In the previous decade, younger patients with newly diagnosed

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1 MYELOMA TREATMENT UPDATE Update on the Initial Therapy of Multiple Myeloma Donna Reece, MD OVERVIEW Advances in myeloma biology and the identification of new anti-myeloma agents have resulted in improved management of younger, transplant-eligible, and older patients. The first novel agents thalidomide, bortezomib, and lenalidomide have been integrated into induction therapy before autologous stem cell transplant (ASCT) as well as into first-line therapy in elderly individuals; phase III trials have established the superiority of these approaches in terms of better response rates, progression-free survival (PFS), and, in some studies, overall survival. With more experience, improvements in dosing have decreased the toxicity of these regimens. Before ASCT, four phase III studies have shown that bortezomib-based regimens confer better outcomes than older regimens. Posttransplant consolidation and maintenance strategies with novel agents provide additional benefit, particularly in terms of a longer PFS. In the elderly population, novel agents can be combined with melphalan plus prednisone (MP). MP plus thalidomide and MP plus bortezomib are commonly utilized, and the regimen of MP plus lenalidomide with lenalidomide maintenance (MPR R) produces superior response rates and longer PFS compared with MP alone. Prolonged maintenance with bortezomib plus thalidomide also appears to extend PFS when given following combinations of MP plus bortezomib. Treatment of very elderly patients, however, remains challenging due to comorbidities and side effects. Lenalidomide plus weekly dexamethasone is also effective in elderly patients, and results of a trial comparing this regimen with MP plus thalidomide should be available soon. Finally, better methods of risk stratification and the availability of even newer drugs will allow future refinements in myeloma treatment. In the previous decade, younger patients with newly diagnosed myeloma were typically treated with induction therapy based on high-dose dexamethasone (dex) (i.e., vincristine/doxorubicin/dexamethasone [VAD] or dex alone) followed by autologous stem cell transplantation (ASCT), whereas older individuals received 6 12 cycles of oral melphalan and prednisone (MP). Results from randomized trials indicated that an approach of VAD and a single ASCT produced an overall response rate ( partial remission [PR]) of 80% with up to 20% complete or nearly complete (CR/nCR) remission, a progression-free survival (PFS) rate of around 24 months, and an overall survival rate of 4 5 years. MP in older patients resulted in overall response rates on the order of 50% with few CR/nCRs; a PFS of approximately months and an overall survival of 3 4 years could be anticipated. 1 More recently, an improved understanding of the biology of myeloma and the identifıcation of new drugs have improved the therapeutic approach to myeloma. Genomic techniques have provided insights into the different molecular subtypes of this disease with differing natural histories. In the clinic, application of the International Staging System (based on the serum levels of beta-2 microglobulin and albumin) and FISH cytogenetics has allowed the defınition of different myeloma risk groups with readily available laboratory tests. Several investigators have reported that the presence of t(4; 14), t(14;16) and deletion 17p identifıes patients with a poorer outcome. More recently, both 1q gains, as well as deletions of 1p22 and 1p32, have been associated with an adverse prognosis in analyses of patients treated on Intergroupe Francophone du Myelome (IFM) studies involving ASCT. 2,3 Following the introduction of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, and the fırst-in-class proteasome inhibitor bortezomib, a series of phase II and III studies in both younger and older patients with myeloma has evaluated the integration of these novel agents into fırst-line therapy. Other recent developments have included an appreciation of the toxicity of the older schedule of pulse dexamethasone (high-dose dex [HDdex] 40 mg/day for day 1 through 4, 9 12, and of a 28-day cycle) and the benefıt of low-dose dex 40 mg/week (LD-dex.) 4 In addition, the incidence and severity of peripheral neuropathy associated with bortezomib can be reduced by weekly, rather than twice weekly, dosing as well as by the subcutaneous, rather than intravenous, route of administration. 5,6 Finally, various maintenance strategies have been evaluated in both younger and older patients in an attempt to improve the duration of remission and overall survival. 5,7 In Europe and Canada, a strategy that maintains the division of newly diagnosed patients into two categories those who are designated for upfront ASCT and those who are transplant-ineligible on the basis of age and comorbidities is still in place. In contrast, some U.S. specialists have From the Princess Margaret Hospital, Toronto, Ontario, Canada. Author s disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Donna Reece, MD, Division of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Avenue, Toronto, ON, M5G 2M9, Canada; donna.reece@uhn.on.ca by American Society of Clinical Oncology. asco.org/edbook 2013 ASCO EDUCATIONAL BOOK e307

2 DONNA REECE TABLE 1. Results of Bortezomib-Containing Pre-ASCT Induction Regimens Reported in Phase III Trials Post-Induction Response Rates Author Induction Regimen ASCT Post-ASCT Therapy PR VGPR CR/nCR Harousseau et al. 8 Bortezomib dex 1 or 2 (lenalidomide maintenance in some) 78% 38% 15% Cavo et al. 9 VTD 2 VTD consolidation dex maintenance 92% 63% 31% Sonneveld et al. 10 PAD 1or2 bortezomib maintenance 83% 42% 15% Rosinol et al. 11 VTD 1 VT bortezomib and thalidomide maintenance 82% 60% 35% Abbreviations: ASCT, autologous stem cell transplantation; CR/nCR, complete remission/near CR; dex, dexamethasone; VTD, bortezomib/thalidomide/dexamethasone; PAD, bortezomib/doxorubicin/ dexamethasone; PR, partial remission; VGPR, very good PR. recommended treating younger individuals, particularly those with standard-risk disease, with regimens based on novel agents for variable periods of time; ASCT is considered optional based on patient preference and other unknown factors. Some of these approaches advocate ASCT at the time of relapse. Although delayed ASCT may ultimately be shown to produce results comparable to fırst-line ASCT, phase III trials evaluating the two strategies have not yet been completed. Moreover, most reports describing the effıcacy of 2-, 3- or even 4-drug regimens include a mix of transplant and nontransplant patients, with a focus on response rates; information regarding longer term outcomes such as PFS is often limited and the contribution of ASCT diffıcult to assess. To more accurately ascertain the results of different therapeutic strategies, the current discussion will, therefore, emphasize the results of randomized trials in which the distinction between ASCT and nontransplant therapy is determined from the onset of study. MANAGEMENT OF TRANSPLANT-ELIGIBLE PATIENTS Induction Therapy The most recent phase III induction studies have evaluated bortezomib-based combinations. Reported regimens have combined bortezomib with corticosteroids (BD), thalidomide (VTD), and/or doxorubicin (PAD). The number of cycles has varied, as has the use of single or tandem ASCT and post-transplant measures such as maintenance or consolidation, which makes the contribution of induction therapy per KEYPOINTS: Bortezomib-based induction regiments before ASCT produce better rates of response, PFS, and OS. Post ASCT measures involving novel agents improve PFS with a variable effoct on overall survival. In elderly pateints, the addition of a novel agent to melphalan and prednisone results in a better antimyeloma effect, but the incidence of grade 3/4 toxicity is relatively high. Lenalidomine plus weekly dexamethasone is also a promising regiment in elderly patients. Newer drugs such as carfilzomib are under evaluation in the first-line setting. se more challenging (Table 1). 8,9,10,11 Nevertheless, taken in aggregate, the median PFS after ASCT has increased from approximately 2 years with VAD or thalidomide dex induction to 3 years when bortezomib is used (Table 2) A recent meta-analysis has also shown that bortezomib-based induction yields better response rates, PFS, and overall survival than older regimens such as VAD or thalidomide dexamethasone. 12 Of note, as bortezomib is associated with an increased risk of varicella zoster reactivation; antiviral prophylaxis should be used in all patients. Several other 3- and 4-drug induction regimens have been reported in phase II trials, with no clear superiority of one particular regimen (Table 3) Three of the most commonly used regimens in community practice include: VRD (bortezomib lenalidomide dex), 13,14 CVD or CYBor-D (cyclophosphamide bortezomib dex) 15,16,17 and VTD (bortezomib thalidomide dex), 9,11,18 even though only the latter has been evaluated in randomized trials comparing it with thalidomide dexamethasone. 9,11 After induction with these regimens, at least 90% have entered PR, with very good PR (VGPR) rates in the range of 50% to 70% and CR/nCR rates of 25% to 50%. The rates of VGPR and CR/ ncr usually increase further post-asct, which is important, as the achievement of such deep remissions correlates with improved outcomes for transplanted patients. Newer, and potentially more potent proteasome inhibitors such as carfılzomib and ixazomib (MLN 9708) as well as the newer IMiD pomalidomide all of which have been reported to have effıcacy in some patients refractory to bortezomib and/or older IMiDs will undoubtedly be evaluated earlier in the disease course in future clinical trials. Already, a phase I-II study of CRd, the combination of carfılzomib lenalidomide dex, has been reported in newly diagnosed patients, and a subsequent trial of CRd induction and consolidation is forthcoming. 23 As well, a cooperative Dutch study has described a similar approach in which carfılzomib thalidomide dex is given as both pretransplant induction and post-transplant consolidation in newly diagnosed patients. 24 The Mayo clinic recently reported a phase II study in which cyclophosphamide is added to CTD in a regimen referred to as CYCLONE as well (Table 2). 25 Although the inclusion of bortezomib, particularly in a 3-drug regimen, seems important for high-risk disease, as indicated by the recent integrated analysis of the four phase III studies of bortezomib induction described previously, 26 the e ASCO EDUCATIONAL BOOK asco.org/edbook

3 MYELOMA TREATMENT UPDATE TABLE 2. Summary of Post-ASCT Outcomes in Phase III Trials Using Novel Agents Post ASCT Response Rates Author VGPR CR/nCR Median PFS Overall Survival Harousseau et al. 8 68% 39% 36 mos NYR 81% (3-yr) Cavo et al. 9 89% 71% NYR 68% (3-yr) NYR 86% (3-yr) Sonneveld et al % 49% 35 mos NYR 61% (5-yr) Rosinol et al. 11 N/A 46% 56.2 mos NYR 74% (4-yr) Abbreviations: ASCT, autologous stem cell transplantation; CR/nCR, complete remission/near CR; mos, months; NYR, not year reached; VGPR, very good partial remission. question of whether less intensive induction before ASCT is appropriate for standard-risk patients has not been prospectively addressed. In particular, the oral regimen lenalidomide LD-dex, as fırst reported in the ECOG E4A03 trial comparing it with lenalidomide HD-dex, produces reasonable overall response rates, albeit with comparatively lower CR/ ncr rates, and is associated with excellent patient tolerance. Prolonged use can compromise, to some extent, blood stem cell mobilization and collection; stem cell collection is still usually possible by using combination approaches. Details regarding patient outcomes by risk stratifıcation are not available from this study, although newer retrospective reports from the Mayo Clinic have suggested the utility of lenalidomide and LD-dex alone for induction. 27 On balance, however, it seems prudent to avoid routine reduction in the intensity of induction therapy in transplant-eligible individuals until further supportive evidence is available. Post-ASCT Therapy The two main post-transplant measures include long-term maintenance, usually with either an IMiD or bortezomib as single agents, or consolidation therapy. Thalidomide maintenance has been evaluated in seven phase III trials in which the dose and duration of thalidomide varied, as did the use of concomitant corticosteroids. These trials consistently demonstrated a signifıcantly better PFS in the range of 6 12 months in patients receiving thalidomide, with a variable effect on overall survival. A recent meta-analysis of these studies concluded that thalidomide as a single agent or in conjunction with corticosteroids improves both progressionfree and overall survival rates. 28 Toxicities such as peripheral neuropathy and thrombotic events were increased, not surprisingly, with thalidomide. These and other unpleasant side effects, in turn, negatively affect the quality of life, as highlighted in the recent analysis of the Canadian NCIC randomized study of thalidomide prednisone compared with observation after ASCT. 29 On the other hand, maintenance with lenalidomide avoids many of the toxicities of thalidomide, although it is associated with the potential for myelosuppression. More recently, lenalidomide maintenance has been assessed in two phase III trials the IFM and CALGB trials in which patients were randomized post-asct to low dose lenalidomide or placebo until disease progression; the IFM trial also included 2 months of full-dose lenalidomide in all patients before beginning the assigned maintenance arm. 30,31 The IFM study TABLE 3. Summary of Selected 3- or 4-Drug Induction Regimens Reported in Phase I-II Trials N with Post-Induction Response Rates Regimen Agents N ASCT PR VGPR CR/nCR VDD 19 Bortezomib pegylated liposomal doxorubicin dex % 63% 40% VRD 14 Bortezomib lenalidomide dex % 62% 23% RVDD 20 Lenalidomide bortezomib pegylated liposomal doxorubicin dex % * 57% * 29% * VTD 18 Bortezomib thalidomide dex % 69% 44% VTDC 18 Bortezomib thalidomide dex % 69% 51% cyclophosphamide CyBorD 17 Weekly oral cyclophosphamide weekly bortezomib % 79% N/A 1.5 mg/m 2 dex CVDD 21 Cyclophosphamide bortezomib pegylated liposomal doxorubicin dex %/100% (standard/high risk) 69%/69% (standard/high risk) RVD vorinostat 22 Lenalidomide bortezomib dex vorinostat % 52% 32% CRd 23 Carfilzomib lenalidomide dex % ** 88% ** 67% ** CTD 24 Carfilzomib thalidomide dex % * 61% * 18% * 25%/50% (standard/high risk) Abbreviations: ASCT, autologous stem cell transplantation; CR/nCR, complete remission/near CR; dex, dexamethasone; mos, months; N/A, not available; PR, partial remission; VGPR, very good PR. * After 4 cycles. ** After 4 cycles. asco.org/edbook 2013 ASCO EDUCATIONAL BOOK e309

4 DONNA REECE found a signifıcant prolongation of PFS from 23 to 41 months (p 0.001), whereas the CALGB trial described a signifıcantly longer time to progression from 27 to 46 months, in the lenalidomide arm (p 0.001). 30,31 The latter study also reported a survival benefıt (p 0.03). 31 Lenalidomide maintenance was generally well-tolerated, although a small but consistent increase in the risk of secondary malignancies has been observed with this agent. 30,31 Some groups are now advocating the use of lenalidomide maintenance for a shorter, fınite period of time (i.e., 1 3 years) in an effort to reduce this risk, although it is currently uncertain whether the same benefıt in terms of PFS and survival will be preserved. The introduction of better methods to assay minimal residual disease post-asct, such as marrow multiparameter flow cytometry or molecular studies, may help direct the optimal use of maintenance therapy in the future. The term consolidation does not have a standard defınition in myeloma but, as in acute leukemia, usually refers to moderately intensive combination therapy given for several cycles after recovery from ASCT. The Arkansas group was with fırst to report the use of consolidation, which has been a major feature of all of their Total Therapy trials. 32 Outside of Arkansas, the Italian cooperative group led by Cavo and colleagues has described excellent results with VTD induction, tandem transplantation, and VTD consolidation followed by maintenance with dexamethasone alone, without a novel agent. 33 Advantages of consolidation compared with long-term maintenance therapy include a fınite period of treatment and, potentially, a lower and more predictable cost. It is not known whether the risk of secondary malignancies will be decreased. The CTN trial (Stamina Trial; BMT-CTN0702) that evaluates different post-transplant strategies will hopefully delineate the optimal approach in the future. In this phase III trial, patients receive induction with RVD followed by ASCT; thereafter, patients are randomized either directly to lenalidomide maintenance for 3 years, to a second ASCT followed by lenalidomide maintenance, or to RVD consolidation and lenalidomide maintenance. This trial has completed accrual, and the results are awaited with considerable interest. In the interim, many centers like the author s institution, Princess Margaret Hospital,, consider some method of risk stratifıcation for transplant-eligible patients. Given Princess Margaret Hospital s current Canadian resources, they use weekly CyBorD induction, anticipating a 90% to 95% overall response rate and 45% to 50% CR/nCR rate pre-asct. 17 This is followed by ASCT with melphalan 200 mg/m 2. High-risk patients with t(4;14), t(14;16) and/or del 17p or plasma cell leukemia undergo a second ASCT; all patients then received lenalidomide maintenance. Of note, a recent single-center report described a similar approach and observed that highrisk patients undergoing tandem transplantation had outcomes similar to standard-risk patients undergoing a single ASCT. 34 In the future, consolidation with a 3-drug combination, analogous to the approach of Cavo and colleagues, would ideally be integrated into therapy, particularly in the high-risk setting. Regardless of the choice of induction and post-asct regimens, the goal should be a median PFS of 3 or more years, in keeping with the results of the phase III trials discussed above. TREATMENT OF TRANSPLANT-INELIGIBLE PATIENTS In non-asct candidates, the two main approaches to improve results have included: (1) the addition of a novel agent (thalidomide, bortezomib, or lenalidomide) to the MP regimen; (2) the continuous use of an IMiD without an alkylating agent and dexamethasone. 1 MP has been compared with MPT in six randomized studies, all of which demonstrated an improvement in PFS to approximately 24 months years, compared with MP, which had a PFS of months. 35,36 Survival outcomes were more variable, but a recent meta-analysis of these trials, including a total of 1685 patients, confırmed a superior 1-year response rate, PFS, and overall survival with MPT. 35 On the other hand, grade 3 or 4 toxicity occurred in 45% to 50% of patients, with a considerably higher risk of both peripheral neuropathy and venous thromboembolism, 36 the latter of which requires thromboprophylaxis. 37 In addition, benefıt was most apparent for patients younger than age 65. An appreciation of the effect of poor performance status on outcomes has been recognized, and dose adjustments in very elderly patients ( 75 years) and more vulnerable individuals has been proposed. 38 VMP ( bortezomib MP) is the other MP-containing regimen that is commonly used in elderly patients. The VISTA trial demonstrated a substantial improvement in response rates, PFS and overall survival with VMP compared with MP. Similar to MPT, the PFS was 24 months with VMP. However, grade 3 4 toxicities were also noted in a high proportion of patients. 39 Peripheral neuropathy was not uncommon, although modifıcations of the regimen, in which bortezomib is given once rather than twice per week, have decreased the incidence of this side effect without compromising the antitumor effect; 5 the use of subcutaneous bortezomib is anticipated to improve patient tolerance as well. 6 The use of prolonged maintenance in subsequent trials, either as VT (bortezomib thalidomide) or VP (bortezomib prednisone), has been reported to extend PFS even further than 2 years in patients initially treated with VMP, VTP, or VMPT, but no signifıcant survival improvement has been realized in either of the two trials exploring this strategy 5,40 Third, lenalidomide has been combined with MP in MM015 study reported by Palumbo and colleagues. This study compared three treatment arms: MP compared with MPR (MP lenalidomide) compared with MPR-R (MPR followed by lenalidomide maintenance until disease progression). MPR-R produced a signifıcant prolongation of PFS over MP (p 0.001), although no signifıcant benefıt in overall survival was observed. 41 Just as in the post-asct setting, MPR-R was associated with a small, but measureable, increase in the incidence of secondary cancers. 42 Additionally, studies of VMP and MPR -R, noted inferior outcomes in patients over the age of 75 years. 41 Historically, the fırst continuous IMiD and corticosteroid regimen used in older patients with myeloma was e ASCO EDUCATIONAL BOOK asco.org/edbook

5 MYELOMA TREATMENT UPDATE thalidomide HD dex. However, this regimen produces excessive toxicity 43 and has been replaced by the combination of lenalidomide weekly dex, which is better tolerated. As shown by Rajkumar and colleagues in the ECOG E4A03 trial, lenalidomide and LD-dex induces remission in approximately 70% of patients, with a median PFS of about 2 years. 4 This regimen is widely used in the United States, and its effıcacy and benignity in an older population will hopefully be illustrated by the results of the MM010 trial, which has completed accrual but has not yet been reported. This large phase III study randomized newly diagnosed patients 65 years of age to a standard regimen of MPT compared with lenalidomide and LD dex until myeloma progression compared with lenalidomide and LD dex for a fıxed period of 18 months. In practice, MPT, VMP, and lenalidomide LD-dex can each be considered for older patients with myeloma, with the choice based on a variety of disease-related and patient-related factors. Although data are limited regarding the optimal therapy for high-risk patients, particularly those with adverse cytogenetics, many experts recommend a bortezomib-containing regimen in such individuals. Mateos and colleagues has published the results of VMP-based regimes and noted that those with t(4;14) and del 17p have better outcomes with VMP than MP, although the results are less favorable than in the setting of standard-risk disease. 44 Given the comorbidities of many older patients with myeloma, the selection of the best approach for those very elderly ( 75 years of age) or very frail patients may be challenging. In this population, specifıc dose reductions have been recommended for the agents in the VMP, MPR, and len dex regimens, as well as for MPT as mentioned above. 38 Newer regimens with less morbidity are also being explored for patients ineligible for ASCT. For example, the combination of weekly oral cyclophosphamide dexamethasone with carfılzomib has recently been reported to produce PR in 91% of elderly patients without signifıcant neuropathy and with relatively few grade 3/4 toxicities; equivalent results in patients below and above the age of 75 years have been described. 39 Trials of 3-drug regimens in which MP is combined with ixazomib and which the monoclonal antibody elotuzumab is combined with len LD-dex are also in progress in an effort to improve therapeutic options for older individuals with myeloma. Disclosures of Potential Conflicts of Interest Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate family member; those marked B are held by the author and an immediate family member. Relationships marked U are uncompensated. Employment or Leadership Position: None. Consultant or Advisory Role: None. Stock Ownership: None. Honoraria: Donna Reece, Bristol-Myers Squibb; Celgene; Merck; Novartis; Ortho Biotech; Otsuka. Research Funding: Donna Reece, Bristol-Myers Squibb; Celgene; Merck; Millennium; Ortho Biotech; Otsuka. Expert Testimony: None. Other Remuneration: None. References 1. Reece DE. Recent trends in the management of newly diagnosed multiple myeloma. Curr Opin Hematol. 2009;16: Avet-Loiseau H, Attal M, Campion L, et al. Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(1p), 1q gains] play a major role in defıning long-term survival. J Clin Oncol. 2102;30: Hebraud B, Leleu X, Lauwers-Cances V, et al. 1p22 and 1p32 deletions are independent prognosis factors in young patients with myeloma: The IFM experience on 1195 patients. Blood. 2012;120 (abstract 933). 4. Rajkumar SV, Jacobus S, Callender NS, et al. Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma; an openlabel randomized controlled trial. Lancet Oncol. 2010;11: Mateos MV, Oriol Z, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: A randomized trial. Lancet Oncol. 2010;11: Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomized, phase 3, non-inferiority study. Lancet Oncol. 201;12: Reece DE. Posttransplantation maintenance therapy and optimal frontline therapy in myeloma. Hematology Am Soc Hematol Educ Program. 2011;2011: Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: Results of the IFM phase III trial. J Clin Oncol. 2010;28: Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before and consolidation therapy after double autologous stem cell transplantation in newly diagnosed multiple myeloma. A randomized phase 3 study. Lancet. 2010;376: Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. 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6 DONNA REECE dexamethasone (VRD) consolidation and lenalidomide maintenance in frontline multiple myeloma patients: Updated results of the IFM 2008 phase II VRD intensive program. Blood. 2011;118 (abstract 1872). 15. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combination bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2102;119: Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2012;115: Areethamsirkul N, et al, submitted to the International Myeloma Workshop Ludwig H, Viterbo L, Greil R, et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013;31: Jakubowiak AJ, Kendall T, Al-Zoubi Y, et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009;27: Jakubowiak AJ, Griffıth KA, Reece DE, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: A phase 1/2 Multiple Myeloma Research Consortium trial. Blood. 2011;118: Alsina M, Baz R, Shain KH, et al. Updated results of a phase II study of cyclophosphamide (cy), bortezomib (bz), pegylated doxorubicin (dox), and dexamethasone (dex), (CVDD), in patients with newly diagnosed myeloma: An effective induction regimen for high risk disease. Blood. 2012;120 (abstract 4071). 22. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase I study. Blood. 2012;120 (abstract 336). 23. Jakubowiak AJ, Dytfeld D, Griffıth KA, et al. A phase1/2 study of carfılzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120: Sonneveld P, Asselbergs E, Zweegman, et al. Carfılzomib combined with thalidomide and dexamethasone (CTD) is a highly effective induction and consolidation treatment in newly diagnosed patients with multiple myeloma who are transplant candidates. Blood. 2012;120 (abstract 333). 25. Mikhael JR, Reeder CB, Libby EN, et al. Results from the phase II dose expansion of cyclophosphamide, thalidomide and dexamethasone (CY- CLONE) in patients with newly diagnosed multiple myeloma. Blood. 2012;210 (abstract 445). 26. Cavo M, Sonneveld P, Moreau P, et al. Impact of bortezomib incorporated into autotransplantation on outcomes of myeloma patients with high-risk cytogenetics: An integrated analysis of 1894 patients enrolled in four European phase 3 studies. Blood. 2012;120 (abstract 749). 27. 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