Advances in therapy of multiple myeloma Joan Bladé and Laura Rosiñol

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1 Advances in therapy of multiple myeloma Joan Bladé and Laura Rosiñol Hematology and Oncology Institute, Hematology Department, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain Correspondence to Joan Bladé, MD, Hospital Clinic, Barcelona, Villarroel 170, Barcelona 08036, Spain Tel: ; fax: ; Current Opinion in Oncology 2008, 20: Purpose of review To summarize the results of treatment of multiple myeloma in the era of novel agents. Recent findings Recent publications comparing autologous stem cell transplantation (ASCT) with conventional chemotherapy in the era of old drugs have shown that the contribution of ASCT in the treatment of multiple myeloma has been modest. Five trials comparing single vs. double ASCT showed an increased progression-free survival in three of them, whereas the overall survival was significantly prolonged in one. The benefit would be only for patients failing to achieve very good partial response with the first transplant. The results of allogeneic transplantation with reduced-intensity conditioning, particularly after debulking with an ASCT, are encouraging. On the contrary, the impact of pretransplant induction regimens with novel agents (thalidomide, bortezomib and lenalidomide) on the posttransplant outcome is being investigated in several large phase III trials. For elderly patients, the combination of old therapies with thalidomide, bortezomib or lenalidomide has resulted in the melphalan prednisone thalidomide, melphalan prednisone Velcade, melphalan prednisone Revlimid and lenalidomide/ dexamethasone regimens, which are highly effective. Summary ASCT has resulted in a modest contribution in the treatment of multiple myeloma. Hopefully, its impact will be increased with the incorporation of novel agents in the pretransplant induction regimens. The combination of thalidomide, bortezomib or lenalidomide with melphalan prednisone or with dexamethasone has resulted in highly effective regimens for patients not eligible for high-dose therapy/stem cell transplantation. Keywords allogeneic transplantation, autologous transplantation, bortezomib, doxorubicin, lenalidomide, multiple myeloma, thalidomide Curr Opin Oncol 20: ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Multiple myeloma is an incurable disease, which accounts for almost 15% of all haematological malignancies. The median survival of patients with multiple myeloma has been of about 3 years and the number of long-term survivors disappointingly less. The introduction of highdose therapy (HDT) followed by stem cell rescue and the incorporation of novel agents (i.e., thalidomide, lenalidomide and bortezomib) is resulting in a higher antimyeloma effect and prolonged survival. In this article, the more recent achievements with HDT/stem cell support and with the use of the above-mentioned novel agents are reviewed. Treatment of patients eligible for high-dose therapy/haematopoietic stem cell transplantation HDT followed by stem cell rescue is considered the gold standard in the treatment of younger patients with multiple myeloma. The results obtained with autologous and allogeneic transplantation are discussed in this section. Autologous stem cell transplantation The results of autologous stem cell transplantation (ASCT) in the era of conventional chemotherapy and with new agents are summarized below. Results with conventional chemotherapy induction regimens HDT/ASCT is currently considered the gold standard as part of the initial therapy in patients younger than 65 years with multiple myeloma. Five trials comparing HDT/ASCT vs. conventional chemotherapy have been published [1]. Two of them showed that HDT/ASCT significantly increased the complete response (CR) rate, event-free survival (EFS) and overall survival (OS), whereas the remaining three showed no benefit of HDT/ASCT in terms of EFS and OS. Whether HDT/ ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /CCO.0b013e

2 698 Leukemia ASCT is beneficial for the majority of patients or the overall benefit is derived from certain subsets of patients is an open question [1]. It seems that the achievement of CR is the most important step for a durable response and prolonged survival in patients with multiple myeloma [2,3]. In fact, in a recent meta-analysis, a highly significant association between maximal response [CR, near complete response (ncr) and very good partial response (VGPR)] after HDT/ASCT and response was observed [4 ]. In this regard, on the contrary, the sensitivity to the initial chemotherapy measured by the M-protein size at the time of transplant is the most important predictor of CR after ASCT [2,3]. Thus, in the meta-analysis by Van de Velde et al.[4 ], a strong association between maximal response to the induction therapy and long-term outcome has been found. The pretransplant induction regimens with different conventional chemotherapy regimens have resulted in a pre and posttransplant immunofixation negative CR of 5 10% and 35 40%, respectively, as well as in a median survival duration of about 6 years in the best circumstances [1]. The ideal induction chemotherapy prior to HDT/ASCT should consist of a regimen with high antimyeloma effect, no interference with stem cell collection and acceptable toxicity pattern. The availability of novel effective drugs such as thalidomide, lenalidomide and bortezomib is providing the opportunity for improving the results of the pretransplantation induction therapy. Hopefully, the higher antimyeloma activity of the new induction regimens should result in better results than those achieved with the old conventional regimens [vincristine Adriamycin dexamethasone (VAD), VADlike or combination chemotherapy]. Results with novel pretransplant induction regimens The combination of thalidomide and dexamethasone has replaced VAD and has been approved by the US Food and Drug Administration for its use as pretransplant induction regimen. In addition, two large trials [5,6 ] have shown that thalidomide and dexamethasone is superior to dexamethasone alone [5,6 ]. The overall response rate (ORR) to thalidomide and dexamethasone is between 58 and 76%; however, the CR rate is only about 5 7%. Furthermore, thalidomide and dexamethasone would not be an optimal regimen for patients with extramedullary disease because of the lack of activity of thalidomide on soft-tissue plasmacytomas and the transient effect of dexamethasone [7]. In this regard, of three reported studies [8 10] comparing pretransplant induction with thalidomide and dexamethasone vs. VAD in only one [10] thalidomide and dexamethasone resulted in an improved posttransplant outcome. In one phase II trial [11 ], the association of lenalidomide and dexamethasone resulted in a response rate (RR) of 91%. However, there are no data on the impact of this regimen on the posttransplantation outcome. The results of two phase II trials combining bortezomib and dexamethasone have been reported. Harousseau et al. [12] used bortezomib and dexamethasone simultaneously and found a RR of 66% with 21% CR (defined by negative electrophoresis). Rosiñol et al. [13 ], using bortezomib and dexamethasone on an alternating schedule, reported similar results with a RR of 65% including 12% immunofixation negative CR. In our series, the RR after transplantation was almost identical to that reported by Harousseau et al. [12] with an ORR of 88%, including 33% CR and 22% VGPR. In a large phase III trial [14], including 482 patients, the French Intergroupe Francophone du Myélome (IFM) group compared bortezomib/dexamethasone vs. VAD. From the preliminary data on the 222 patients already analysed, the CR and ncr after induction was significantly higher with bortezomib/dexamethasone (22 vs. 9%, P ¼ 0.008) with encouraging posttransplant results, but longer follow-up is needed. Thalidomide and bortezomib are increasingly used in combination with dexamethasone or anthracyclines resulting in the so-called triple regimens. The PAD 1 regimen [bortezomib (PS 341) Adriamycin dexamethasone] yielded a posttransplant ORR of 95% with 24% CR [15]. The posttransplant CR rate after induction with PAD was 43%. However, almost half of the patients developed peripheral neuropathy, this leading to a reduction in the bortezomib dose from 1.3 to 1 mg/m 2 (PAD 2) in a subsequent study from the same group [16]. With PAD 2 the incidence of neuropathy decreased to 16% and the ORR was still 89%. However, the CR rate after induction and transplant were lower (11 and 37%, respectively) than with PAD 1 [15,16]. Wang et al. [17] from the MD Anderson group reported an ORR of 92% with 19% CR in 36 patients treated with bortezomib (Velcade) thalidomide dexamethasone (VTD). The posttransplant ORR was 89% with only a 31% CR. Cavo et al. [18] have recently reported that VTD was superior to thalidomide and dexamethasone in terms of CR rate both before and after transplant. The Spanish Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) group is comparing thalidomide and dexamethasone vs. VTD vs. vincristine, bcnu, melphalan, cyclophosphamide, prednisone (VBMCP)/vincristine, BCNU, adriamycin, dexamethasone (VBAD) (four cycles) and two cycles of bortezomib as pretransplant induction therapy. The HOVON group is comparing PAD vs. VAD in a large phase III trial. Finally, the French IFM group has just started a phase III trial comparing bortezomib/dexamethasone vs. VTD. The combination of bortezomib (Velcade)/Doxil/dexamethasone (VDD) resulted in a postinduction ORR of 93%, including 43% CR/nCR. The CR/nCR rate after transplant was 65% [19]. A summary of the results before

3 Advances in therapy of multiple myeloma Bladé and Rosiñol 699 Table 1 Transplant candidates Regimen CR before ASCT (%) CR after ASCT (%) Old regimens DEX/VAD 5 35 Cyclophosphamide/DEX 7 32 VBMCP/VBAD New regimens Thalidomide/DEX Bortezomib/DEX Bortezomib/Adriamycin/DEX (PAD 1) Bortezomib/Adriamycin/DEX (PAD 2) Bortezomib/THAL/DEX (VTD) Bortezomib/Doxil/DEX (VDD) 32 (electrophoresis) 54 (electrophoresis) Results before and after transplant after induction with old and new drugs. ASCT, autologous stem cell transplantation; CR, complete response; DEX, dexamethasone; THAL, thalidomide; VAD, vincristine Adriamycin dexamethasone; VBMCP, vincristine BCNU melphalan cyclophosphamide prednisone; VBAD: vincristine, BCNU, adriamycin, dexamethasone. and after transplant achieved with the so-called old and new induction regimens are shown in Table 1. Results of single vs. tandem double autologous stem cell transplant The results of five prospective randomized trials comparing single vs. double ASCT are summarized in Table 2 [20,21,22,23,24 ]. Two trials showed a significant increase in CR or CR/nCR [21,23], three showed a prolonged EFS [20,21,23] and only one a significantly longer OS [20] in favour of tandem transplant. In contrast, a recently published trial [24 ] comparing single transplant followed by 6-month thalidomide maintenance vs. double ASCT showed that the single transplant arm was superior to tandem transplant in both RR and survival. From two of these studies [20,21 ], it seems that the patients who benefit from a second ASCT were only those failing to achieve at least VGPR with the first transplant. The most consistent finding from these studies is the prolongation of EFS or PFS with double transplant. In fact, a recent meta-analysis [25] on these trials of single vs. tandem ASCT, involving 1569 patients, showed that the most significant improvement with tandem ASCT was in EFS. On the contrary, the role of maintenance [26] as well as the concept of early intensification [27] with novel drugs are interesting and deserve further investigation. It is evident that there are a number of unsolved questions in ASCT: will the induction with new regimens improve the final patient s outcome? Can the efficacy of high-dose regimens be improved? Is there a definite role for posttransplant maintenance/consolidation therapy? Do patients who attain CR with primary therapy benefit from HDT/ASCT? Is there still a role for HDT/ASCT in the era of novel agents? Ongoing and future prospective studies are extremely important to answer the above questions [28 ]. Allogeneic stem cell transplantation The best curative approach in multiple myeloma is allogeneic transplantation. However, allogeneic transplantation with conventional/myeloablative conditioning (MAC) results in a transplant-related mortality (TRM) up to 50% and the proportion of patients long-term diseasefree and possible cured does not exceed 10 15% [29 ]. For these reasons, allogeneic transplantation with MAC has almost universally been replaced by the so-called dose-reduced intensity conditioning allogeneic transplantation with reduced-intensity conditioning (Allo- RIC) [29,30,31]. The current conditioning consists of fludarabine/mel-140 or fludarabine/low-dose total body irradiation (TBI). The TRM has decreased 10 20%, whereas the CR rate is about 40 50%. The incidence of acute and chronic graft-versus-host disease (cgvhd) is 30 and 50%, respectively. The most important predictors of outcome are the development of cgvhd and chemosensitive disease with a low tumour burden at the time of transplant. The European Group for Blood and Marrow Transplantation (EBMT) has recently reported a retrospective study [32 ] comparing the results of MAC vs. Allo-RIC in patients allografted between 1998 and Table 2 Single vs. double transplant Reference No. of patients RR (%) EFS months OS months Attal et al. [20] vs. 50 (P ¼ NS) 25 vs. 30 (P ¼ 0.03) 48 vs. 58 (P ¼ 0.01) Cavo et al. [21 ] vs. 47 (P ¼ 0.008) 23 vs. 35 (P ¼ 0.001) 65 vs. 71 (P ¼ NS) Fermand [22] vs. 39 (P ¼ NS) 31 vs. 34 (P ¼ 0.75) 57 vs. 73 (P ¼ 0.09) Sonneveld et al. [23] vs. 32 (P < 0.001) 24 vs. 27 (P ¼ 0.006) 50 vs. 55 (P ¼ NS) Abdelkefi et al. [24 ] vs. 51 (P ¼ 0.024) 85 vs. 57% (P ¼ 0.038) 88 vs. 63% (P ¼ 0.052) EFS, event-free survival; OS, overall survival; RR, response rate.

4 700 Leukemia Although the CR rate and PFS were favourable to the conventional conditioning, the final outcome in terms of OS was not significantly different as the higher TRM with conventional conditioning was compensated by a lower relapse rate [32 ]. Considering that an important requisite for the success of Allo-RIC is a low tumour mass at the time of transplantation, the use of HDT/ASCT to reduce tumour burden followed by Allo-RIC in order to obtain a benefit from graft-versus myeloma (GVM) effect has been recently investigated with promising results. In this regard, there are three studies in which the efficacy of a tandem ASCT vs. single autograft followed by Allo-RIC in patients with newly diagnosed multiple myeloma with an available sibling donor have been compared. The French IFM group reported no difference between the two approaches [33]. In contrast, the Italian group found an increased CR rate and a significant survival advantage in favour of Allo-RIC with a survival plateau beyond 4 years of allografting, whereas no plateau was observed in the tandem ASCT group [34 ]. In a Spanish PETHEMA study, there were no significant differences in EFS and OS between the two groups. However, the curves of Allo- RIC patients showed an encouraging survival plateau beyond 3 years of follow-up [35 ]. The poor results reported in the French IFM study can be explained by the fact that only poor-risk patients were included (13q deletion and high beta2-microglobulin) or by the use of antithymocyte globulin (ATG) resulting in a decreased GVM effect [33]. The most promising approach seems Allo-RIC from related or unrelated donors after debulking with an ASCT. With the current data, it is obvious that there is a need for continuing the investigation of conditioning intensity and posttransplant strategies aimed at enhancing the GVM effect while minimizing the GVHD [29,36]. Treatment of patients not eligible for high-dose therapy/haematopoietic stem cell transplantation In patients not eligible for HDT/SCT (i.e. age >65 years or younger with comorbidities) the conventional therapy has consisted of alkylating-based regimens, mainly melphalan and prednisone or dexamethasone-based therapies such as VAD and VAD-like regimens or even dexamethasone alone. With these regimens, the ORR was about 50% with less than 5% CR and median survivals of about 3 years. With the incorporation of novel agents, with different mechanisms of action than conventional therapy, an improvement in response rate (RR) and, generally in survival are being consistently reported [28 ]. The French IFM group compared melphalan prednisone vs. two cycles of VAD followed by two courses of MEL-100 vs. melphalan prednisone thalidomide (MPT) [37 ]in patients aged years. The MPT resulted in a significantly higher ORR and CR rate as well as in significantly longer EFS and OS. The same group compared melphalan prednisone vs. MPT (with a thalidomide dose of 100 mg/day) in patients older than 75 years [38]. The RR was significantly higher with MPT (62 vs. 31%). Most importantly, the PFS (median 24.1 vs. 19 months) and the OS (median 45.3 vs months) were significantly longer with MPT. The Italian group also compared the efficacy of MPT vs. melphalan prednisone [39]. They also reported a significantly higher ORR and CR rate as well as a longer PFS in favour of the MPT arm. However, the OS between MPT and melphalan prednisone was not significantly different [39]. Finally, the Nordic Myeloma Group found a significantly longer PFS in favour of MPT with no differences in OS [40]. Concerning toxicity, peripheral neuropathy is of concern in thalidomide-containing regimens and the risk of deep vein thrombosis (DVT)/pulmonary embolism makes mandatory the use of prophylactic anticoagulation when thalidomide is combined with cytotoxic agents or with high-dose glucocorticoids. In a phase II trial, the association of melphalan prednisone with bortezomib showed very encouraging results [41 ]. In a subsequent large randomized trial including 682 patients, melphalan prednisone was compared with MPV [melphalan prednisone Velcade (Millennium, Cambridge, Massachusetts 02139, USA)] [42]. The ORR (71 vs. 36%), the CR rate (30 vs. 4%), the PFS (median 24 vs months) and the OS (82.6 vs at 2 years) were all in favour of MPV. Interestingly, MPV was superior to melphalan prednisone in all prognostic subgroups including patients with poor cytogenetics. It seems that bortezomib-containing regimens can overcome the adverse cytogenetics such as 13q deletion, t(4;14), t(14,16) or 17p deletion [13,41,42 44]. In a phase 2 study, the association of melphalan prednisone lenalidomide (Revlimid) (MPR) was very promising with 81% partial response (PR) rate including 24% immunofixation negative CR [45 ]. The EFS and OS at 1 year were 92 and 100%, respectively. A large phase 3 international trial comparing melphalan prednisone with MPR is currently ongoing. The results comparing thalidomide/dexamethasone with VAD or dexamethasone alone have been discussed in a previous section of this review. Ludwig et al. [46] compared thalidomide dexamethasone with melphalan prednisone and found a significantly higher RR with thalidomide and dexamethasone (68 vs. 51%). However, the number of deaths during the first year was significantly higher with thalidomide and dexamethasone and there was a trend towards a superior EFS (median 43 vs. 25 months) and a significantly longer OS (median 58 vs.

5 Advances in therapy of multiple myeloma Bladé and Rosiñol 701 Table 3 Front-line therapy studies for patients with myeloma not eligible for high-dose therapy/stem cell transplantation Reference Regimen ORR (%) CR (%) EFS OS Palumbo et al. [39] MPT vs. melphalan prednisone 76 vs vs vs. 27% at 2 years 80 vs. 64% at 3 years Facon et al. [37 ] MPT vs. melphalan prednisone 76 vs vs. 2 HR 0.56 (in favour of MPT) 51.6 vs months Hulin et al. [38] MPT vs. melphalan prednisone 62 vs vs vs. 19 months 45.3 vs months San Miguel et al. [42] MPV vs. melphalan prednisone 71 vs vs vs months 82.6 vs. 69.5% at 2 years Ludwig et al. [46] THAL/DEX vs. melphalan prednisone 68 vs vs vs. 25 months 58 vs. 45 months Rajkumar et al. [47] LEN/Dex vs. LEN/dex 82 vs. 70 NR NR 87 vs. 75% at 2 years Rajkumar et al. [6 ] THAL/DEX vs. DEX 63 vs vs vs months vs. not reached Palumbo et al. [45 ] MPR % at 1 year 100% at 1 year CR, complete response; EFS, event-free survival; HR, hazard ratio; LEN/DEX, lenalidomide/dexamethasone; LEN/dex, lenalidomide/low-dose dexamethasone; ORR, overall response rate; OS, overall survival; MPR, melphalan prednisone lenalidomide; MPT, melphalan prednisone thalidomide; MPV, melphalan prednisone bortezomib; NR: not reported; THAL/DEX, thalidomide/dexamethasone. Main toxicities melphalan prednisone: myelosuppression; MPT: myelosuppression, peripheral neuropathy, DVT; MPV: myelosuppression, thrombocytopenia, peripheral neuropathy; THAL/DEX: DVT; LEN/DEX or LEN/dex: myelosuppression, DVT; MPR: myelosuppression, DVT. 45 months) in favour of melphalan prednisone [46]. Interestingly, a large Eastern Cooperative Oncology Group (ECOG) trial [47] compared lenalidomide/dexamethasone at full doses of dexamethasone vs. lenalidomide/dexamethasone at low dose of dexamethasone (40 mg once weekly). Although the RR was lower with low-dose dexamethasone [47], the OS at 1 and 2 years was significantly longer with lenalidomide/low-dose dexamethasone because of a significantly lower toxicity and mortality [47]. It seems evident that the association of an old regimen such as melphalan prednisone or dexamethasone with a new agent such as thalidomide, bortezomib or dexamethasone will become the treatment of choice for multiple myeloma in the very near future. It appears that the melphalan prednisone combinations are resulting in a higher RR than dexamethasone-based combinations. Concerning MPT and MPV, the results in RR and in survival are very similar. Once they are approved for their use as up-front therapy, the first choice will be based on age, aggressiveness of the disease, cytogenetics and patients preference. For patients with very advanced age, less aggressive disease or both, MPT would be preferable. In contrast, for patients aged years with an aggressive presentation (i.e., extensive symptomatic bone involvement, extramedullary disease or both) or with poor cytogenetics, a bortezomib-containing regimen could be more appropriate. For elderly patients with peripheral neuropathy, a lenalidomide-based regimen (lenalidomide/low-dose dexamethasone or MPR) would be preferable. In patients with renal failure, a bortezomibcontaining regimen such as bortezomib/dexamethasone would be the initial treatment of choice [48,49,50]. A summary of the recent trials in the treatment of myeloma patients not eligible for HDT/SCT is shown in Table 3. Treatment of relapsed/refractory myeloma The treatment of patients with relapsed/refractory myeloma is a real challenge. In this situation, the choice of the salvage therapy must depend on many factors such as: the components of the initial therapy including whether or not the patient has received HDT/ASCT, the degree and duration of response to primary therapy [i.e., deep responses with a time to progression (TTP) longer than 2 years relapsing off therapy might benefit from retreatment with the initial option], performance status and age at time of relapse (older patients and/or with poor performance status should be treated with more gentle approaches), type of relapse (aggressive relapses should be treated with bortezomib-based regimens whereas more indolent relapses might be treated with thalidomide or lenalidomide-containing regimens, saving bortezomib for subsequent relapses) and previous toxicity (i.e., in patients with significant peripheral neuropathy avoid thalidomide and bortezomib) (Table 4). A recent review [51] on thalidomide therapy in multiple myeloma highlights that in patients with relapsed refractory disease: the RR to single agent thalidomide is between 30 and 40%, that thalidomide/dexamethasone combinations induce RR ranging from 40 to 65% and that extramedullary disease rarely responds to thalidomide. Table 4 General considerations in the treatment of relapsed myeloma Components of initial therapy Efficacy of initial therapy Patient status and circumstances of relapse Alkylating based Degree of response Age and performance status Dexamethasone based Timing of relapse Aggressive vs. nonaggressive relapse HDT/SCS HDT, high-dose therapy; SCS: stem cell support.

6 702 Leukemia Table 5 Randomized trials on treatment of relapsed/refractory myeloma Reference Regimen ORR (%) CR (%) TTP OS Richardson et al. [53] Bort vs. DEX 38 vs vs vs vs. 66% at 1 year Orlowski et al. [55 ] Bort þ Doxil vs. Bort 44 vs vs vs vs. 65% at 15 months Weber et al. [56 ] LEN/DEX vs. DEX 61 vs vs vs vs months Dimopoulos et al. [57 ] LEN/DEX vs. DEX 60.2 vs vs vs. 4.7 Not reached vs months Bort, bortezomib; CR, complete response; DEX, dexamethasone; LEN, lenalidomide; ORR, overall response rate; OS, overall survival; TTP, time to progression. In the study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy (SUMIT) trial, bortezomib produced a RR of about 35% in patients with advanced/refractory multiple myeloma [52]. The Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial showed that bortezomib was superior to dexamethasone in RR, PFS and OS [53]. An extended follow-up of this study has shown that the ORR and CR rate to bortezomib was 43 and 9%, respectively and that higher response quality was associated with longer response duration [54 ]. A large phase 3 trial comparing bortezomib and pegylated liposomal doxorubicin vs. bortezomib alone showed that the combination was superior in CR and VGPR (27 vs. 19%, P ¼ 0.02), TTP (median 9.3 vs. 6.5 months, P < 0.001) and OS at 15 months (75 vs. 65%, P ¼ 0.03) [55 ]. Lenalidomide, as single agent, produces a RR of only 20%. However, when combined with dexamethasone, the RR is about 60% including 15% CR vs % including only 1 4% CR with dexamethasone alone [56,57 ]. Compared with dexamethasone alone, the combination of lenalidomide and dexamethasone was superior not only in RR but also in TTP (median 11 vs. 5 months; P < 0.001) and in OS (median 29.6 vs months; P < 0.001) [56,57 ] (Table 5). An increasing number of three and four drug combinations including old and novel agents showing a high RR in patients with relapsed/refractory disease is being reported. However, these studies have several shortcomings such as: low number of patients, possible favourable patients selection, short follow-up, considerable toxicity and high economic cost. The authors of these reviews are more inclined to use a sequential therapy approach in subsequent relapses. Taking into account that dexamethasone has likely only an additive effect when combined with thalidomide and bortezomib and that it is clearly synergistic with lenalidomide, we recommend thalidomide alone or with dexamethasone, bortezomib alone or with dexamethasone or lenalidomide/dexamethasone rather than combination of multiple agents in patients with relapsed, and refractory multiple myeloma or both. The selection of therapy will depend on the previous drug exposure, previous response, toxicity pattern and type of relapse (aggressive vs. indolent ). In patients with chemosensitive relapse, an ASCT as rescue therapy should be considered. Also, in patients relapsing after HDT/ASCT a second HDT approach could be of benefit provided that the duration of response with the first ASCT was longer than 2 years. If there is an available human leukocyte antigen (HLA)-matched donor and the patient has chemosensitive relapse and is younger than 65 years an Allo-RIC should be considered [29,32 ]. There is an extensive review [58] by the International Myeloma Working Group on the prophylaxis of thrombotic events in thalidomide and lenalidomidecontaining regimens. Of note, two recent studies [59,60] have shown a significant improvement in the survival of patients with multiple myeloma since the introduction of novel agents. Although there is still plenty of room for future improvement, the current data already represent a real hope for patients with multiple myeloma. Conclusion The incorporation of novel drugs with new mechanisms of action is resulting in an improved outcome in patients with multiple myeloma. In the ASCT setting, the new induction regimens are resulting in a higher pretransplant tumour reduction which will hopefully end up with a high proportion of patients in CR after transplant, thus leading to a longer PFS and OS when compared with previous studies. The Allo-RIC is promising and deserves further investigation in prospective clinical trials. A major step forward is being accomplished in the treatment of elderly patients, particularly when combining melphalan prednisone with thalidomide (MPT), bortezomib (MPV) or lenalidomide (MPR) or with dexamethasone and lenalidomide. In the relapse setting, the availability of thalidomide, bortezomib and lenalidomide has resulted in more effective salvage regimens. A large number of phase III trials by different national cooperative groups, both in patients eligible and not eligible for ASCT, are ongoing. Hopefully, the results of these trials, along with a better understanding of the biology of the disease, will allow us the selection of a more individualized antimyeloma therapy, likely based on the molecular genetic status.

7 Advances in therapy of multiple myeloma Bladé and Rosiñol 703 Acknowledgement The present work has been supported in part by grant 06/0020/0005 from Instituto Carlos III (Spanish Institute of Health). References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Harousseau JL. Role of stem cell transplantation in multiple myeloma. Hematol Oncol Clin North Am 2007; 21: Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 2001; 27: Nadal E, Giné E, Bladé J, et al. High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: predictors of complete remission. Bone Marrow Transplant 2004; 33: Van de Velde HJK, Liu X, Chen G, et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92: This is a meta-analysis on transplant trials on multiple myeloma showing a close relationship between the depth of response and PFS and OS. 5 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 Group. J Clin Oncol 2006; 24: Rajkumar SV, Rosiñol L, Hussein M, et al. A multicenter, randomized, doubleblind, placebo-controlled study of thalidomide plus dexamethasone versus dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 2008; 26: A large phase 3 trial involving 470 patients showing that thalidomide/dexamethasone is superior to dexamethasone alone in RR (63 vs. 46%, P < 0.001) and in TTP (22.6 vs. 6.5 months, P < 0.004). There were no significant differences in OS. 7 Rosiñol L, Cibeira MT, Bladé J, et al. Escape of extramedullary disease to the thalidomide effect in multiple myeloma. Haematologica 2004; 89: Macro M, Divine M, Uzunhan Y, et al. Dexamethasone plus thalidomide compared to VAD as a pretransplant treatment in newly diagnosed multiple myeloma [abstract #57]. Blood 2006; 108:22a. 9 Thomas SK, Giralt SA, Wang M, et al. Survival outcomes of patients receiving thalidomide/dexamethasone for previously untreated multiple myeloma [abstract #3569]. Blood 2006; 108:1019a. 10 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. Haematologica 2008; 93: Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 2007; 82: First phase II study showing the efficacy of lenalidomide/dexamethasone in RR (91%) with an encouraging 3-year survival rate of 88%. 12 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. Haematologica 2006; 91: Rosiñol L, Oriol A, Mateos MV, et al. A phase II trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumour response kinetics. J Clin Oncol 2007; 25: A phase 2 study showing that dexamethasone and bortezomib have only an additive effect and that 80% of all the antimyeloma activity is achieved with the first two cycles (one each of bortezomib and dexamethasone). 14 Harousseau JL, Mathiot C, Attal M, et al. Velcade/dexamethasone versus VAD as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: updated results of the IFM 2005/01 trial [abstract #450]. Blood 2007; 110:139a. 15 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 2005; 129: Popat R, Oakervee HE, Curry N, et al. Long-term follow-up of PAD for untreated multiple myeloma [abstract #PO-725]. Haematologica 2007; 92(Suppl 2). 17 Wang M, Giralt S, Delasalle K, et al. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 2007; 12: Cavo M, Patriarca F, Tachetti P, et al. Bortezomib (Velcade)-thalidomidedexamethasone (VTD) versus thalidomide-dexamethasone (TD) in preparation for autologous stem cell transplantation in newly diagnosed multiple myeloma [abstract #73]. Blood 2007; 110:30a. 19 Jakubowiak AJ, Al-Zoubi A, Kendall T, et al. Combination therapy with bortezomib (VELCADE), Doxil, and Dexamethasone (VDD) in newly diagnosed myeloma: updated results of a phase II clinical trial [abstract PO-721]. Haematologica 2007; 92(Suppl 2). 20 Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem cell transplantation for multiple myeloma. N Engl J Med 2003; 349: Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous transplantation for multiple myeloma. J Clin Oncol 2007; 25: Basically reproduces the results of the IFM trial, except that there are no differences in OS. 22 Fermand JP. High-dose therapy supported with autologous blood stem cell transplantation in multiple myeloma: long-term follow-up of prospective studies of the MAG group [abstract]. Haematologica 2005; 90: Sonneveld P, van der Holt B, Segeren CM, et al. Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term followup of the Dutch Cooperative Group HOVON 24 trial. Haematologica 2007; 92: Abdelkefi A, Ladeb S, Torjman L, et al. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 2008; 111: In this trial, all patients received induction therapy with thalidomide and dexamethasone and were randomized to single ASCT and 6-month thalidomide maintenance and rescue ASCT at relapse vs. double ASCT. The results after ASCT and 6-month thalidomide and after double ASCT were favourable to single ASCT and thalidomide: CR and VGPR 68 vs. 54% (P ¼ 0.04), PFS at 3 years 85 vs. 57% (P ¼ 0.02) and OS at 3 years 85 vs. 65% (P ¼ 0.04). 25 Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood 2006; 108: Ladetto M, Pagliano G, Avonto I, et al. Consolidation with bortezomib, thalidomide and dexamethasone induces molecular remissions in autografted multiple myeloma patients [abstract #530]. Blood 1007; 110:163a. 27 Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic stem cell transplantation for treatment of multiple myeloma: a meta-analysis of randomized controlled trials [abstract #936]. Blood 2007; 110:264a. 28 San Miguel JF, Harousseau JL, Joshua D, Anderson K. Individualizing treatment of patients with myeloma in the era of novel agents. J Clin Oncol 2008; 26: A concise review on how to individualize the treatment of multiple myeloma in the era of novel agents. 29 Bensinger W. Stem-cell transplantation for multiple myeloma in the era of novel drugs. J Clin Oncol 2008; 26: An extensive review on the role of ASCT in the era of novel agents. 30 Crawley C, Lalancette M, Szydio R, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005; 105: Pérez Simón JA, Sureda A, Fernández-Avilés F, et al. Reduced-intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia 2006; 20: Crawley C, Iacobelli S, Björkstrand B, et al. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109: This is a retrospective analysis from the EBMT registry comparing 320 patients who underwent Allo-RIC with 196 who received a MAC between 1998 and The TRM at 2 years was significantly higher with MAC (37 vs. 24%, P ¼ 0.002), the PFS was longer with MAC (34.5 vs. 18.9%, P ¼ 0.001) with no significant difference in OS (50.8 vs.38.1%, P ¼ NS). On multivariate analysis, Allo-RIC was associated with a reduced TRM, which was offset by an increase in relapse risk and the conditioning regimen had no significant impact on PFS or OS. 33 Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) in high-risk de novo multiple myeloma. Blood 2006; 107:

8 704 Leukemia 34 Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting in newly diagnosed myeloma. N Engl J Med 2007; 356: A prospective trial comparing double auto vs. auto followed by Allo-RIC. All patients were included, irrespective of the prognostic features and the response status after the first ASCT. The CR rate was significantly higher with auto/allo-ric than with double ASCT (55 vs. 26%, P ¼ 0.004), the OS was significantly longer with Allo-RIC (median, notreached vs. 58months, P ¼ 0.03) andtherewas a trend fora longer EFS with Allo-RIC (median, 43 vs. 33 months, P ¼ 0.07). On a multivariate analysis, both EFS and OS were significantly longer with Allo-RIC than with double autologous. 35 Rosiñol L, Pérez-Simón JA, Sureda A, et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reducedintensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008 [Epub ahead of print]. A prospective trial comparing double ASCT vs. allograft followed by Allo-RIC in patients failing to achieve at least ncr with the first ASCT. The conditioning for Allo-RIC was fludarabine and melphalan. The CR rate was significantly higher with Allo-RIC (40 vs. 11%, P ¼ 001), there was a trend for PFS in favour of Allo-RIC (median, 31 months vs. not reached, P ¼ 0.08) with a plateau beyond 3 years of follow-up. There was no significant difference in OS between the two groups. 36 Cavo M. Nonmyeloablative allotransplantation for myeloma: light and shade. Blood 2007; 109: Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma. Lancet 2007; 370: This study basically compared MPT vs. melphalan prednisone vs. VAD/MEL-100 in patients with multiple myeloma aged years. Concerning the comparison of MPT vs. melphalan prednisone, MPT resulted in a significantly higher RR (76 vs. 35%, P < ), CR rate (13 vs. 2%, P < ) as well as in a prolonged EFS (HR 0.56, P ¼ ) and OS (median 51.6 vs months, P < 0.001). There were no significant differences in PFS and OS between melphalan prednisone and VAD followed by MEL-100). 38 Hulin C, Facon T, Rodon P, et al. Comparison of melphalan-prednisonethalidomide (MP-T) demonstrates a significant survival advantage in elderly patients >75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized double-blind, placebo controlled trial, IFM [abstract #75]. Blood 2007; 110:31a. 39 Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomized controlled trial. Lancet 2006; 367: Waage A, Gimsing P, Juliusson G, et al. Melphlan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo-controlled phase III trial [abstract #77]. Blood 2007; 110:32a. 41 Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica 2008; 93: San Miguel JF, Schlag R, Khuageva N, et al. A phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma [abstract #76]. Blood 2007; 110:31a. 43 Sagaster V, Ludwig H, Kaufmann H, et al. Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 2007; 21: 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 2007; 21: Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA- Italian Multiple Myeloma Network. J Clin Oncol 2007; 25: First trial reporting the efficacy of melphalan prednisone lenalidomide (MPR). In this phase II study, including 54 patients, the overall RR was 81% including 24% immunofixation negative CR. The 1-year EFS and OS were 92 and 100%, respectively. 46 Ludwig H, Tothova 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 [abstract #529]. Blood 2007; 110:163a. 47 Rajkumar SV, Jacobus S, Callander N, et al. A randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group [abstract #74]. Blood 2007; 110:31a. 48 Chanan-Khan AA, Kaufmann JL, Metha J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007; 109: This study reports an impressive RR to bortezomib in a retrospective series of patients with myeloma and advanced renal failure requiring dialysis. The toxicity pattern was similar to that observed in patients with normal renal function. 49 Kastritis E, Anagnostopoulos A, Roussou M, et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone and the impact of novel agents. Haematologica 2007; 92: Ludwig H, Drach J, Graf H, et al. Reversal of acute renal failure by bortezomibbased chemotherapy in patients with multiple myeloma. Haematologica 2007; 92: Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008; 111: Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: Richardson P, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110: This is an extended follow-up of the APEX trial comparing bortezomib with dexamethasone in patients with relapsed or refractory myeloma. After a median follow-up of 22 months, the median survival was 29.8 months for bortezomib vs months for dexamethasone, this 6-month benefit was despite a substantial crossover from dexamethasone to bortezomib. The overall RR and CR rate were 43 and 9%, respectively. 55 Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007; 25: This is a large phase 3 trial, including 646 patients, comparing bortezomib and pegylated liposomal doxorubicin with bortezomib alone. The CR and PR rate was not significantly different (44 vs. 41%).Thetimetoprogression(median9.3 vs. 6.5 months, P < 0.001) and a 15-month survival rate (76 vs. 65%, P ¼ 0.03) were significantly favourable to the combination. The median duration of response was increased from 7 to 10.2 months (P < 0.001) with the combination. 56 Weber D, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357: A large phase 3 trial including 353 patients comparing lenalidomide and dexamethasone with dexamethasone alone. Lenalidomide/low-dose dexamethasone was superior to dexamethasone alone in overall RR (61 vs. 19.9%, P < 0.001), CR rate (14.1 vs. 0.6%, P < 0.001), time to progression (median 11.1 vs. 4.7 months, P < 0.001) and OS (median 29.6 vs months, P < 0.001). Myelosuppression and DVT were more common with lenalidomide/low-dose dexamethasone. 57 Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: Also a phase 3 trial with identical design to the one in [56 ] and including 351 patients. Lenalidomide and dexamethasone was superior to dexamethasone alone in overall RR (60.2 vs. 24%, P < 0.001), CR rate (15.9 vs. 3.4%, P < 0.001), time to progression (median 11.3 vs.4.7 months, P < 0.001) and OS (median not reached vs months, P ¼ 0.03). Again, the incidence of severe neutropenia and DVT were significantly higher with lenalidomide/ dexamethasone. 58 Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomideand lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: This is an extensive review on the thalidomide and lenalidomide-associated thrombotic events with prophylactic recommendations to prevent these events. 59 Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008; 111: Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: