Individualizing Treatment of Patients With Myeloma in the Era of Novel Agents

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1 V O L U M E 2 6 N U M B E R 1 6 J U N E JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E Individualizing Treatment of Patients With Myeloma in the Era of Novel Agents Jesús San-Miguel, Jean-Luc Harousseau, Douglas Joshua, and Kenneth C. Anderson From the Servicio de Hematología, Hospital Universitario de Salamanca (Centro de Investigación del Cáncer Instituto de Biología Molecular del Centro del Cáncer, Universidad de Salamanca-Consejo Superior de Investigaciones Científicas) Salamanca, Spain; University Hospital Nantes, Nantes, France; Institute of Hematology, Royal Prince Alfred Hospital, Sidney, Australia; and the Dana-Farber Cancer Institute, Boston, M A. Submitted November 16, 2007; accepted February 14, 2008; published online ahead of print at on April 21, Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Jesús San-Miguel, MD, PhD, Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58, Salamanca, Spain; sanmigiz@usal.es by American Society of Clinical Oncology X/08/ /$20.00 D OI: /JC O A B S T R A C T Progress in the understanding of multiple myeloma (M M) cell biology has led to the identification of ne w relevant prognostic factors and subsequently different risk groups. This concept, together with the recent discovery of ne w drugs with novel mechanisms of action, will probably lead to individualized treatm ent according to the different patients characteristics. In this revie w, w e focus on current available agents already approved for M M, and discuss individualized treatm ent approaches for both transplantation candidates (subdivided into standard and high-risk patients) and elderly patients. Future progress in M M will be based on using science to inform the design of the optimal combined treatm ents, and high throughput assays that can assess the ability of combination therapies to induce death of M M cells, both alone and in the bone marro w microenvironm ent. J Clin O ncol 26: by A m erican Society of Clinical O ncology INTRODUCTION Progress in the understanding of multiple myeloma (MM) cell biology has led to the identification of new relevant prognostic factors and subsequently different risk groups, which may benefit from different therapeutic strategies. 1,2 This concept, together with the recent discovery of new drugs with novel mechanisms of action, 3 will probably lead to individualized treatment according to the different patients characteristics (Fig 1). 2 Herein, we share our view of alternatives for treatment individualization in patients with MM. In a newly diagnosed patient, treatment should be stratified according to two elements: age and risk factors. In this review, we focus on currently available agents already approved for MM, and discuss individualized treatment approaches for both transplantation candidates (subdivided into standard and high-risk patients) and elderly patients. We would like to remark that some of the proposals we will make, particularly in the firstline setting, are not feasible in current practice in many countries, because the use of drugs, such as thalidomide, lenalidomide or bortezomib, has just been approved for relapsed patients. Moreover, we want to emphasize that the best way to define the optimal role of these novel agents is through inclusion of patients in well designed clinical trials. NEWLY DIAGNOSED STANDARD RISK PATIENT AND TRANSPLANT CANDIDATE The dream goal for these young patients should be their eventual cure and until then to achieve longterm survival ( 10 years). Induction Treatment Novel drug combinations appear to be superior to conventional chemotherapy (vincristine, doxorubicin, and dexamethasone [VAD]-like regimens) to decrease tumor burden pretransplantation. As presented in Table 1, 4-16 three randomized trials have compared thalidomide (Thal)-based regimens (Thal dexamethasone [Dex] or Thal, doxorubicin, and Dex [TAD], or Thal VAD) versus either high-dose Dex or VAD as initial therapy in transplantation-eligible patients. In all studies, Thal combinations were superior to conventional induction treatment, although the response rate ( partial response) obtained with Thal plus Dex (63%) was lower than that achieved with TAD or Thal VAD (80%). 4-6 In studies evaluating bortezomib (Velcade; Millennium Pharmaceuticals Inc, Cambridge, MA; Johnson & Johnson Pharmaceuticals, Research and Development, Raritan, NJ) combination therapy, data from an Intergroupe Francais du Myélome (IFM) randomized trial comparing bortezomib plus Dex versus VAD show superiority of bortezomib plus Dex, both before and after transplant (Tables 1 and 2). 7 Cavo et al 8 have reported similar results on 2008 by American Society of Clinical Oncology 2761

2 San-Miguel et al Individualizing Treatment in the Era of Novel Agents Progress in M M Cell Biology Prognostic factors and Myeloma subtypes Discovery of New Drugs Singular mechanism of action Individualize and Tailor Treatment Fig 1. Progress in multiple myeloma (M M) cell biology has led to the identification of new prognostic factors and myeloma subtypes. This together with the discovery of new drugs will favor the development of individualized treatments for patients with myeloma. Table 2. Changes in Response Rate Before and After ASCT in Patients Treated With Novel Agents as Induction Therapy Regimen Pre-ASCT CR and ncr (%) Post-ASCT Bortezomib and Dex Bortezomib and Dex Bortezomib and Dex (alt) Bortezomib, doxorubicin, and Dex PAD Bortezomib, Thal, and Dex Bortezomib, Thal, and Dex TAD Abbreviations: ASCT, autologous stem-cell transplant; CR, complete response; ncr, near CR; Dex, dexamethasone; alt, alternate; Thal, thalidomide; PA D, bortezomib, doxorubicin, dexam ethasone; TA D, thalidomide, doxorubicin, and dexamethasone. CR very good partial response for pre-asct 32%; for post-asct 49%. comparing bortezomib and Thal plus Dex versus Thal plus Dex alone (Tables 1 and 2). This high efficacy of bortezomib-based regimens as induction treatment is consistent with several pilot studies using either bortezomib plus Dex alone or in combination with doxorubicin/doxil or Thal, with response rates usually more than 80% and complete response (CR) rates of 18% to 32% Regarding lenalidomide (Len), two large randomized studies 15,16 have shown that the majority of patients ( 90%) respond to Len plus Dex induction. Thal or bortezomib combinations did not affect stem-cell collection or granulocyte and platelet recovery post-transplantation. For Len, three recent reports indicate a decrease in CD34-positive cells collected, and recommended harvesting early in the courses of induction with Len and/or to use cyclophosphamide along with granulocyte colony-stimulating factor. Current data suggest that: VAD will no longer be preferred; most patients ( 80%) will respond to induction regimens based on novel Table 1. Response Obtained With Induction Treatments Based on Novel Agents for Standard Risk and Transplant Candidate Patients Regimen No. of Patients PR or Better Response (%) CR ncr Thal and Dex v Dex v v 2.6 Thal and Dex v VAD v 47 TAD v VAD v 63 7 v 3 Thal VAD v VAD v 66 Bortezomib and Dex v VAD v v 8 Bortezomib and TD v TD v v 9 Bortezomib and Dex Bortezomib and Dex Bortezomib, Dex, and Dox Bortezomib, Dex, and doxil Bortezomib and doxil Bortezomib, Dex, and Thal Len and Dex Abbreviations: PR, partial response; CR, complete response; ncr, near CR (positive immunofixation but negative electrophoresis); Thal, thalidomide; Dex, dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; TAD, thalidomide, doxorubicin, and dexamethasone; TD, thalidomide and dexamethasone; Dox, doxorubicin; Len, lenalidomide. drug combinations; and that Thal plus Dex is now probably suboptimal. Nevertheless, these statements are based on either pilot studies or still ongoing randomized trials which require longer follow-up. ASCT: None, One, Or Two? In order to define the current role of ASCT in young patients with MM, one important question is whether or not this procedure enhances the response rates obtained with novel agents. In seven studies based on bortezomib regimens, 7-14 including two randomized trials, 7,8 it was observed that thecr rate was improvedafter ASCT (Table 2), suggesting that induction with novel agents and ASCT are complementary rather than alternative treatment approaches. Nevertheless, the benefit in terms of event-free survival (EFS) and overall survival (OS) remains to be seen. Regarding Thal, the German/Dutch group, 20 as well as the Fermand group, 21 have shown that the initial advantage of a Thal-based regimen (TAD) versus VAD was not evident after ASCT (only benefit in terms of very good partial response). Data on Len are very encouraging, although still scanty. 15 Nevertheless, some investigators may argue that this approach of a short induction with novel agents followed by ASCT may be challenged by the optimal results obtained with long-term treatment with melphalan and prednisone (MP)-based combinations (MP plus Thal or MP plus bortezomib [MPV]) or Len plus Dex Although a randomized trial comparing these two approaches would be most interesting, the transplantation approach induces a very high CR rate (a goal in all hematologic malignancies) and patients enjoy a long-term period free of treatment. Taking all this information together, we would support the use of novel drug combinations as initial therapy (four to six cycles; the most mature data is for bortezomib), followed by ASCT, because these approaches appear to be complementary. Nevertheless, it may be that patients in CR after induction with novel agents may not gain benefit from early high-dose therapy and in these cases the transplantation could be postponed until first relapse. Only an appropriate randomized study or molecular/immunophenotypic studies designed to evaluate minimal residual disease could clarify the preferable alternative. Regarding tandem ASCT, its role is now challenged for three reasons. According to both IFM 27 and Italian 28 experience, only patients achieving less than VGPR with the first transplantation benefit by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 Treatment Choices for Patients With Myeloma from the second. Results from induction regimens with novel agents followed by one ASCT are similar if not better than those achieved with conventional induction plus tandem ASCT. 7,8,20,21,27,28 Similar efficacy is obtained using Thal as consolidation/maintenance posttransplantation therapy. 29,30 Moreover, the Tunisian group have recently shown that one ASCT followed by 6 months of Thal was superior to two autologous stem-cell transplants (ASCTs). 31 Nevertheless, this study is rather small and should be confirmed by large randomized trials. Therefore, from our point of view, second transplantations in a tandem fashion should be used judiciously especially in patients not in very good partial response after the first transplantation. The final benefit of the second transplantation is currently challenged by the high efficacy of novel drugs used as induction followed by one ASCT and their efficacy as post-asct consolidation. The potential reduction in the number of second transplantations in tandem fashion may be compensated by the more frequent use of late second transplantations. Although the first goal should be to cure standard risk patients, and allogeneic transplantation is probably the only curative treatment so far available, we would not recommend it as first-line treatment in standard-risk patients due to the high morbidity and mortality. Maintenance Consolidation Treatment Maintenance with interferon or corticosteroids have shown little benefit and have been abandoned. The availability of novel agents (particularly those in oral formulations: Thal and Len) has renewed the concept of maintenance in an attempt to prolong the duration of the responses after transplantation. The IFM group 29 has shown that Thal maintenance after tandem ASCT is significantly superior to no maintenance or pamidronate alone in terms of EFS (52%, 36%, and 37% at 3 years, respectively) and OS (87% v 74% at 4 years for patients receiving maintenance therapy with or without Thal, respectively). This superiority has been confirmed by an Australian study comparing Thal plus prednisone versus prednisone alone. 30 Of note, the Barlogie et al 32 group has also observed that the use of Thal as part of induction and maintenance phase was associated with longer EFS, although this does not translate into a prolonged OS. This raises an important concern about whether the continuous use of novel agents may induce more resistant relapses. Moreover, the benefit of Thal maintenance for patients who are already in CR, as well as for those with poor cytogenetics, is not well established. According to what we have already described, in our opinion maintenance/consolidation treatment with Thal is justified in patients who do not achieve CR post-asct. If the patient does not enter into CR after approximately 6 months of Thal maintenance, and is in plateau phase, long-term treatment ( 1 year) may increase the risk of toxicity and may select resistant clones. Regarding the impact and the duration of maintenance treatment in CR patients, the IFM trial would partly answer this question, because a high number of patients in CR after consolidation are randomly assigned between no further treatment and Len maintenance. Finally, the role of Len and bortezomib is currently being evaluated by randomized trials. Treatment of Relapse In order to individualize treatment of relapsing patients after transplantation, it is important to discriminate three cohorts of patients: early relapse ( 1 year), intermediate relapse (1 to 3 years), and late relapse ( 3 years). If the relapse occurs within the first year after transplantation, the patients should be immediately considered as a high risk, and in order to overcome drug resistance, rescued with either a combination of all potentially effective drugs such as Dex, Thal, cisplatin, doxorubicin, cyclophosphamide, and etoposide; or Dex, Thal, cisplatin, doxorubicin, cyclophosphamide, and etoposide plus bortezomib 33,34 ; or bortezomib, Len, and Dex; or alternating cycles of two combinations of noncrossresistant agents (ie, bortezomib/cyclophosphamide/dex alternating with Len or Thal/doxorubicin/Dex). Nevertheless, it must be pointed out that this type of combination should ideally be conducted within controlled clinical trials. If CR is achieved, the patient could proceed to an allogeneic transplant with reduced intensity conditioning regimen (RIC-allo), although this must be considered as an investigational approach. An alternative to RIC would be to consolidate the response with maintenance therapy with immunomodulatory drugs. If relapse occurs between 1 and 3 years after transplantation, we would favor rescue with novel agents used in a sequential (not simultaneous) manner. First, one line of treatment (different from the one used as induction), and shifting to the second and subsequent lines only when disease progression occurs. Within this category of patients, for those that are young ( 55 years) with an HLA-identical sibling and who had suboptimal response to the first line of treatment, the possibility of a RIC-allo-Trx can be reconsidered. Finally, if the relapse has occurred more than 3 years after the first transplantation, an attractive possibility is reinduction with the initial treatment or other novel agent combination, followed by a second ASCT. NEWLY DIAGNOSED HIGH-RISK PATIENT AND TRANSPLANTATION CANDIDATE High-risk patients can be considered as those with high proliferative activity of plasma cells (labeling index or S phase) and advanced stage (International Staging System grade III), but particularly those with poor cytogenetics including: t(4;14), t(14;16), and t(14;20), chromosome 13 deletion by conventional cytogenetics, inactivation of p53 (17p13), complex karyotype, and hypodiploidy. 35,36 Patients with renal failure and disease progression on induction therapy will be discussed separately. New agents appear to overcome the adverse influence of these cytogenetic abnormalities 22,37,38 ; therefore, it is possible that a simple induction treatment with novel drugs followed by ASCT may overcome the adverse prognosis of cytogenetic abnormalities. The value of allo-transplantation in these patients has not been demonstrated yet. 39 Accordingly, it would be reasonable not to expose these patients to the risk of a tandem auto plus RIC-allo, at least until further randomized trials are able to prove that allo is superior to ASCT. 39,40 If investigational targeted-designed drugs prove to be efficient in the relapse setting, 41,42 they could be eventually integrated in the first-line treatment of patients with specific genetic abnormalities (eg, t(4;14)). Primary Refractory Patients Rescue treatment with myeloablative regimens (ie, melphalan 200 mg/m 2 ) supported by ASCT has been considered the most useful approach for primary resistant MM However, most of these by American Society of Clinical Oncology 2763

4 San-Miguel et al patients were treated with VAD, and accordingly they were just refractory to high-dose Dex; therefore, it is not unexpected that they responded to high-dose melphalan. Nevertheless, the Spanish group has shown that the outcome after double ASCT is clearly different in nonresponding, nonprogressing patients (similar survival to responding patients) as compared with those with progressive disease under induction therapy (truly refractoriness, with short survival). 46 Accordingly, this latter group should be considered as very high risk, and as soon as progressive disease is detected, they should be scheduled to receive drugs with new mechanism of action, such as the bortezomib, Len, and Dex followed by RIC-allo or alternatively by maintenance with novel agents. By contrast, in nonresponding nonprogressive patients we can either take a more conservative approach of stopping and observing until symptomatic progression is detected, or to test the sensitivity to novel agents. Nevertheless, the overall situation may change on using new drugs as part of induction treatment. Patients With Renal Insufficiency In patients with renal insufficiency, VAD was the treatment of choice because in contrast to alkylating agent-based regimens it does not require dose adjustment. Although Thal has been used for more than 6 years, very limited information on its efficacy and toxicity in patients with renal failure is available. 47 Len can be toxic particularly in patients with severe renal dysfunction; accordingly, recent guideline recommendations have been generated (the dose should be reduced to 10 mg/24 hours if creatinine clearance 30 to 50 ml/min or 15 mg/48 hours is creatinine clearance 30 ml/min). Bortezomib with or without Dex is highly effective in this setting, including patients on dialysis, and does not require dose adjustment Moreover, for patients who recover normal renal function after bortezomib, ASCT could be safely performed as consolidation therapy. NEWLY DIAGNOSED ELDERLY PATIENT AND NON-TRANSPLANTATION CANDIDATE The goal in these patients should be to prolong survival and to maintain a good performance, avoiding hospitalization as much as possible. Induction Treatment MP has been the gold standard for more than 40 years. However, three randomized trials, including one conducted in patients 75 years of age, have shown that MP plus Thal (MPT) is superior to MP, in terms of a higher response rate (RR; average, 80% v 40%), longer EFS (average, 28 v 15 months) and, in two trials, the MPT arm had an 18-month benefit in OS (Table 3). 24,25 In contrast, Thal plus Dex was not superior to MP. 51 In a pilot study, it has been shown that combination of MP plus Len (MPL) yielded 81% RR, with a 17% CR and 87% EFS at 16 months. 26 Finally, MPV was also associated with a high RR (88%; with 32% CR), EFS of 27.2 months, and OS of 85% at 3 years. 22 These data has recently been confirmed in a large randomized trial comparing MPV with MP. 52 Interestingly, these combinations overcome the adverse prognostic influence of cytogenetic abnormalities. In summary, in patients 65 years old, the combination of any of the new agents (Thal, Len, and bortezomib) with MP is superior to the standard MP. However, the higher efficacy of these new regimens should be balanced against their higher toxicity (ie, peripheral neuropathy [PN] and fatigue in the case of bortezomib; PN and deep venous thrombosis (DVT) for Thal, DVT, and neutropenia for Len) and more frequent hospital visits (for intravenous injections or blood cell counts). The duration of treatment perhaps could be reduced from the conventional 12 months of MP to six cycles of these more active combinations. The next question is whether there is any preference for one of these three MP combinations. Again, an individualized treatment approach would probably be valuable: the most mature data are with MPT and MPV; for patients with antecedent or risk of DVT, MPV could be the preferable option; in patients with antecedent PN, MPL should be the choice; in patients with renal insufficiency, MPV is safe; in patients living long distances from hospital, oral treatment (MPT or MPL) would be preferable; in patients with poor compliance with treatment, MPV could be better; and finally, if costs are a concern, MPT is less expensive. Nevertheless, these MP combinations are being challenged by the recent results reported with Len plus Dex, particularly using low-dose Dex (40 mg on days 1, 8, 15, and 22 every 4 weeks), with 94% survival at 1 year in patients 65 years old. 15 Regarding very elderly patients ( 75 years),the IFM group has also confirmed the superiority of MPT versus MP, 25 and superior response and survival was also observed in the Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone trial for patients older than 75 years treated with MPV. 52 Nevertheless, in this fragile population it would be recommended to use modifiedregimens, withalower dose of Thal (100 mg), Len (15 to 20 mg), or bortezomib (1 mg/m 2 or a weekly schedule). One additional possibility in these patients is to substitute melphalan with cyclophosphamide (50 mg/d or 1 g/21 days), since this latter Regimen Table 3. Results With Induction Treatment in Newly Diagnosed Elderly Patients No. of Patients PR Response (%) CR ncr Thal and MP v MP v v 2 29 v 13 months 80 v 64 at 24 months Thal and MP v MP v M EL v v 2 28 v 17 months 54 v 32 months Thal and MP v MP ( 75 years) v v 8 24 v 19 months 45 v 27 months Thal and Dex v MP v v v 43 months 44 v 58 months Len and MP at 1 year 100 at 1 year Bortezomib and MP v 20 months 85 v 47 at 30 months Abbreviations: PR, partial response; CR, complete remission; ncr, near CR; EFS, event-free survival; OS, overall survival; Thal, thalidomide; MP, melphalan and prednisone; M EL100, autologous stem-cell transplantation using 100 mg/m 2 of MP as conditioning regimen; Dex, dexamethasone; Len, lenalidomide. EFS OS by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 Treatment Choices for Patients With Myeloma agent is less myelotoxic. In very elderly patients, special attention must be paid to infectious episodes (require active treatment) and renal function (appropriate hydration), particularly during the first 3 months of treatment when they are responsible for the high incidence of early deaths. Maintenance Treatment Although there are no data to support it, maintenance treatment for 1 year with daily low doses of an oral IMID (50 mg of Thal or 10 mg of Len with or without corticosteroids) or pulses (every 3 months) is an attractive, although experimental, option. Moreover, this should be counterbalanced by the risk of inducing more resistant relapses. Treatment of Relapse Treatment decisions at relapse must take into account the general condition of the patient. If he is suitable for further treatment, alternative schemes, different from those used as induction, should be given. At second or subsequent relapse, usually after having been treated with bortezomib and at least one IMID, a clinical trial with experimental agents should be encouraged. If the patient is not a candidate for active therapy, palliative treatment with oral cyclophosphamide (50 mg on alternating days) and prednisone (30 mg/d) can be considered. As we already mentioned in the introduction, many of the options described in this article are opinion based on recently available evidence. However, many of these data still require consolidation through long-term follow-up analysis, and other data such as the role of allo-transplantation, require confirmation in large randomized trials. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jesús San-Miguel, Pharmion (C), Janssen Cilag (C), Celgene (C); Douglas Joshua, Johnson & Johnson (C), Pharmion (C) Stock Ownership: None Honoraria: Jesús San-Miguel, Pharmion, Janssen Cilag, Celgene; Jean-Luc Harousseau, Pharmion, Celgene, Janssen Cilag Research Funding: Kenneth C. Anderson, Millennium, Celgene, Novartis Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Jesús San-Miguel, Jean-Luc Harousseau, Douglas Joshua, Kenneth C. Anderson Manuscript writing: Jesús San-Miguel, Jean-Luc Harousseau, Douglas Joshua, Kenneth C. Anderson Final approval of manuscript: Jesús San-Miguel, Jean-Luc Harousseau, Douglas Joshua, Kenneth C. Anderson REFERENCES 1. Hideshima T, Bergsagel PL, Kuehl W M, et al: Advances in biology of multiple myeloma. Blood 104: , Ste wart AK, Bergsagel PL, Greipp PR, et al: A practical guide to defining high risk myeloma for clinical trials, patient counselling and choice of therapy. Leukemia 21: , San Miguel JF, Mateos MV, Pandiella A: Novel drugs for multiple myeloma. Hematology 2: , Rajkumar SV, Blood E, Vesole D, et al: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24: , Lokhorst HM, Bertsch U, Sonneveld P, et al: Thalidomide in induction treatment increases the very good partial response (VGPR) rate before and after high-dose therapy in previously untreated multiple myeloma. Hematologica 93: , Zerva K, Mihou D, Katodritou I, et al: VADdoxil vs VAD-doxil plus thalidomide as initial treatment in patients with multiple myeloma: A multicenter randomized trial of the Greek myeloma study group. Blood 108:238a, 2006 (abstr 794) 7. Harousseau JL, Mathiot C, Attal M, et al: Velcade/dexamethasone (Vel/D) vs VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in ne wly diagnosed multiple myeloma: Updated results of the IFM 2005/01 trial. Blood 110:139a, 2007 (abstr 450) 8. Cavo M, Patriarca F, Tacchetti P, et al: Bortezomib (Velcade)- thalidomide-dexametasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (M M). Blood 110: 30a, 2007 (abstr 73) 9. Rosinol L, Oriol A, Mateos MV, et al: A phase II Pethema trial of alternating bortezomib and dexamethasone as induction regimen prior to autologous stem cell transplantation in younger patients with multiple myeloma: Efficacy and clinical implications of tumor response kinetics. J Clin Oncol 25: , Harousseau JL, Attal M, Leleu X, et al: Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IF M phase II study. Haematologica 91: , Orlowski RZ, Peterson BL, Sanford B, et al: Bortezomib and pegylated liposomal doxorubicin as induction therapy for adult patients with symptomatic multiple myeloma: Cancer and Leukemia Group B Study Blood 108:239a, 2006 (abstr 797) 12. Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129: , Jakubowiak AJ, Al-Zoubi A, Kendall T, et al: High rate of complete and near complete responses (CR/nCR) after initial therapy with bortezomib (Velcade), doxil, an dexamethasone (VDD) is further increased after autologous stem cell transplantation (ASCT). Blood 108:882a, 2006 (abstr 3093) 14. Wang M, Giralt S, Delasalle K, et al: Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 12: , Rajkumar SV, Jacobus S, Callander N, et al: A randomized trial of lenalidomide plus high dose dexamethasone (RD) versus lenalidomide plus low dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. Blood 110: 31a, 2007 (abstr 74) 16. Zonder J, Cro wley J, Hussein M, et al: Superiority of lenalidomide (Len) plus high dose dexam ethasone (H D) compared to H D alone as treatment of ne wly diagnosed multiple myeloma (ND M M): Results of the randomized, doubleblinded, placebo-controlled SW O G trial S0232. Blood 110:32a, 2007 (abstr 77) 17. Paripati H, Ste wart AK, Cabou S, et al: Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia doi: /sj.leu [epub ahead of print on January 24, 2008] 18. Kumar S, Dispenzieri A, Lacy M Q, et al: Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with ne wly diagnosed myeloma. Leukemia 21: , Mazumder A, Kaufman J, Niesvizky R, et al: Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia doi: /sj.leu [epub ahead of print on November 22, 2007] 20. Sonneveld P, van der Holt B, Segeren C M, et al: Intermediate-dose melphalan compared with by American Society of Clinical Oncology 2765

6 San-Miguel et al myeloablative treatment in multiple myeloma: Longterm follow-up of the Dutch cooperative group HO- VON 24 trial. Haematologica 2: , Macro M, Divine M, Uzumhan Y, et al: Dexamethasone thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in ne wly diagnosed multiple myeloma (M M): A randomized trial. Blood 108:22a, 2006 (abstr 57) 22. Mateos MV, Hernández JM, Hernández MT, et al: Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase 1/2 study. Blood 108: , Palumbo A, Bringhen S, Caravita T, et al: Italian Multiple Myeloma Network, GIM E M A: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367: , Facon T, Mary J, Benboubker L, et al: M elphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IF M 99-06): A randomised trial. Lancet 370: , Hulin C, Facon T, Rodon P, et al: M elphalanprednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan prednisone (MP) in a randomized, doubleblind, placebo controlled trial, IF M 01/01. Blood 110:31a, 2007 (abstr 75) 26. Palumbo A, Falco P, Benevolo G, et al: M elphalan, prednisone, and lenalidomide treatment for ne wly diagnosed myeloma: A Report From the GIMEMA Italian Multiple Myeloma Network. J Clin Oncol 25: , Attal M, Harousseau JL, Facon T, et al: Intergroupe Francophone du Myélome: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349: , 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 25: , Attal M, Harousseau JL, Leyvraz S, et al: Intergroupe Francophone du Myélome (IFM): Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108: , Spencer A, Prince M, Roberts A W, et al: First analysis of the Australian leukaemia and lymphoma group (ALLG) trial of thalidomide and alternate day prednisone following autologous stem cell transplantation (ASCT) for patients with multiple myeloma (ALLGM M6). Blood 108:22a, 2006 (abstr 58) 31. Abdelkefi A, Ladeb S, Torjman L, et al: Single autologous stem cell transplantation follow ed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: Results of a multicenter randomized clinical trial. Blood 111: , Barlogie B, Tricot G, Anaissie E, et al: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J M ed 354: , Lee CK, Barlogie B, Munshi N, et al: DTPACE: An effective, novel combination chemotherapy with thalidomide fro previously treated patients with myeloma. J Clin Oncol 21: , Barlogie B, Anaissie E, Van Rhee F, et al: Incorporating bortezomib into upfront treatment for multiple myeloma: Early results of total therapy 3. Br J Haemat 138: , Gutiérrez NC, Castellanos MV, Martín ML, et al: GEM/PETHEMA Spanish Group: Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: T(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21: , Avet-Loiseau H, Attal M, Moreau P, et al: Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myélome. Blood 109: , Jagannath S, Richardson P, Sonneveld P, et al: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21: , 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 21: , Garban F, Attal M, Michallet M, et al: Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IF M99-04 trial) in high-risk de novo multiple myeloma. Blood 107: , Bruno B, Rotta, M, Patriarca F, et al: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356: , Trudel S, Ste wart AK, Rom E, et al: The inhibitory anti-fgfr3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 107: , Baughn LB, Di Liberto M, Wu K, et al: A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 66: , Alexanian R, Dimopoulos MA, Hester J, et al: Early myeloablative therapy for multiple myeloma. Blood 84: , Vesole DH, Tricot G, Jagannath S, et al: Autotransplants in multiple myeloma: What have w e learned? Blood 88: , Kumar S, Lacy M Q, Dispenzieri A, et al: Highdose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant 34: , Rosiñol L, Garcia-Sanz R, Lahuerta JJ, et al: A Pethema study of high dose therapy/stem cell support (HDT), including tandem transplant, in primary refractory multiple myeloma (M M): Identification of two populations with different outcome. Haematologica 92:815, Tosi P, Zamagni E, Cellini C, et al: Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 73:98-103, Jagannath S, Barlogie B, Berenson JR, et al: SUM MIT/CREST Investigators: Bortezomib in recurrent and/or refractory multiple myeloma: Initial clinical experience in patients with impaired renal function. Cancer 103: , San Miguel JF, Richardson PG, Sonneveld P, et al: Bortezomib in renally impaired multiple myeloma patients. Haematologica 92:1114, Chanan-Khan AA, Kaufman JL, Mehta J, et al: Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study. Blood 109: , Ludwig H, Tóthová E, Hajek R, et al: Thalidomide dexamethasone vs melphalan- prednisone as first line treatment and thalidomide-interferon vs interferon maintenance therapy in elderly patients with multiple myeloma. Blood 110:163a, 2007 (abstr 529) 52. San Miguel JF, Schlag R, Khuageva N: M MY- 3002: A phase 3 study comparing bortezomib-melphalanprednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. Blood 110:31a, 2007 (abstr 76) by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY