Addressing THE. Introduction

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1 Addressing THE CURRENT CHALLENGES OF multiple myeloma TREATMENT This CME-certified activity is based on information presented at a satellite symposium held on December 7, 2012, in Atlanta, Georgia. Faculty Paul G. Richardson, MD Program Chair Faith Davies, MBBCh, MRCP, MD, FRCPath Johannes Drach, MD Andrzej Jakubowiak, MD, PhD María-Victoria Mateos, MD, PhD Author Lynne Lederman, PhD Release date: March 13, 2013 Expiration date: March 13, 2014 Estimated time to complete activity: 1 hour Jointly sponsored by Multiple Myeloma Research Foundation Support for this activity has been provided through educational grants from Amgen, Bristol-Myers Squibb, Celgene Corporation, Merck Sharp & Dohme Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. Introduction The past several years have seen significant advances in the management of multiple myeloma. This has been due in large part to a better understanding of the biology of the disease and the development of several highly effective therapies. Current approaches to improving response rates and, ultimately, overall survival focus on taking an individualized approach to treatment, since multiple myeloma is a heterogeneous disease. Patients with multiple myeloma can have different clinical outcomes and responses to treatment based on underlying genomics. To better understand the correlation between genetic factors and mechanisms of disease, drug response, and patient relapse, research is under way to identify molecular and genomic markers important in multiple myeloma pathogenesis. In particular, the Multiple Myeloma Research Foundation (MMRF) has launched a landmark study, CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile), to identify the molecular profiles and clinical characteristics that define certain subsets of myeloma patients. These profiles will provide a better understanding of multiple myeloma pathology and further facilitate the development of new therapeutic agents and strategies for individualizing patient care. To achieve optimal results, oncologists must be adept at individualizing patient-management strategies, including stratifying patients based on risk and maximizing the depth and duration of treatment response. Physicians must consider an individualized approach in the context of both newly diagnosed and relapsed and relapsed/refractory disease, and they must have a high degree of familiarity with current novel therapies and next-generation agents, either of which may be useful for patients who become resistant to regimens used in the frontline setting. Addressing the current challenges of myeloma treatment was the goal of a symposium held December 7, 2012, in Atlanta, Georgia, prior to the American Society of Hematology Annual Meeting. Paul G. Richardson, MD, served as Program Chair and led a panel of experts, including Johannes Drach, MD; María-Victoria Mateos, MD, PhD; Andrzej Jakubowiak, MD, PhD; and Faith Davies, MBBCh, MRCP, MD, FRCPath, in discussions that covered recent clinical data and the latest advances in multiple myeloma therapy.

2 Activity Overview To achieve optimal results, oncologists who treat multiple myeloma must be adept in individualizing patient management strategies, which includes stratifying patients based on risk and maximizing the depth and duration of treatment response. Oncologists also need to be aware of these approaches in the context of relapsed or refractory disease and the next generation of agents that may be useful for patients that become resistant to current regimens. Target Audience This activity has been designed to meet the educational needs of hematologist-oncologists and medical oncologists involved in the care of patients with multiple myeloma. Learning Objectives Upon completion of this activity, participants should be able to: Use cytogenetics, fluorescence in situ hybridization (FISH), and gene expression profiling to define patient prognosis and risk stratification Outline a treatment plan to achieve the desired response while balancing the risk for toxicities in high-risk and standard-risk myeloma patients Implement evidence-based strategies to prolong the duration of response in multiple myeloma patients Incorporate current consensus recommendations, guidelines, and the latest clinical evidence in the management of multiple myeloma Evaluate clinical data regarding the use of new agents in patients who develop resistance to or relapse from their initial therapy Faulty Paul G. Richardson, MD Program Chair RJ Corman Associate Professor of Medicine Harvard Medical School Clinical Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts Faith Davies, MBBCh, MRCP, MD, FRCPath Cancer Research UK Senior Cancer Fellow Consultant Hematologist Royal Marsden Hospital Institute of Cancer Research London, United Kingdom Johannes Drach, MD Professor of Medicine, Hematology and Oncology Program Director, Multiple Myeloma and Malignant Lymphoma Medical University of Vienna Department of Medicine I/Clinical Division of Oncology Vienna, Austria Andrzej Jakubowiak, MD, PhD Professor of Medicine Director, Myeloma Program The University of Chicago Chicago, Illinois María-Victoria Mateos, MD, PhD Consultant Physician University Hospital of Salamanca Salamanca, Spain Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Penn State College of Medicine, Curatio CME Institute, and the Multiple Myeloma Research Foundation. Penn State College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Penn State College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Method of Participation There are no fees for participation in this CME activity. To receive credit during the period March 13, 2013 to March 13, 2014, participants must (1) read the learning objectives and disclosure statements, (2) study the educational activity, and (3) complete the posttest and activity evaluation, including the certificate information section. The posttest and evaluation can be accessed at the end of the activity OR completed online at: Please any questions to cmeinfo@curatiocme.com. For questions about CME credit for this activity, contact Penn State at ContinuingEd@hmc.psu.edu or (717) Reference course # G R Disclosure In accordance with the ACCME Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of everyone in a position to control content of an educational activity. A relevant financial relationship is a relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control. Relationship information appears below: Faith Davies, MBBCh, MRCP, MD, FRCPath, has disclosed the following relevant financial relationships: Speaker and Advisory Board: Celgene, Janssen, Lilly, Merck Sharp & Dohme Corporation, Millennium: The Takeda Oncology Company, Novartis Dr. Davies discusses the unlabeled or investigational use of a commercial product. Johannes Drach, MD, has disclosed the following relevant financial relationships: Consultant/Speaker: Celgene, Janssen Investigator: Roche, Mundipharma Dr. Drach discusses the unlabeled or investigational use of a commercial product. Andrzej Jakubowiak, MD, PhD, has disclosed the following relevant financial relationships: Advisory Board: Bristol-Myers Squibb, Celgene, Millennium: The Takeda Oncology Company, Onyx Consultant: Bristol-Myers Squibb, Celgene, Millennium: The Takeda Oncology Company, Onyx Speaker: Celgene Dr. Jakubowiak discusses the unlabeled or investigational use of a commercial product. 2 u March 2013

3 María-Victoria Mateos, MD, PhD, has disclosed the following relevant financial relationships: Consultant: Bristol-Myers Squibb, Celgene, Janssen, Millennium: The Takeda Oncology Company, Mundipharma, Onyx Dr. Mateos discusses the unlabeled or investigational use of a commercial product. Paul G. Richardson, MD, has disclosed the following relevant financial relationships: Advisory Board: Bristol-Myers Squibb, Celgene, Johnson & Johnson, Millennium: The Takeda Oncology Company, Novartis Dr. Richardson discusses the unlabeled or investigational use of a commercial product. Curatio CME Institute Denise C. LaTemple, PhD, President, Curatio CME Institute, has disclosed no relevant financial relationships. Jonathan S. Simmons, ELS, Senior Managing Editor, has disclosed no relevant financial relationships. Multiple Myeloma Research Foundation Anne Quinn Young, MPH, Vice President, Communications, has disclosed no relevant financial relationships. Penn State College of Medicine Faculty and staff involved in the planning and review of this activity have nothing to disclose. Core Principle Solutions, LLC Dana Delibovi, copy editor, has disclosed no relevant financial relationships. Lynne Lederman, PhD, medical writer, has disclosed the following financial relationships: Consultant: Infinity Discovery, Inc., a division of Infinity Pharmaceuticals and Oncology Business Review Ms Lederman discusses the unlabeled or investigational use of a commercial product. Media A downloadable/printed newsletter and the Internet were selected as the instructional formats to accommodate the learning preferences of a significant portion of the target audience. Disclaimer The information presented in this activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician regarding diagnosis and treatment of a specific patient s medical condition. Policy on Privacy and Confidentiality Curatio CME Institute collects the information provided by the user. The information is used to notify users about upcoming programs and educational information that may be of interest. The information is not shared or used for commercial purposes unless prior permission has been granted by the user. Curatio CME Institute may collect standard Web traffic data such as time and date of visit. Curatio CME Institute uses this information to administer its Web site. Browsing activity is recorded to form aggregate and anonymous demographic information, which is used as described above. Curatio CME Institute does not sell or offer to sell any user data, including registration and billing information, to any third parties for commercial purposes. Curatio CME Institute does, when required, provide the minimum subset of information to third parties that are responsible for accreditation of and issuance of certification for CME/CE tests. By participating in the Web-based activity, the user agrees that Curatio CME Institute has full permission to provide this minimum subset of information to the third parties as required by law. Unapproved Product Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Curatio CME Institute, Penn State College of Medicine, the Multiple Myeloma Research Foundation, Amgen, Bristol-Myers Squibb, Celgene Corporation, Merck Sharp & Dohme Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals do not recommend the use of any agent outside the labeled indications. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Curatio CME Institute, Penn State College of Medicine, the Multiple Myeloma Research Foundation, Amgen, Bristol-Myers Squibb, Celgene Corporation, Merck Sharp & Dohme Corporation, Millennium: The Takeda Oncology Company, or Onyx Pharmaceuticals. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Generic Name Trade Name Approved Use (if any) Unapproved/Investigational Use Bortezomib Velcade Treatment of patients with multiple myeloma (MM) Maintenance therapy Carfilzomib Kyprolis Treatment of patients with MM who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy Frontline therapy Ixazomib NA NA Treatment of MM Lenalidomide Revlimid Treatment of MM, in combination with dexamethasone, in patients who have received at least one prior therapy Pomalidomide Pomalyst Treatment of patients with MM who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy Frontline therapy; maintenance therapy Frontline therapy Thalidomide Thalomid Treatment of patients with newly diagnosed MM in combination with dexamethasone Relapsed/refractory MM; frontline therapy in combination with melphalan-prednisone; maintenance therapy Vorinostat Zolinza Treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease on or following two systemic therapies Treatment of MM Addressing the Current Challenges of Multiple Myeloma Treatment u 3

4 Cytogenetics and Risk Stratification The International Staging System (ISS) 1 based on serum β2-microglobulin and serum albumin though prognostic for survival classically does not take molecular or genetic information into account. Dividing myeloma into hyperdiploid or nonhyperdiploid groups using metaphase karyotyping adds substantial prognostic value. 2 Nonhyperdiploidy includes a high frequency of 14q translocations and 13q deletions and is associated with a poorer prognosis. 3 Fluorescence in situ hybridization (FISH) analysis may be a more informative method of stratifying risk, with t(4;14), t(14;16), and del(17p) associated with poor prognosis, del(13q) associated with intermediate prognosis, and all other abnormalities associated with more favorable prognosis after conventional therapy, recognizing that myeloma remains incurable in the longer term. 4,5 The International Myeloma Working Group (IMWG) has proposed a new multiple myeloma risk-stratification schema that combines FISH data with ISS staging to improve risk assessment. 6 Advanced testing via gene expression profiling (GEP) 7,8 and single-nucleotide polymorphism array 9 also holds promise, and the Mayo Clinic msmart risk classification system incorporates plasma cell FISH, metaphase cytogenetics, and plasma cell labeling index (PCLI) in its risk classification approach. 10 A summary of current risk categories used in multiple myeloma is shown in Table 1. 2,11-13 Research to determine whether novel therapies can overcome highrisk cytogenetics in multiple myeloma is ongoing. Several trials have assessed the efficacy of thalidomide in patients with adverse cytogenetic profiles but have generally failed to show that this drug can overcome cytogenetic risk For example, the Medical Research Council (MRC) Myeloma IX trial recently reported that thalidomidebased maintenance therapy did not yield a survival benefit in patients with adverse findings on FISH testing. 15 In contrast, lenalidomide and bortezomib may overcome unfavorable cytogenetics and lead to good outcomes One study of lenalidomide plus dexamethasone in the relapsed/refractory setting showed that treatment with this regimen overcame the negative prognostic effect of del(13q) and t(4;14) but not del(17p). 17 Another study of initial therapy found that, across high-risk groups of patients whose cytogenetic abnormalities were treated with lenalidomide and dexamethasone, overall survival (OS) did not differ significantly from the standard risk group. 18 In an analysis of relapsed and refractory patients, however, OS was significantly shorter among patients with del(13q) and t(4;14) who received this regimen compared with patients who did not have these cytogenetic abnormalities. 24 Bortezomib has demonstrated the ability to overcome adverse cytogenetics, including del(17p). A recent report Table 1. Multiple myeloma: risk categories summary. 2,11-13 Risk Factors FISH Standard Risk (Expected OS: 6 7 Yrs) t(11;14) t(6;14) High Risk (Expected OS: 2 3 Yrs) del(17p) t(4;14)* t(14;16) Cytogenetics Hyperdiploidy Nonhyperdiploidy del(13q) β2m* Low (<3.5 mg/l) High ( 5.5 mg/l) PCLI <3% High ( 3%) Isotype IgA GEP Good risk High risk *Patients with t(4;14), β2m <4 mg/l, and Hb 10 g/dl may have intermediate-risk disease. β2m, β2 microglobulin; FISH, fluorescence in situ hybridization; GEP, gene expression profile; Hb, hemoglobin; IgA, immunoglobulin A; OS, overall survival; PCLI, plasma cell labelling index. Table 2. Median survival in patients with del(17p) in the phase 3 HOVON-65/ GMMG-HD4 trial. 21 VAD ASCT T Maintenance PAD ASCT P Maintenance Patients (n) Median PFS (months) Median OS (months) Statistical Significance HR, % CI, P= Not reached at 55 months HR, % CI, P=0.003 CI, confidence interval; ASCT, autologous stem cell transplantation; HR, hazard ratio; OS, overall survival; PAD, bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; VAD, vincristine, doxorubicin, dexamethasone; T, thalidomide. from the HOVON trial observed a survival benefit in patients with this chromosomal abnormality who were treated initially with bortezomib-based therapy (Table 2). 21 Five-year data from the VISTA trial showed that bortezomib-based initial therapy in a transplant-ineligible population resulted in improved OS compared with conventional chemotherapy, regardless of cytogenetic risk group. 23 However, in earlier investigations by the Intergroupe Francophone du Myelome (IFM), OS benefit was observed for del(13q) and t(4;14) but not for del(17p), although this is likely due to the shorter bortezomib exposure seen in these studies compared to both VISTA and HOVON. 20 Based on available evidence, the most recent consensus by the International Myeloma Workshop Consensus Panel 2 is that bortezomib and lenalidomide may be able to overcome some high-risk features of multiple myeloma and help achieve greater clinical benefit. 11 However, 4 u March 2013

5 the IMWG asserts that it is still too early to mandate definitive treatment decisions based solely on cytogenetics and recommends further clinical trials based on risk stratification that includes not only cytogenetic risk but other risk categories. 11 Current Approaches to Newly Diagnosed Patients Complete response (CR) is an important treatment goal in multiple myeloma. Patients who achieve CR particularly CR that is confirmed by immunophenotypic testing or positron emission tomography/ computed tomography (PET/CT) often experience superior progression-free survival (PFS) and OS Although achievement of high-quality, sustained CR is important, it should be balanced with acceptable treatment-related toxicity. New multidrug regimens based on novel, molecularly targeted agents are replacing conventional chemotherapy for newly diagnosed multiple myeloma patients and are increasing the likelihood of CR. In a phase 1/2 study examining both transplant-eligible and transplant-ineligible patients, initial therapy with a combination of lenalidomide, bortezomib, and dexamethasone (RVD) produced a 100% response rate, with 29% patients attaining CR and 67% attainting at least a very good partial response (VGPR) overall 28 ; similar results were achieved in a second study evaluating the efficacy of RVD as part of a large, randomized phase 2 trial. 29 Transplant-eligible patients treated initially with bortezomib, thalidomide, and dexamethasone (VTD) also achieved a higher rate of CR than did patients treated with TD alone (31% vs 11%, P<0.0001) as part of a landmark phase 3 trial confirming the superiority of a threedrug combination over a two-drug regimen in this setting. 19 Not only are novel drugs now a mainstay of induction regimens, but they are finding their way into pretransplant conditioning. The addition of bortezomib 30 or busulfan 31 may improve conditioning with high-dose melphalan prior to autologous stem cell transplantation (ASCT). Consolidation and maintenance with novel drugs 29 are now being used more frequently posttransplantation to reduce the risk of relapse and prolong PFS and OS. Maintenance with novel agents has in fact replaced interferon maintenance, which is no longer the standard because of its significant toxicity, with lenalidomide and bortezomib currently the preferred novel agents for maintenance therapy. Specifically, in the IFM and CALGB studies, use of maintenance lenalidomide post-asct improved CR/VGPR and duplicate PFS compared with placebo 32,33 ; an OS benefit was also observed in the CALGB trial. 33 However, some concern arose in these studies over the potential for secondary malignancies in the lenalidomide maintenance arm, but these appear rarely, are primarily driven by genotoxic chemotherapy, and appear not to affect overall clinical benefit. Maintenance with Table 3. VISTA: Key end points, VMP versus MP at 5-year follow-up. 23 End Point VMP (n=344) MP (n=338) P Value Median OS (mo) year OS (%) NR Median time to next < treatment (mo) Median treatment-free interval (mo) < MP, melphalan plus prednisone; NR, not reported; OS, overall survival; VMP, bortezomib, melphalan, and prednisone. bortezomib was a key part of the HOVON trial, in which treatment with bortezomib-based induction followed by ASCT and bortezomib maintenance resulted in greater posttransplant CR and OS than was seen in patients receiving conventional chemotherapy followed by thalidomide maintenance. 21 In another study, the addition of bortezomib to thalidomide maintenance improved both CR and PFS relative to single-agent maintenance with thalidomide or interferon. 34 It should be noted that thalidomide may not be an optimal choice for maintenance, because of the potential for deleterious effect on survival seen after relapse 35 and reduced quality of life due to cumulative toxicity. 36 Because novel-agent induction has been shown to achieve good rates of CR and VGPR, researchers are investigating the potential benefits of delaying ASCT until the time of relapse; however, until results of these trials are available, induction with novel agents and ASCT up front remains the preferred strategy. Older patients who are not eligible for ASCT now have treatment choices that are more effective than melphalan plus prednisone (MP), the older standard of care. 23,37-43 Several newer regimens retain melphalan while incorporating a novel agent; these combinations have yielded significant benefit in terms of PFS and OS. For example, in the phase 3 VISTA trial, after a median follow-up of 5 years, the median OS for patients receiving bortezomib, melphalan, and prednisone (VMP) is approximately 60 months (Table 3). 23 Other melphalan-based regimens showing favorable outcomes in clinical trials include melphalan, prednisone, and thalidomide (MPT); bortezomib, melphalan, prednisone, and thalidomide (VMPT) followed by bortezomib and thalidomide maintenance (VT); and melphalan, prednisone, and lenalidomide (MPR) followed by lenalidomide maintenance (R). 38,40,44 The MPR-R regimen, for example, showed significantly greater response rate and median PFS than did MPR or MP. 40 It is noteworthy that several of these trials included a maintenance phase a harbinger of a trend toward providing novel-agent maintenance in the population of multiple myeloma patients who cannot receive ASCT. Other regimens that incorporate Addressing the Current Challenges of Multiple Myeloma Treatment u 5

6 Figure 1. Nonhematologic adverse events significantly greater with RD versus Rd in the phase 3 E4A03 trial. 43 From Lancet Oncology 11(1), Rajkumar SV, et al. 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, Copyright 2012, with permission from Elsevier P= RD (n=223) Rd (n=220)* P= P= P= P= DVT/PE Infection/pneumonia Nonneuropathic weakness Any grade 3 AE in Early mortality first 4 months (first 4 months) *Data unavailable for 2 patients. DVT/PE, deep vein thrombosis/pulmonary embolism; RD, lenalidomide and high-dose dexamethasone; Rd, lenalidomide and low-dose dexamethasone. Patients, % novel agents are cyclophosphamide plus bortezomib or thalidomide and lenalidomide plus dexamethasone. In selecting a therapeutic regimen, clinicians must consider toxicities related to the use of novel agents and combinations, especially nonhematologic adverse events (AEs) such as the venous thromboembolism associated with thalidomide and lenalidomide. Tailoring treatment can be an effective strategy for reducing the incidence and severity of certain AEs. For example, lenalidomide should be administered with low-dose rather than high-dose dexamethasone, especially in older patients, since data show that toxicity from high-dose dexamethasone reduces survival benefit when this combination is used (Figure 1). 43 When bortezomib is used, reducing the intravenous (IV) dosing schedule from twice weekly to once weekly 45 (in multidrug combination therapy) or using a subcutaneous (SC) route of administration twice weekly 46 has proven to be effective for reducing the frequency and severity of some AEs, including neurotoxicity. SC bortezomib has yielded comparable efficacy to the IV form while reducing the incidence of peripheral neuropathy (PN) of any grade from 53% to 38%. 46 Advances in Relapsed/Refractory Myeloma There are numerous strategies available for the treatment of relapsed/ refractory multiple myeloma, including cytotoxic drugs, novel agents, and new combination regimens. Several factors may affect treatment choice, including age, prognostic factors, comorbidities, the quality and duration of response to prior therapy, and the number of relapses that have occurred. Disease progression during treatment with a specific combination does not preclude a patient s response to another combination containing one of the same drugs, but overcoming resistance remains a challenge. Data suggest that multidrug combinations appear to be more effective and result in high overall response rates (ORRs) and response rates. Novel molecularly targeted agents are used increasingly in combination therapies for patients with relapsed and/or refractory disease. Regimens incorporating bortezomib or lenalidomide with dexamethasone have consistently proved superior to the previous standard, dexamethasone monotherapy These two-drug regimens are now important options in the relapsed/refractory setting, but data continue to accrue in support of three-drug regimens that contain two novel agents. Three-drug combinations have the potential to protect against resistance to a drug in the regimen by providing coverage via multiple molecular pathways; efficacy results have been favorable with the RVD regimen in the relapsed and refractory setting. 51,52 The VTD regimen has been shown to be superior to TD alone in both response rate and PFS, though not in OS. 53 The next-generation proteasome inhibitor carfilzomib is now approved for the management of patients with relapsed/refractory myeloma who have received at least two prior therapies including bortezomib and an immunomodulator. 54 A phase 2 clinical trial reported a 23.7% ORR with a median duration of response of 7.8 months when carfilzomib was used as a single agent with low-dose dexamethasone as premedication 6 u March 2013

7 in patients with relapsed and refractory multiple myeloma who had a median of five prior therapies, including bortezomib. 55 The incidence of PN in this trial was 12.4% (mainly grades 1 and 2), and other toxicities proved manageable, though less common AEs included renal, cardiac, and pulmonary dysfunction, as well as hypertensive episodes. Another phase 2 trial in relapsed and refractory patients reported an ORR of 17.1% and a median duration of response >10.6 months. No exacerbation of baseline PN occurred in this trial. 56 Carfilzomib is currently being studied in combination with lenalidomide and dexamethasone, as well as other agents, including thalidomide and cyclophosphamide, for the treatment of newly diagnosed patients. With the great need for novel therapies, the number of new agents in various stages of development (e.g., oral proteasome inhibitors, histone deacetylase [HDAC] inhibitors, monoclonal antibodies) is encouraging and are discussed in more detail below. Managing Disease- and Treatment-Related Toxicities Myeloma-related bone disease, neuropathy, and venous thromboembolic events (VTEs) are significant challenges confronting the clinicians who manage patients with multiple myeloma. Bone disease, in particular, remains a significant problem. Approximately 70% of patients with multiple myeloma present with a lytic bone lesion in their axial skeleton at the time of diagnosis. 57 Accurately identifying bone disease is essential, and techniques to accomplish this are continuing to evolve. Although skeletal surveys remain the standard for identifying myeloma-related bone disease newer techniques, such as CT scans and PET/CT scans, may be more sensitive and are being implemented more frequently. The IV bisphosphonates zoledronic acid and pamidronate are the current standard of care for preventing and minimizing myeloma-related bone disease due to their proven efficacy. The Medical Research Council (MRC) Myeloma IX trial, which compared IV zoledronic acid to the oral bisphosphonate clodronic acid, reported that zoledronic acid was associated with a lower incidence of skeletal-related events at a median follow-up of 3.7 years (Table 4). Zoledronic acid was associated with increased survival, independent of reduction of skeletalrelated events, suggesting an antimyeloma effect. 58 Table 4. Outcomes in multiple myeloma patients treated with zoledronic acid vs clodronic acid in the Medical Research Council (MRC) Myeloma IX Study. 58 Outcome Variable Zoledronic Acid (n=981) Clodronic Acid (n=979) P Value SREs (%) SREs in subset of patients with bone lesions at baseline (%) SREs in subset of patients without bone lesions at baseline (%) Vertebral fractures (%) Other fractures (%) New osteolytic lesions (%) 5 10 < SRE, skeletal-related events. Data reported at a median of 3.7 years of follow-up. The optimal duration of bisphosphonate therapy is still unknown. The results of the MRC trial, which continued therapy at least until relapse, led to changes in some guidelines; those predating publication of this study suggested giving bisphosphonates for up to 2 years. The 2012 National Comprehensive Cancer Network guidelines recommend bisphosphonates for patients with multiple myeloma until disease progression. 59 The 2011 British Committee for Standards in Haematology/ United Kingdom Myeloma Forum guidelines state that although there are no definitive data on the optimal duration of bisphosphonate therapy, clinicians should take into account individual factors such as remission status, extent of skeletal disease, renal function, patient preference, and the occurrence of AEs, such as osteonecrosis of the jaw. 60 To preserve quality of life, it is important for clinicians to assess myeloma patients for signs and symptoms of peripheral neuropathy (PN) before initiating neurotoxic drugs, such as thalidomide and bortezomib. Once PN develops, interrupting the drug regimen or modifying the dose, along with controlling symptoms, must be a priority to avoid compromising future therapy. Thalidomide-based PN is typically sensory, often limits dose and duration of treatment, and may be irreversible if not addressed promptly. Bortezomib-related PN, which tends to be based more in the legs, is predominately sensory, often reversible, and can typically be managed with dose reduction. 61 Reducing the dosing schedule of IV bortezomib from twice weekly to once weekly has been shown to deliver the same dose intensity with a lower incidence of PN. 44,45,62,63 This strategy may actually improve the efficacy of the regimen because patients are often able to remain on therapy longer. Changing the mode of administration of bortezomib is another effective approach. In a recent study, SC administration of bortezomib was shown to reduce PN significantly, without any reduction in efficacy, compared with the same dose administered IV. In addition, the time to the development of neuropathy was also delayed. 46 In some cases, it may be necessary to switch to another agent, such as lenalidomide or carfilzomib, both of which are associated with much less neurotoxicity, if patients still experience significant PN with bortezomib use. Addressing the Current Challenges of Multiple Myeloma Treatment u 7

8 Figure 2. IMWG consensus opinion on VTE prophylaxis. 66 Prior to therapy with IMiDs Risk factors? 0 1 risk factors >1 risk factors or High-dose dexamethasone ( 480 mg/cycle) or Doxorubicin therapy or combination chemotherapy ASA 100 mg/day LMWH (equivalent to dalteparin 5,000 IU/day, enoxaparin 40 mg/day, fondaparinux 2.5 mg/day) At least 4 6 months, if necessary, continuing thrombosis prophylaxis if risk factors remain or new risk factors are encountered ASA, acetylsalicylic acid; IMiD, immunomodulatory drug, LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. Patients with multiple myeloma may be at risk for VTEs due to the disease itself, age, comorbidities, or specific agents. 64,65 Proper assessment is critical prior to and during therapy, especially when agents such as lenalidomide or thalidomide are used. Medications used to prevent thromboembolism include aspirin, warfarin, and low-molecular-weight heparin. The IMWG has developed a consensus on VTE prophylaxis, 66 which is summarized in Figure 2. If a patient develops a VTE while on antimyeloma therapy, it is usually possible to continue with antimyeloma treatment once adequate anticoagulant control has been achieved. Future Directions in Multiple Myeloma Clinical Research Prior to 2003, it had been 30 years since the approval of any new therapy for multiple myeloma, but in the last 10 years, six agents have been approved. There are currently many more drugs under investigation, some of which are close to receiving approval (Table 5). These include agents that target the myeloma cell itself, some that target the bone marrow microenvironment, and some that are aimed at both targets. 67 The challenge remains for these agents to proceed through the approval process and rapidly emerge into the clinic once efficacy is shown; toxicity profiles will be an especially important consideration, as the ability to continue therapy in myeloma is especially important. Specifically, some of the second- and third-generation drugs appear to be more tolerable, and novel oral agents may allow increased adherence to and persistence with therapy. For example, ixazomib, a proteasome inhibitor currently in later-phase development, has shown clinical activity in relapsed and refractory multiple myeloma, with an 11% incidence of PN, all grades 1 and Several trials have shown that a next-generation immunomodulator, pomalidomide, is active in multiple myeloma, with an ORR up to 43% when combined with dexamethasone in a relapsed/refractory setting Most recently, as of February 2013, pomalidomide was approved by the US Food and Drug Administration (FDA) for patients who have received at least two prior therapies of established benefit, which included both bortezomib and lenalidomide, and who have demonstrated disease progression on the last therapy. Some agents, such as HDAC inhibitors, have been disappointing as monotherapy but may be more active in combination with other novel drugs. These agents can be rationally combined to target different disease pathways in myeloma. 72 Combining vorinostat with bortezomib has been shown to reduce the risk of disease progression in relapsed/ refractory patients, but side effects constrained the overall clinical benefit. The hope is that other agents such as panobinostat, romidepsin, and the HDAC6 selective inhibitor ACY-1215, all now under study, prove more effective. 72,73 This therapeutic approach of rational combinations should improve response and survival while reducing toxicity and allowing prolonged treatment. Other important advances include the development of highly active monoclonal antibody therapy for mul- 8 u March 2013

9 tiple myeloma, other small-molecule inhibitors (such as perifosine, a potent modulator of AKt, JNK, and NFκB), specific agents addressing targets in myeloma-related bone disease pathways, and personalized therapy based on genomic profiling. 72,74 The Multiple Myeloma Research Consortium (MMRC) has played a significant role in the ongoing efforts to augment the therapeutic armamentarium for multiple myeloma. Focusing on phase 1 and 2 clinical trials with associated correlative science studies, the MMRC has facilitated the launch of more than 30 clinical trials of novel compounds and combination approaches. The efforts of the MMRC and its partners have contributed to the FDA approval of four new treatments for multiple myeloma in just 4 years. However, substantial challenges remain, such as identifying effective ways to treat patients who have del(17p) and/or extramedullary disease. Summary and Conclusion Recent advances in the management of multiple myeloma include new criteria for risk assessment, novel agents, and combination regimens for newly diagnosed and relapsed/refractory disease, and improved strategies for preventing and minimizing AEs. Efforts are under way to improve upon the existing methods for determining prognosis in myeloma, including a new risk-stratification schema that will combine FISH data with ISS staging, GEP, and single-nucleotide polymorphism array. Although treatment regimens incorporating novel agents such as bortezomib and lenalidomide are showing promising results in patients with certain chromosomal abnormalities, additional studies are necessary, especially in patients with del(17p), which is associated with a poor prognosis. Achieving durable CR remains a critical goal for all patients with multiple myeloma. For young, fit patients, ASCT remains the standard of care, with induction, consolidation, and maintenance therapies utilizing novel agents leading to better outcomes. For older or frail patients who cannot tolerate ASCT, melphalan and prednisone combined with a novel agent, or other novel combination therapies, are recommended. Dose adjustments should be considered based on age and comorbidities to enable optimal delivery of effective therapy. Table 5. Selected novel drugs being explored in multiple myeloma. Second-/thirdgeneration agents Proteasome inhibitors IMiDs Carfilzomib,* ixazomib (MLN9708), marizomib (NPI-0052), oprozomib Pomalidomide* Novel classes HDAC inhibitors Vorinostat, panobinostat, romidepsin, rocilinostat (ACY-1215) Akt/PI3K/mTOR inhibitors Aurora kinase inhibitors FGFR3 inhibitors CDK inhibitors Bcl inhibitor Hsp90 inhibitor BTK inhibitors Monoclonal antibodies IMiD, immunomodulatory drug; HDAC, histone deacetylase. *Recently approved. Phase 3 trials ongoing or planned. Perifosine, everolimus, temsirolimus TAK-901, MLN8237 Dovitinib (TKI258), MFGR1877S PD , dinaciclib (SCH ), AT7519 Navitoclax (ABT-263) Ganetespib (STA-9090) Ibrutinib (PCI-32765), AVL-292 Elotuzumab, siltuximab (CNTO 328; anti IL-6), daratumumab (anti-cd38), BHQ880 (anti-dkk1) It is important to consider disease- and treatment-related AEs in all patients with multiple myeloma, as these can lead to increased morbidity and mortality, as well as decreased quality of life. Prompt management of these events is critical to avoid negative outcomes. Dose reductions of novel agents may often be used to prevent exacerbation of symptoms while ensuring that patients can still reap the benefits of therapy. Future directions in the management of multiple myeloma include the development of personalized medicine, immune (vaccine) therapies, and novel agents that target the tumor cell in its microenvironment. In this respect, HDAC inhibitors, other small-molecule inhibitors, monoclonal antibodies, and next-generation proteasome inhibitors and immunomodulatory drugs show great promise and continue to be evaluated in ongoing clinical trials. References 1. Greipp PR, San MJ, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23: Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23: Debes-Marun CS, Dewald GW, Bryant S, et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia. 2003;17: Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101: Addressing the Current Challenges of Multiple Myeloma Treatment u 9

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