.13 VTD, a popular regimen in certain areas of the United States, provided an impressive depth of response (CR/near-CR [nCR], 22%; PR, 41%; ORR, 63%), a respectable OS (22 months), and a modest event-free survival (EFS; 6 months) after a median follow-up of 46 months. The percentage of patients off treatment due to toxicity was low (9%). This was a heavily pretreated population; although the 85 patients in this study were bortezomib-naïve, 92% had received a prior transplant, 65% had received two transplants, and 74% had received prior thalidomide. In addition, although OS and EFS were significantly longer in the absence of prior thalidomide exposure, this is another piece of evidence suggesting that the addition of a novel agent, such as the proteasome inhibitor in this case, can compensate for previous exposure to another therapy. Lenalidomide/doxorubicin/dexamethasone. The use of doxorubicin (Adriamycin) and dexamethasone in conjunction with lenalidomide (RAD) was based on the observation that vincristine (Vincasar PFS; Oncovin), doxorubicin continuous infusion, and dexamethasone (VAD) was effective in MM that was resistant to alkylator therapy.14 In a phase 1/2 trial conducted in Germany that included 69 intensively treated patients (77% received RAD as

third- or fourth-line treatment) with relapsed or relapsed-refractory MM, this combination induced substantial and durable remission with an acceptable safety profile.14 The ORR was 73% for the entire study population. At the highest dose level, 74% of patients achieved a CR or very good partial response (VGPR); median TTP was 45 weeks, and 1-year survival probability was 88%. No significant relationship was noted between depth of response and TTP; however, the number of patients in each group was small. The incidence of thromboembolic events was 4.5% despite use of aspirin or low-molecular-weight heparin prophylaxis. In this study, response rates and PFS were similar among patients with or without del(13q) or t(4;14), corroborating earlier reports of novel agents overcoming the negative clinical impact of these prognostic factors.15,16 However, del(17p) and elevated 2-microglobulin were associated with significantly inferior response and shortened TTP.14 Of note, whereas 84% of patients in this study had received previous anthracycline treatment, only 20% of patients received prior therapy with thalidomide and none of the patients received prior therapy with lenalidomide. A majority of the patients, 57%, were previously exposed to bortezomib.14 Future studies will have to assess the efficacy of RAD as salvage therapy in patients heavily pretreated with IMiDs. Bortezomib/cyclophosphamide plus steroid. There is preclinical evidence that bortezomib, when used with anthracyclines and alkylators in MM, may act synergistically, providing a rationale for clinical investigation.17 In the clinical setting, a number of recent studies have shown that the combination of bortezomib, cyclophosphamide (Cytoxan), and a steroid (dexamethasone or prednisone) displays notable activity in advanced MM (Table 3).18-20 These studies used standard or once-weekly bortezomib dosing. A regimen that included once-weekly bortezomib at 1.5 mg/m2, once-weekly cyclophosphamide at 300 mg/m2, and alternate-day prednisone at 100 mg resulted in an 85% ORR, a 54% CR rate, and excellent 1-year PFS and OS in a phase 1/2 study in relapsed/refractory MM.20 Bortezomib/lenalidomide/dexamethasone. Another highly active regimen that is gen-

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MULTIPLE MYELOMA erating much interest is the combination of bortezomib, lenalidomide, and dexamethasone (VRD). Primary Induction Failure Results of a phase 2 study in relapsed/refractory MM showed a CR/nCR rate of 26% with the combination among 62 evaluable patients; an additional 69% of patients achieved a PR or VGPR, Nonresponders/ Nonresponders/ Progressive Disease for an ORR of 95%.21 VRD is Nonprogressor Nonprogressor <5% of Patients active in patients who have Non-Medicare Patients Medicare Patients received prior therapy with bortezomib, lenalidomide, thalidomide, or SCT. Responses were durable, with a median TTP of 12 months Salvage Options Modified Begin Triple or Quadruple Salvage Options Modified CVAD/DTPACE Therapy, Proceed to Stem CVAD/DTPACE after 17 months of follow-up, and Quadruple Therapy Cell Collection and Stem Quadruple Therapy appear to be independent of ID Melphalan Cell Transplantation as ID Melphalan adverse cytogenetics and other Stem Cell Collection soon as possible Stem Cell Collection recognized adverse prognostic factors. Median PFS was 12 months, and OS was 29 months at time of Figure 1. Proposed Treatment Algorithm for Patients Not Responding to Frontline Induction with Novel follow-up. A prospective study is Therapies examining the impact of cytoge- CVAD indicates cyclophosphamide, vincristine, doxorubicin, and dexamethasone; DTPACE, dexamethasone, thalidomide, netic abnormalities on response cisplatin, doxorubicin, cyclophosphamide, and etoposide; ID, autologous stem cell transplantation utilizing intermediatedose melphalan. and TTP with VRD therapy, pre- Developed by The University of Texas M. D. Anderson Cancer Center. liminary results of which were Source: Giralt SA. Written communication. December 2009. reported at the American Society of Hematology (ASH) annual Table 3. Studies Evaluating Bortezomib, Cyclophosphamide, and Steroid meeting in 2009.22 Combination Therapy in Advanced Multiple Myeloma It is difficult to compare the Study parameter Kropff M, et al Davies FE, et al Reece DE, et al efficacy of the various triple-drug regimens because the study popuDosing: 1.3 mg/m , days 1, 4, 8, 1.3 mg/m , 1.5 mg/m , Bortezomib 11  8/days 1, 8, 15, 22  3 days 1, 4, 8, 11 days 1, 8, 15 lations are not necessarily the same. There is also the question Cyclophosphamide 50 mg/day 500 mg, days 1, 8, 15 300 mg/m , as to whether all agents should be days 1, 8, 15, 22 used together, or whether they Steroid dexamethasone dexamethasone (40 mg, alternate-day would be best used in sequence or (20 mg/day) days 1, 2, 4, 5, 8, 9, 11, 12) prednisone as alternating blocks of non(100 mg) cross-resistant drugs. Finally, Number of patients 54 16 13 there is the question of cost-effecMedian number of 3 (1-6) 3 (1-6) 2 (1-6) tiveness of combinations such as previous lines of VRD. Although well-designed therapy (range) studies are needed to help answer ORR (PR) 82% 75% 85% these complex questions, some CR/nCR 16% 31% 54% recent investigations are shedMedian EFS 12 months --ding light on these issues. For example, a retrospective review Median OS 22 months --presented at ASH of patients in Median PFS -7 months Not reached Ontario who were provided 1-year PFS --83% access to bortezomib following 1-year OS --100% progression on LD provides a CR indicates complete response; EFS, event-free survival; nCR, near-complete response; ORR, overall response rate; OS, unique opportunity to assess the overall survival; PFS, progression-free survival; PR, partial response. effectiveness of a novel agent fol23 Dosing and data shown are for the group receiving weekly bortezomib at a dose of 1.5 mg/m , including an expanded lowing sequential MM relapses. cohort (dose level 6). To further improve efficacy, a Median follow-up, 12 months. number of four-drug regimens 18

20,a

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MULTIPLE MYELOMA Table 4. Potential Treatment Guidelines for Relapsed/Refractory Multiple Myeloma Patient population

Potential treatment(s)

Young patients Relapse <1 year post-ASCT

• Combination therapy, ie: • Bortezomib, lenalidomide, and dexamethasone plus cyclophosphamide • Bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) • If VGPR or CR achieved,  RIC-allo or consolidation with maintenance therapy

Relapse 1-3 years post-ASCT

• Rescue with sequential novel agent therapy • One line of treatment different from that used for induction • Use of second and subsequent lines only at time of disease progression • Possibility of RIC-allo after second relapse in patients <55 years of age

Relapse >3-4 years post-ASCT

• Re-induce with initial treatment or another novel agent combination  second ASCT

Elderly patients First relapse

• Rescue with regimen different from that used for induction unless first remission is long enough to consider retreatment with same regimen

Second and subsequent relapse

• After use of bortezomib and at least one IMiD, clinical trial with experimental agents • If not a candidate for active therapy, palliative treatment with oral cyclophosphamide and prednisone

ASCT indicates autologous stem cell transplantation; CR, complete response; IMiD, immunomodulatory drug; RIC-allo, allogeneic stem cell transplantation using a reduced-intensity conditioning regimen; VGPR, very good partial response. Source: Reference 43.

have been evaluated in the relapsed/ refractory setting, including lenalidomide/ melphalan/pre dnisone/thalidomide (RMPT); bortezomib/cyclophosphamide/ thalid omide/dexamethasone (V-CTD); and bortezomib/doxorubicin/melphalan (Alkeran)/prednisone (VAMP) alternating with a three-drug combination of thalidomide/cyclophosphamide/dexamethasone.24-26 However, the potential for increased toxicity with additional agents must be considered. Adding additional drugs may actually require lowering the dose of the most effective individual drug in the combination in an effort to mitigate overall toxicity, and unless there is true synergy, this may negatively impact efficacy. Role of transplantation The most common role of transplantation is that of planned consolidation of frontline therapy as evaluated in large 18

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European trials. However, the application of transplantation is not as uniform in the United States, because it may also be used in the treatment of primary refractory or relapsed MM, or as salvage therapy after a prior transplantation for refractory disease. Use in primary refractory myeloma. Primary refractory (or “resistant”) MM, defined as the failure to achieve at least a 50% reduction in tumor burden with initial therapy, used to be a relatively common condition, affecting up to 40% of patients receiving pulse dexamethasone.27 The incidence has declined, however, with the use of more effective therapies, such that with quadruple therapy (ie, an alkylator, steroid, IMiD, and proteasome inhibitor); fewer than 15% of patients will fail to achieve a 50% reduction in tumor burden.28,29 In the context of pulse dexamethasone, the most effective means of achieving long-

term disease control was high-dose melphalan and autologous transplantation. In an early study of 89 patients with primary resistant myeloma, this strategy led to a response rate of 69%, including 16% CR, and improved long-term disease control.30 Autologous stem cell transplant (ASCT) continues to be an effective option for patients who do not respond to frontline lenalidomide or bortezomib therapy. An algorithm developed by The University of Texas M. D. Anderson Cancer Center recommends attempting to collect stem cells with chemotherapy mobilization and proceeding to transplantation as soon as possible following primary induction failure (Giralt SA, written communication, December 2009) (Figure 1). Because Medicare guidelines do not qualify transplantation in patients who have not had at least a 50% reduction in tumor burden, use of a combination-based regimen is recommended to try to achieve PR or better to qualify for transplantation. A similar strategy is recommended in progressive disease; however, these patients tend to do very poorly and are usually not able to proceed to transplantation. Use in relapse after primary ASCT therapy. An issue that is increasingly being faced by the transplantation community in the United States is that of patients relapsing following primary non-SCT therapy. Due to the improved response rates seen with the use of novel agents as frontline therapy, more patients are opting for delayed transplantation. However, little data are available regarding the role of delayed transplantation in the era of novel therapies. Historically, most of the randomized trials that compared transplantation and conventional chemotherapy used transplantation as part of first salvage therapy in patients in the nontransplantation arm.31-34 As a result, OS was often similar for both transplantation and nontransplantation arms.31-34 This contrasts with data from an earlier retrospective analysis that demonstrated limited value of ASCT in improving outcome for patients who had failed multiple lines of prior alkylator-based regimens.35 Although these data were obtained before the use of novel agents, it would be prudent to consider using transplantation as first- or second-line salvage therapy in this setting.

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MULTIPLE MYELOMA Use in relapse after initial ASCT. There is a clear distinction between tandem versus salvage transplantation regarding both Lenalidomide timing and cause for consideramaintenance: Register and tion. A tandem transplantation is MEL 200 Randomize 10 mg daily  3 VRD  4 a planned therapy occurring withmg/m2 months, then in 6 months of the first transplan15 mg daily  3 tation in an effort to improve the years MEL depth and prolong duration of 2 200 mg/m the response for patients who achieved only a PR or stable disease after the initial transplantation.36 In contrast, a salvage trans- Figure 2. BMT CTN 0702 Schema plantation is one considered in MEL indicates autologous peripheral blood transplantation using melphalan 200 mg/m ; VRD, bortezomib 1.3 mg/m on patients who have relapsed (an days 1, 4, 8, 11; lenalidomide 15 mg on days 1 to 14; and dexamethasone 40 mg on days 1, 8, 15. event typically occurring beyond Source: Reference 44. 6 months from the time of first SCT). It is recommended that patients Use as salvage therapy for refractory dis- arm. However, EFS was similar in both who relapse after a prior autograft and have ease. SCT in patients failing to respond to groups as a result of significantly lower stored stem cells available should be con- salvage therapy is possible and effective. probability of disease progression followsidered for salvage consolidation trans- Remissions are possible, but the duration ing allografting. plantation at that time.36 The rationale for is often short. What is not known, howReduced-intensity allografting has also this recommendation is that when done as ever, is the value of SCT consolidation of been implemented in the salvage setting as a frontline therapy, SCT increases the CR a second or subsequent remission in trans- means to reduce TRM while retaining the rate, extends PFS, and reduces the need for plantation-naïve patients who have graft-versus-myeloma effect. A retrospective maintenance therapy. However, it is rec- received novel therapies versus its value analysis of outcomes at The M. D. Anderson ommended that a transplantation be per- in transplantation failures. In addition, Cancer Center after salvage autologous (n = formed only in patients failing to achieve a although response rates are high with 14) or reduced-intensity allogeneic transmajor response (ie, VGPR or better) after common therapies, some people still plantations (RIC-allo; n = 26) in patients salvage therapy. This minimizes the burden achieve only PR at best, and it remains to with disease recurrence after an autograft of treatment by using high-dose therapy be seen whether transplantation in this shows both strategies to be feasible.41 only as a vehicle to obtain a VGPR or bet- setting will improve response. Nonetheless, disease progression remained ter. It also allows use of high-dose therapy the major cause of failure in both groups. later on, when disease is more resistant and When done as frontline The median OS was relatively longer in fewer therapeutic options are available. the patients receiving a salvage autograft therapy, SCT increases the Unfortunately, salvage transplantation (29.5 vs 13 months in those receiving an is currently performed in few instances, CR rate, extends PFS, and allograft), but this could be due to a numdespite the availability of cells, the incor- reduces the need for ber of factors, including shorter follow-up rect rationale being that if it did not work and fewer patients in this group, as well as maintenance therapy. the first time, it will not work now. Thus, the heterogeneous patient population, use many salvage transplantations are done of different preparative regimens, and in the context of refractory relapsed disnumber of lines of prior therapy. Patients ease, for which responses are generally Role of allogeneic transplantation receiving a RIC-allo in this series had a short-lived. Data such as those presented The issue of autologous versus allo- median of five lines of prior therapy, sugat ASH based on retrospective single- geneic SCT for relapse post-ASCT is gesting that the potential graft-versusinstitution reviews of patients receiving a controversial. Autografting was shown myeloma benefit of the allogeneic transsecond ASCT as salvage therapy37,38 or a sec- to be superior to allografting in OS in a plantation may best be exploited by ond salvage ASCT39 should help clarify the case-controlled study of 42 patients who performing the procedure earlier in the role of transplantation as salvage therapy. received salvage autologous or allogene- course of the disease. In addition, patients In cases in which a patient does not ic transplantation for MM refractory to who were in remission for longer than 1 have cells available, re-collection may be or relapsing following a first-line auto- year prior to receipt of the RIC-allo transattempted with plerixafor (Mozobil), graft (OS at 3 years, 54% vs 29%, respec- plant had significantly better OS than with or without chemotherapy mobiliza- tively).40 This outcome was primarily due those in remission for a shorter period, tion; however, this strategy requires fur- to significantly lower transplantation- suggesting a significant benefit of this ther exploration. related mortality (TRM) in the autograft strategy that needs to be studied further. 2

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MULTIPLE MYELOMA The issue of autologous versus full- or reduced-intensity allogeneic transplantation as salvage therapy continues to be investigated.42 Potential treatment guidelines At present, the use of novel agent combinations and transplantation in treatment of relapsed/refractory MM is empiric. It is not yet known definitively whether IMiDs and bortezomib are truly synergistic with each other in this setting, or whether they are more synergistic with alkylators or anthracyclines. In addition, dexamethasone is a critical synergistic drug that must be used early for optimal outcome. Appropriately designed trials are needed to help identify optimal regimens. A series of potential treatment guidelines for relapsed/refractory MM was recently proposed by JesĂşs F. San Miguel, MD, of the University of Salamanca, based on some of the rapid advances in the field (Table 4).43 He posits that three key factors must be taken into account when making treatment decisions: previous lines of therapy and the degree and duration of response achieved; type of relapse; and patient characteristics such as age, comorbidities, performance status, quality of life, previous toxicities, and life expectancy. His potential guidelines propose more aggressive therapy with a combination of all effective drugs in younger patients with early relapse to overcome drug resistance, but perhaps sequential use of active agents could be used in patients with less aggressive disease. He adds that the use of autologous and RICallo transplantations as salvage therapy should also be considered. Future directions The only way to advance our knowledge in this area is through participation in clinical trials. As an example, a phase 3 trial being conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702) aims to identify optimal consolidation in the context of novel therapies.44 This frontline study is comparing three strategies: (1) tandem autologous transplantation plus lenalidomide maintenance; (2) single autologous transplantation plus consolidation therapy with lenalidomide/bortezomib/dexamethasone 20

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(RVD), followed by lenalidomide maintenance; and (3) single autologous transplantation plus lenalidomide maintenance (Figure 2).44 RVD dosing mirrors that used in the Eastern Cooperative Oncology Group (ECOG) E1A05 trial of RVD induction and consolidation in the nontransplantation setting, whereas the lenalidomide maintenance dosing is based on that used in the Cancer and Leukemia Group B (CALGB) 100104 trial of single autologous transplantation followed by either placebo or lenalidomide until disease progression. The primary endpoint of the study is 3-year PFS. â&#x2014;?

Patients who were in remission for longer than 1 year prior to receipt of the RIC-allo transplant had significantly better OS than those in remission for a shorter period, suggesting a significant benefit of this strategy that needs to be studied further. Acknowledgement The reviewer thanks Marie S. Recine for medical writing assistance. References

1. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498. 2. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114:772-778. 3. Weber DM, Chen C, Niesvizky R, et al; for the Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 4. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901. 5. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110:3557-3560.

6. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002; 100:3063-3067. 7. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108: 3458-3464. 8. Zangari M, Tricot G, Zeldis J, et al. Results of a phase I study of CC-5013 for the treatment of multiple myeloma patients who relapse after high dose chemotherapy (HDCT). Blood (ASH Annual Meeting Abstracts). 2001;98:Abstract 3226. 9. Dimopoulos M, Spencer A, Attal M, et al; for the Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 10. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008; 112:4445-4451. 11. Weber D, Knight R, Chen C, et al. Prolonged overall survival with lenalidomide plus dexamethasone compared with dexamethasone alone in patients with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 412. 12. Sonneveld P, Hajek R, Nagler A, et al. Impact of prior thalidomide (T) therapy on the efficacy of pegylated liposomal doxorubicin (PLD) and bortezomib (B) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2007;25(18S): Abstract 8023. 13. Pineda-Roman M, Zangari M, van Rhee F, et al. VTD combination therapy with bortezomibthalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia. 2008;22:1419-1427. 14. Knop S, Gerecke C, Liebisch P, et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood. 2009;113:4137-4143. 15. Sagaster V, Ludwig H, Kaufmann H, et al. Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia. 2007;21:164-168. 16. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21:151-157. 17. Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9:1136-1144. 18. Kropff M, Bisping G, Schuck E, et al; for the Deutsche Studiengruppe Multiples Myelom. Bortezomib in combination with intermediatedose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007;138:330-337.

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MULTIPLE MYELOMA 19. Davies FE, Wu P, Jenner M, et al. The combination of cyclophosphamide, velcade and dexamethasone induces high response rates with comparable toxicity to velcade alone and velcade plus dexamethasone. Haematologica. 2007; 92:1149-1150. 20. Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol. 2008;26:4777-4783. 21. Anderson KC, Jagannath S, Jakubowiak A, et al. Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (MM): Encouraging outcomes and tolerability in a phase II study. J Clin Oncol. 2009;27(15S):Abstract 8536. 22. Dimopoulos MA, Kastritis E, Christoulas D, et al. Treatment of patients with relapsed/refractory multiple myeloma (MM) with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 958. 23. Reece DE, Trieu Y, Chen C, et al. Sequencing novel agents in relapsed/refractory multiple myeloma: use of bortezomib-based therapy after lenalidomide + dexamethasone. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 1853. 24. Cavallo F, Larocca A, Petrucci MT, et al. A prospective randomized phase I/II study of lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 2864. 25. Kim Y-K, Lee J-J, Sohn S-K, et al. Clinical efficacy of VEL-CTD (bortezomib, cyclophosphamide, thalidomide, and dexamethasone) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 3693. 26. Colado E, Mateos M-V, Moreno M-J, et al. VAMP/ThaCyDex: Velcade® (bortezomib), adriamycin, melphalan and prednisone alternating with thalidomide, cyclophosphamide and dexamethasone as a salvage regimen in relapsed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 3694.

27. Sinha S, Rajkumar SV, Lacy MQ, et al. Impact of dexamethasone responsiveness on long term outcome in patients with newly diagnosed multiple myeloma. Br J Haematol. December 3, 2009. Epub ahead of print. 28. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide for initial treatment of elderly multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2009;14:Abstract 128. 29. Palumbo A, Bringhen S, Rossi D, et al. A prospective, randomized, phase III study of bortezomib, melphalan, prednisone and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma patients. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 652. 30. Alexanian R, Weber D, Delasalle K, et al. Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma. Bone Marrow Transplant. 2004;34:229-234. 31. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97. 32. Fermand JP, Ravaud P, Chevret S, et al. Highdose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-3136. 33. Blade J, San Miguel JF, Fontanillas M, et al. Increased conventional chemotherapy does not improve survival in multiple myeloma: longterm results of two PETHEMA trials including 914 patients. Hematol J. 2001;2:272-278. 34. Child JA, Morgan GJ, Davies FE, et al. Highdose chemotherapy with hematopoietic stemcell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883. 35. Alexanian R, Dimopoulos M, Smith T, et al. Limited value of myeloablative therapy for late multiple myeloma. Blood. 1994;83:512-516. 36. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Multiple

Myeloma. V.3.2010. February 5, 2010. www. nccn.org/professionals/physician_gls/PDF/myelo ma.pdf. Accessed February 10, 2010. 37. Mikhael JR, Zadeh S, Stewart AK, et al. Second autologous stem cell transplant (ASCT) as salvage therapy in patients with relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 1217. 38. Chaidos A, Giles C, Auner HW, et al. Second autologous stem cell transplantation is effective salvage therapy for relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 1229. 39. Fenk R, Liese V, Bruns I, et al. Reapplication of high-dose chemotherapy and autologous blood stem cell transplantation as salvage treatment for patients with relapsed or refractory multiple myeloma—a single center experience. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 3418. 40. Mehta J, Tricot G, Jagannath S, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant. 1998;21:887-892. 41. Qazilbash MH, Saliba R, De Lima M, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer. 2006;106:1084-1089. 42. Bashir Q, Thall P, Hosing C, et al. Salvage autologous or allogeneic stem cell transplantation after the failure of first autograft in patients with multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 1186. 43. San Miguel JF. Relapse/refractory myeloma patient: potential treatment guidelines. J Clin Oncol. 2009;27:5676-5677. 44. Blood and Marrow Transplant Clinical Trials Network. BMT CTN Protocol 0702: a trial of single autologous transplant with or without consolidation therapy versus tandem transplant with lenalidomide maintenance for patients with multiple myeloma. Version 1.0. June 24, 2009. Available at: https://web.emmes.com/ study/bmt2/protocol/0702_protocol/0702_MM_ v1.pdf. Accessed January 15, 2010.

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Self-Assessment Questions Highlights from a Symposium—Unifying Practice Patterns Among Academic and Community Clinicians: Focus on Myeloma For each question, select the one statement that provides the best answer.

1. A patient with newly diagnosed multiple myeloma who achieves a complete response after autologous stem cell transplantation (ASCT) should undergo a second transplantation within 6 months. A. True B. False 2. Which of the following agents is recommended by the National Comprehensive Cancer Network (NCCN) for use as maintenance therapy after ASCT for newly diagnosed myeloma? A. Bortezomib B. Lenalidomide C. Thalidomide D. Both B and C 3. When evaluating the literature about the role of ASCT in the management of newly diagnosed myeloma patients, which of the following caveats is most important? A. The major randomized trials were conducted before novel agents became a routine component of induction regimens B. The major randomized trials were conducted when stem cells were largely derived from the bone marrow rather than the peripheral blood C. Most trials utilized overall survival as the primary endpoint, and we now know that the 3year complete response (CR) rate should be used instead D. Most trials utilized 3-year CR rate as the primary endpoint, and we now know that overall survival should be used instead

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4. Which of the following regimens would be most appropriate as initial treatment for an elderly patient with newly diagnosed myeloma? A.ASCT B. Lenalidomide/high-dose dexamethasone (LD) C. Bortezomib/melphalan/prednisone (VMP) D. Bortezomib/thalidomide/dexamethasone (VTD) 5. Which of the following agents that is currently commonly used in the treatment of elderly patients with myeloma is associated with an increased risk of developing leukemia? A.Bortezomib B. Lenalidomide C. Melphalan D. Thalidomide 6. In the phase 3 APEX trial, which of the following was not achieved with single-agent bortezomib compared with dexamethasone? A.Higher overall response rates B. Longer duration of response C. Longer time to progression (TTP) and survival D. All of the above were achieved 7. Which of the following statements regarding the effect of prior thalidomide exposure in the prospective subgroup analysis of data pooled from the MM-009 and MM-010 phase 3 trials of lenalidomide/dexamethasone is true? A.The overall response rate was similar in thalidomide-naïve and thalidomide-exposed patients B. Progression-free survival was similar in thalidomide-naïve and thalidomide-exposed patients C. Lenalidomide/dexamethasone was active in patients who had not previously responded to or relapsed on thalidomide D. None of the above

8. Which of the following was not a finding of the phase 3 trial comparing bortezomib-pegylated liposomal doxorubicin (PLD) and bortezomib monotherapy? A.TTP was significantly increased with the addition of PLD B. The overall response rate was higher in the bortezomib-PLD arm C. TTP was similar in both thalidomide-naïve and thalidomideexposed patients who received bortezomib-PLD D. All of the above were findings 9. Which of the following statements is true regarding salvage autologous transplant? A.It is recommended for patients who relapse after a prior autograft and have stored stem cells available B. It is recommended only in patients failing to achieve a major response after salvage therapy C. It is performed infrequently D. All of the above 10. According to the recently proposed treatment guidelines for relapsed/refractory myeloma (J.F. San Miguel), which of the following is most appropriate for younger patients relapsing less than 1 year post-ASCT? A.Use of combination novel agent therapy B. Rescue with sequential novel agent therapy C. Reinduction with the initial treatment, followed by a second ASCT D. All of the above

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Activity Evaluation Form Highlights from a Symposiumâ&#x20AC;&#x201D;Unifying Practice Patterns Among Academic and Community Clinicians: Focus on Myeloma To obtain continuing education credit within four (4) weeks following receipt of a completed form, please: (1) Complete the attached self-assessment and evaluation by March 5, 2011; (2) Fax the form to 215-337-0959 or mail completed form to MediCom Worldwide, Inc., 101 Washington St., Morrisville, PA 19067. Kindly remember to fax or mail both pages; (3) All participants must achieve a minimum score of 70% on the self-assessment portion of the form to qualify for CE credit; (4) The participant will be mailed his/her CE certificate within four (4) weeks following receipt of the completed, qualified form. Participant Information Name: Mailing Address:

City: __________________________________________________________State: __________________ Zip: __________________ License Number/State:

Date of Completion: Professional Degree:

MD____

DO____

PharmD____

RPh____

RN____

LPN____

NP____

PhD____

PA_____

Other: Specialty: Years in practice: Number of myeloma patients seen/week:

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MULTIPLE MYELOMA

Activity Evaluation Form Highlights from a Symposium—Unifying Practice Patterns Among Academic and Community Clinicians: Focus on Myeloma Please rate the activity using the following scale for statements 1-2: (A) Excellent (B) Good (C) Fair (D) Poor 1. Overall content

❏A ❏B ❏C ❏D

2. Format

❏A ❏B ❏C ❏D

Please rate the degree to which the activity met its stated objectives using the following scale for statements 3-5: (A) Strongly Disagree (B) Disagree (C) Neutral (D) Agree (E) Strongly Agree 3. Describe best strategies for tailoring multiple myeloma management according to patient-specific needs ❏A ❏B ❏C ❏D ❏E 4. Contrast and compare strategies for treatment of multiple myeloma in patients with newly diagnosed disease compared with those with recurring or refractory disease ❏A ❏B ❏C ❏D ❏E 5. Correlate evidence related to efficacy and safety of biologic agents to application of treatment regimens in non-study clinical environments ❏A ❏B ❏C ❏D ❏E 6. Do you believe the activity was useful to you in your practice setting?

❏ Yes

7. Do you believe that fair balance was maintained for all therapeutic options? 8. Would you participate in future self-study activities?

❏ Yes

9. How long did it take you to complete this activity?

❏ 1 hour

❏ No ❏ Yes

❏ No

❏ No ❏ 1 hour, 15 minutes

❏ 1 hour, 30 minutes

Please provide detailed comments and suggestions for future activities.

❏ I certify that I have completed this educational activity as designed. Signature:

Date:

For additional information on multiple myeloma, please visit www.ManagingMyeloma.com ❏ Please contact me regarding upcoming medical education opportunities.

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MULTIPLE MYELOMA

❏A ❏B ❏C ❏D

2. Format

❏A ❏B ❏C ❏D

❏ Yes

7. Do you believe that fair balance was maintained for all therapeutic options? 8. Would you participate in future self-study activities?

❏ Yes

9. How long did it take you to complete this activity?

❏ 1 hour

❏ No ❏ Yes

❏ No

❏ No ❏ 1 hour, 15 minutes

❏ 1 hour, 30 minutes

Please provide detailed comments and suggestions for future activities.

❏ I certify that I have completed this educational activity as designed. Signature:

Date:

For additional information on multiple myeloma, please visit www.ManagingMyeloma.com ❏ Please contact me regarding upcoming medical education opportunities.

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MULTIPLE MYELOMA

❏A ❏B ❏C ❏D

2. Format

❏A ❏B ❏C ❏D

❏ Yes

7. Do you believe that fair balance was maintained for all therapeutic options? 8. Would you participate in future self-study activities?

❏ Yes

9. How long did it take you to complete this activity?

❏ 1 hour

❏ No ❏ Yes

❏ No

❏ No ❏ 1 hour, 15 minutes

❏ 1 hour, 30 minutes

Please provide detailed comments and suggestions for future activities.

❏ I certify that I have completed this educational activity as designed. Signature:

Date:

For additional information on multiple myeloma, please visit www.ManagingMyeloma.com ❏ Please contact me regarding upcoming medical education opportunities.

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