Cure of multiple myeloma more hype, less reality

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1 (2006) 37, 1 18 & 2006 Nature Publishing Group All rights reserved /06 $ REVIEW more hype, less reality P Hari 1, MC Pasquini 1 and DH Vesole 2 1 Medical College of Wisconsin, Milwaukee, WI, USA and 2 St Vincent s Comprehensive Cancer Center, New York, NY, USA Randomized studies have firmly established the role of autologous transplant as initial therapy in multiple myeloma (MM). Indeed, MM has emerged as the commonest indication for autologous SCT in North America. The conceptual basis for high-dose therapy is the goal of complete remission (CR)through steep reduction in tumor burden affected by single and tandem transplants. Careful analysis of the data challenges the notion of CR as a surrogate to success. Intrinsically aggressive MM, defined by known unfavorable biologic risk factors, overrides the benefit of CR. In contrast, subgroups of patients with favorable biological risk factors may achieve prolonged survival, often without ever achieving CR. Unfortunately, even with tandem transplants, there is no plateau in survival curves. To this end, sequential autologous followed by nonmyeloablative allotransplants are a novel attempt at curing myeloma, but the results thus far have failed to show a definite plateau in survival. Given the improvements in supportive care and concomitant reduction in transplant-related mortality, conventional myeloablative allogeneic transplants need to be re-examined as an option in high-risk aggressive myeloma. At the same time, novel antimyeloma therapies, newer risk stratification and staging tools are transforming the treatment algorithm. We examine the changing role of transplantation in myeloma in the context of novel drug therapy, biologic risk stratification and improving supportive care while arguing that the current one size fits all transplant approaches are far from a cure. (2006) 37, doi: /sj.bmt ; published online 31 October 2005 Keywords: multiple myeloma; hematopoietic stem cell transplants; autologous; allogeneic Introduction There are approximately patients with multiple myeloma (MM) in the United States, reflecting an annual Correspondence: Dr P Hari, Division of Neoplastic Diseases and Related Disorders, Medical College of Wisconsin, 9200 West Wisconsin Ave, Milwaukee, WI 53226, USA. phari@mcw.edu Received and accepted 8 September 2005; published online 31 October 2005 incidence of about and a median survival of about 3 years. 1 Two prospective randomized clinical trials, 2,3 several nonrandomized comparisons 4 7 and two large systematic reviews 8,9 have shown that high-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (HSCT) is superior to conventional chemotherapy (CC) in prolonging event-free survival (EFS) and overall survival (OS). Currently, MM is the most common indication for autologous HSCT transplants in North America, with over 5000 transplants performed yearly (approximately 4500 autologous and 500 allogeneic from the Center for International Blood and Marrow Transplant Research (CIBMTR) data). Barlogie and others have coined the term operationally cured to define a subgroup of MM patients who survive beyond 10 years 10 in remission or in a state similar to monoclonal gammopathy of undetermined significance (MGUS). Unfortunately, the vast majority of patients eventually relapse and succumbto their disease. Strategies aimed at improving the outcomes of transplantation have focused on tandem HSCT, sequential autologous transplants followed by allogeneic transplantation using reduced-intensity conditioning and post transplant maintenance therapy. At the same time, novel antineoplastic agents have expanded nontransplant options available to MM patients. We discuss current studies of transplantrelated strategies, the impact of novel antimyeloma agents, the role of maintenance therapy and newer risk stratification tools in redefining transplant strategies. Single autologous transplants Observations in the early 1980s that high-dose melphalan (MEL) followed by autologous bone marrow transplant could produce meaningful remissions even in relapsed and/or refractory MM patients 11 led to randomized trials in which HSCT was compared to CC in newly diagnosed patients. Attal et al. 2 and Child et al. 3 have demonstrated that patients randomized to HDT with HSCT had significantly higher complete remission (CR) rates, CR duration, EFS and OS. Two other randomized studies 12,13 presented in abstract form, however, have not shown a survival benefit to HSCT. Comparison between these trials is difficult due to variability in patient eligibility (age), induction chemotherapy, the conditioning regimen for HSCT and the definitions of response. However, with the

2 2 Table 1 Randomized trials of conventional chemotherapy compared to single HSCT as upfront therapy Author Group N Age (years) CR (%), CC versus SCT P Criteria for defining CR Attal 2 IFM p65 5 versus 22 S Electrophoresis Child 3 MRC7 401 p64 8 versus 44 S EBMT-IBMTR (IF) Blade 13 PETHEMA 164 p65 11 versus 30 S EBMT-BMTR (IF) Palumbo 14 IMMSG versus 25 S Electrophoresis Crowley 15 USIG 899 o70 15 versus 17 NS EBMT-IBMTR (IF) Segeren 16 HOVON 261 o65 13 versus 29 S Immunofixation CC ¼ conventional chemotherapy; SCT ¼ stem cell transplant; S ¼ statistically significant; NS ¼ not significant; IF ¼ immunofixation. exception of the US Intergroup S9321 trial, all other trials have shown a significant increase in CR in the transplant arm (Table 1). Single autologous transplantation differences between studies The US Intergroup study and the Spanish PETHEMA study offer interesting insights since they were not straightforward comparisons of CC versus HSCT. In the PETHEMA trial, only patients responding to initial chemotherapy were randomized to HSCT versus continuing CC, thus excluding initial nonresponders. This study did not demonstrate a difference in the EFS or OS between CC and HSCT in patients responding to initial chemotherapy. However, a higher CR rate in the HSCT arm of this study caution against accepting CR as a surrogate for benefit in HSCT for MM. Also, there may not be a benefit to HSCT in patients who are responding to CC. The US Intergroup Study, S9321, is the largest study comparing CC to HSCT. Newly diagnosed MM patients received 3 4 cycles of VAD chemotherapy, high-dose cyclophosphamide for stem cell mobilization and were then randomized to receive MEL 140 mg/m 2 with total body irradiation (TBI) 1200 cgy or VBMCP for 1 year. Responding patients in each arm underwent a second randomization to either observation or interferon (IFN) maintenance. At the time of relapse in the VBMCP arm, patients were encouraged to undergo HSCT. Prior to the first randomization, patients under age 55 years with an HLA-compatible sibling could elect to receive an allogeneic transplant. (Owing to a 41% transplant-related mortality (TRM) in the first 38 patients, this arm was subsequently closed to accrual.) The VBMCP and early HSCT groups were similar in terms of EFS (21 versus 25 months, P ¼ 0.14). Interpretation of the results for OS was murkier since 52% of patients in the VBMCP arm had a late transplant at relapse/progression. Thus, the OS rates (53 versus 62 months, P ¼ 0.87) were not statistically different. Interestingly, the CR rates were also not significantly different between CC and HSCT (15 versus 17%). This may be a reflection of the conditioning therapy employed: MEL 140 mg/m 2 with TBI 1200 cgy may be an inferior regimen compared to MEL 200 mg/m 2. MEL 140 mg/m 2 plus TBI 800 cgy has been shown to have similar EFS but inferior OS (P ¼ 0.05) compared to MEL 200 mg/m 2 in the randomized French study IFM Even so, the similar EFS rates for VBMCP and HSCT is surprising and may reflect the superiority of VBMCP maintenance over prior CC and a failure to achieve a substantial increase in the CR with the suboptimal conditioning regimen used (MEL 140 mg/m 2 þ TBI 1200 cgy). Thus, the S9321 trial, in effect, showed that upfront HSCT and salvage HSCT at the time of relapse or progression were comparable. In an earlier French study, Fermand et al. 18 (MAG 95) had also shown comparable survival differences between early and delayed transplantation. The timing of transplants in MM Although comparable OS have been reported for both early and late HSCT by the US Intergroup 15 and the MAG 95 trials, 18 the latter trial demonstrated superior quality of life indices in patients receiving early transplantation. In contrast to these two randomized trials, the timely administration of tandem HSCT within 12 months of diagnosis resulted in superior EFS and OS in multivariate analysis reported by the Arkansas group. 19 Therefore, most myeloma experts recommend early transplant for their patients as de novo strategy. 9 CR as the goal of initial therapy is CR a good surrogate for survival? MM is unique among the hematologic malignancies in that HSCT is the main modality of achieving CR (unlike other hematologic malignancies where induction therapy remains the primary means to a CR) with an expected CR rate of 25 35% with a single HSCT and 35 50% with tandem HSCT (Table 1). These CR rates are superior to CC, which historically yielded CR rates in single digits. Novel transplant strategies (tandem transplantation, maintenance therapy, MEL dose intensification) aim to increase CR rates further. It should be noted that not all studies show an absolute benefit from achieving CR. Rajkumar et al. 20 reported the Mayo Clinic experience wherein patients who underwent HSCT had a similar progression-free survival (PFS) and OS whether they achieved CR or not following HSCT. The Arkansas group has also reported recently that achieving a stringently defined CR after tandem transplantation may not be predictive of survival (41 versus 39% for CR and no CR, respectively). Using a time-dependent covariate analysis in Total Therapy I (TTI) patients, they demonstrated that achieving a CR at the 1-year landmark after transplant was not significantly related to OS (hazard ratio: 0.83; P-value 0.39). 21 The Arkansas group also found that in patients who had preceding MGUS or smoldering MM,

3 stringently defined CRs were significantly lower compared to de novo MM, but these lower CR rates did not translate into survival differences after tandem HSCT. 22 The Mayo experience with single autologous transplantation and the Arkansas group s analysis of their tandem transplant patients challenge the central role of CR in determining the success of HSCT. How is CR defined? Clinical trials of HSCT in MM cannot always be directly compared since the definition of CR varies among studies (Table 1). For example, the older IFM studies used electrophoretic criteria for defining CR rather than the now widely used immunofixation-based EBMT-IBMTR criteria (EBMT: European Group for Blood and Marrow Transplant). 23 However, the method used to define CR may or may not be predictive for outcome Davies et al. 25 found that in their series of 96 newly diagnosed patients, the method used to define CR (electrophoresis versus immunofixation versus IgH PCR) did not translate into OS differences. Lahuerta et al. 26 on the contrary found that achieving an immunofixation-negative CR after HSCT defined a subset of patients with better prognosis compared to an electrophoretic CR. In the allogeneic transplant setting, preliminary pooled data from nine EBMT centers do show a survival advantage for patients achieving molecular CR established by PCR analysis. 24 There is a trend to expand good results to include the IFM terminology of very good partial response defined as decrease of greater than 90% in the serum paraprotein level 2 to the Italian near CR defined as a CR using the Blade EBMT-IBMTR criteria with the exception of immunofixation positivity. These modifications to the Blade criteria continue to confound our ability to compare outcomes from study to study. The International Myeloma Working Group is in the process of modifying the Blade criteria to establish universally accepted response criteria. Response to initial induction therapy and transplant outcomes Several studies have shown that for patients who do not respond to initial induction chemotherapy, HDT benefits by improving outcomes. Alexanian et al. 27 compared VADnonresponsive patients who had undergone HDT with a control group who could not undergo such therapy. Despite the methodological shortcomings incumbent on historic comparisons, it was shown that for patients with primary resistant disease who received intensification within 1 year, there was a high (69%) frequency of response, including 16% with CR. HDT beyond 1 year was less effective, affirming the greater value of early intensive therapy for these patients. Thus, patients with primary resistant disease who underwent HSCT lived approximately 2 years longer than controls. Singhal et al. 28 report that 40% of nonresponders to initial CVAMP therapy achieve CR and only 12% of initial nonresponders remained nonresponders after HDT with MEL 200 mg/m 2. In the most recent Mayo Clinic experience reported by Kumar et al., 29 20% patients in the primary refractory group achieved complete responses following HDT compared to 35% in the chemosensitive group, and the groups had similar PFS. Lack of response to initial induction does not therefore preclude a good response to HSCT. Finally, recent Arkansas data 30 for Total Therapy II (TTII) do not show a difference in 3-year EFS or OS between patients who achieved a PR or less than a PR, whereas a stringently defined CR correlated with a statistically superior EFS (P ¼ 0.04). In summary, these data suggest that even patients who have primary refractory MM achieve significant benefit (with or without attaining CR) with HDT strategies when transplanted early in their disease course. Heterogeneity of disease biology and CR In the PETHEMA study and the recent Arkansas reports, 21,22 CR was not a prerequisite for survival benefit. How do we reconcile these data with the contrary paradigm that emphasizes the attainment of a stringently defined CR as critical to benefit from HSCT? Heterogeneity of biologic risk in MM may explain the fact that CR may not be the best surrogate for survival in all cases. Biological risk factors provide more important prognostic implications beyond the attainment of CR. Identification of subsets of patients who will not benefit from HSCT is a challenge. The effect of adverse biologic risk factors, even in the setting of CR, is manifested as early progression post transplant. Since post transplant benefit may not always be estimated by presence or absence of clinical response to induction chemotherapy or transplant, biologic risk stratification factors associated with outcomes are paramount. There are numerous examples for these heterogeneous situations: in patients whose MM evolved from a prior MGUS or SMM and also in patients who had survived 41 year after tandem HSCT, the nonattainment of stringent CR did not turn out to be prognostically significant. 10,21,22 These patients presumably had biologically less aggressive disease and may have been induced into a chronic indolent disease state (without true CR). This may lead to the concept of operational cure, as proposed by Barlogie and co-workers 31 and Powles et al. 32 In contrast, MM with certain cytogenetic abnormalities (e.g. t(4;14)) is associated with far inferior EFS and OS despite comparable HSCT response rates, mainly because of rapid progression after HSCT. 33,34 A combined analysis of 1555 patients enrolled in four different SWOG phase III protocols over a decade also showed that while the magnitude of response with frontline anti-myeloma therapy did not predict outcome in terms of OS, the only variable that was found to predict survival was the time to progression. In other words, progression rather than the magnitude of response was significant. 35 Biologic risk stratification in MM MM has distinct biologic features that predict the natural history and response to therapy. Currently, initial treatment of MM is not yet tailored to specific risk categories. Several known risk factors have been associated with poor outcomes such as elevated b-2 microglobulin, low serum 3

4 4 albumin, high plasma cell labeling index, circulating plasma cells, elevated lactate dehydrogenase (LDH) and cytogenetic abnormalities. 36,37 Through the analysis of a large series of patients, modeling several disease-specific variables a prognostic staging, the International Staging System (ISS) was created. 37 This simplified staging uses serum albumin and b-2 microglobulin to stratify patients in three distinct stages with median survival of 62, 44 and 29 months, respectively. Despite the large number of patients present in the ISS analysis, less than 5% had available cytogenetic information, which explains the current lack of significant correlation between cytogenetic abnormalities and ISS stage. Distinct abnormalities with chromosome 13 (D13), either deletion or monosomy, are the most studied cytogenetic changes linked with significant poor outcome. The proportion of cases bearing D13 depends on detection techniques: 15% by metaphase karyotyping and 50 60% by fluorescent in situ hybridization (FISH) Patients enrolled in the ECOG E9486 study, which compared different standard dose chemotherapy regimens, were analyzed based on the presence or absence of D13 detected by FISH. D13 was associated with lower objective response (63 and 74%), median PFS of 24 months compared to 32.5 months and OS of 35 compared to 51 months, respectively. 45 Detection of D13 by either technique is associated with poor outcome: D13 by metaphase karyotyping is more strongly associated with unfavorable outcomes with CC and HSCT. 36 Impact of cytogenetics on transplant outcomes The negative impact of D13 on outcome is not overcome by transplant strategies. Median survival after at least a single HSCT in patients with D13 ranges from 24 to 27 months compared to greater than 60 months in patients without D The Arkansas group confirmed that the dismal results in patients with D13 (detected by metaphase karyotyping) persisted even after tandem HSCT 16 versus 44% 5-year OS in patients without D Similarly, the HOVON 24 study, which compared intermediate doses of MEL with autologous HSCT, found that the presence of 1p/1q abnormalities was highly correlated with D13 and associated with worse OS and EFS. 47 Even allogeneic transplantation appears to be insufficient to overcome the poor prognosis associated with D13. Initial results with reduced-intensity conditioning allogeneic transplants for D13 MM were reported by Kroger et al. 48 The relapse rate, disease-free survival at 2 years and OS were 77, 18 and 18% compared with 44, 42 and 67%, respectively, in non-d13 patients while TRM was identical (18%). These data suggest that any graft-versus-myeloma (GVM) effect resulting from reduced-intensity allogeneic transplants is insufficient to prevent progression in patients with D13. The failure to overcome the adverse impact of D13 even with tandem transplants, autologous/autologous or autologous/ allogeneic, indicates that novel therapeutic approaches are required in this subgroup. Cytogenetic abnormalities involving immunoglobulin heavy chain (IgH) locus (14q32) are emerging as a subtype associated with variable outcomes depending on the translocation partner. 33,49 51 Translocations involving IgH and 4p16 or 16q23 are associated with poor outcomes. The frequency of t(4;14) identified by FISH is between 15 and 20%. 33,52 55 Patients with t(4;14) experience significantly poorer PFS and OS after standard chemotherapy and HSCT. 34,51 The IFM 33 also showed worse outcomes with this abnormality (22.8 versus 66% at 80 months, P ¼ 0.002), which was not attributed to differences in initial response to therapy. The translocation t(14;16) is detected in less than 10% of cases and is also associated with poor outcome. 51 Hypodiploidy and the presence of MDS like cytogenetic abnormalities associated with MM have also been suggested as independent poor prognostic markers. 56,57 In contrast, the t(11;14) translocation, the cyclin D1 (CCD1) locus, is associated with improved survival. After standard dose chemotherapy, median OS is superior for patients with t(11;14) than those without this abnormality (50 versus 39 months). 51 This beneficial impact seems even higher for patient undergoing HSCT, with 87.5% OS at 80 months compared to 55%. 33 The identification of IgH involvement assisted the development of the first MM classification-based gene expression status. 58 This translocation and cyclin (TC) classification stratifies IgH-positive MM in different subtypes depending upon the level of oncogene expression derived from the translocation with 11q13 (CCND1), 4p16 (FGFR3 and MMSET), 6p21 (CCND3), 16q23 (MAF) and 20q11(MAFB). This classification once validated in MM population studies might assist in defining different molecular signatures for targeted therapy. Risk stratification in MM has thus defined subsets of patients who have poor outcomes despite intense treatment allocation. It is important to recognize such patients who may not derive optimal benefit from transplant approach and utilize risk-adapted strategies to guide the treatment in high-risk patients (Table 2). Impact of novel pretransplant therapies Virtually all of the randomized studies of CC versus HSCT in MM utilize corticosteroid-based combinations for induction therapy. Novel antimyeloma agents (bortezomib, thalidomide and lenalidomide) that have transformed the therapeutic options in relapsed and/or refractory MM are now being integrated into therapy for newly diagnosed myeloma patients. The initial trials have shown impressive improvements over the historical response rates for CC (e.g. response rate exceeding 90% within 1 2 months of therapy 65 for the combination of lenalidomide plus dexamethasone). Preliminary reports of these newer agents, alone or in combinations, have resulted in CR rates of up to 25%. Table 3 summarizes recent response data with novel agent combinations. While these response rates are encouraging, it is yet to be established if these newer agents will result in significantly longer remission duration compared to CC. Preliminary results from two randomized phase III trials (the French IFM and an Italian multicenter trial) comparing conventional MEL and prednisone (MP) with MEL/prednisone/thalidomide (MPT) in older patients

5 Table 2 Impact of cytogenetic abnormalities: PFS and OS in patients with specific changes compared to those without 5 Author Treatment Abnormality compared PFS OS Desikan et al. 46 HCT tandem autologous D13 (metaphase) 0 at 5 years versus 20% at 5 years 16% at 5 years versus 44% at 5 years Tricot et al. 59 HCT tandem autologous D13 (metaphase) 19 versus 35 mo 26 versus 55 mo Fonseca et al. 45 Standard dose chemotherapy D13 (FISH) 24 versus 32.5 mo 35 versus 51 mo Zojer et al. 42 Standard dose chemotherapy a D13 (FISH) NA 24.2 versus 460 mo Kroger et al. 48 HSCT auto/ric allo D13 (FISH) 18% at 2 years versus 42% at 2 years 18 versus 67% at 2 years Facon et al. 44 HSCT single autologous D13 (FISH) 17 versus 33 mo 27 versus 65 mo Fonseca et al. 51 Standard dose chemotherapy t(11;14)(q13;q32) 33 versus 27 mo b 50 versus 39 mo b t(4;14)(p16;q32) 17 versus 31mo 26 versus 45 mo t(14;16)(q32;q23) 9 versus 30 mo 16 versus 41 mo Gertz et al. 60 HSCT at least one autologous t(11;14)(q13;q32) 20.1 versus 15.3 mo b 36.6 versus 34.8 mo b t(4;14)(p16;q32) 8.2 versus 17.8 mo 18.8 versus 43.9 mo 17p versus 16.1 mo 15.1 versus 38.8 mo Moreau et al. 33 HSCT c t(11;14)(q13;q32) NA 87.5 versus 55.4% at 80 mo b t(4;14)(p16;q32) 20 versus 28.5 mo 22.8 versus 66% at 80 mo a Five patients underwent high-dose therapy followed by autologous hematopoietic stem cell transplant. b No statistically significant difference (P40.05). c All patients underwent HSCT: 86 patients single autologous HSCT, 72 tandem autologous HSCT and 10 patients standard dose allogeneic. mo ¼ months. Table 3 Impact of novel induction strategies on CR rates Author Regimen Overall response rates CR or near-cr rates N Harvest or HDT after initial therapy Palumbo 66 MPT 81% 26% 102 NR Cavenagh 67 PAD 95% 29% 21 PBSCT Harrousseau 68 VD 73% 17% 18 Adequate harvest Jagannath 69 VD or V 88% 25% 32 Successful HDT Alexanian 70 VDT 80% NA 30 Successful harvest Richardson 62 V 45% 4% 33 NR Facon 71 MPT 84% IFM trial Mateos 72 VMP 91% 18% 11 NR Barlogie 73 VDT-PACE NR 26% 57 Successful tandem transplants Uy 74 (not initial V 90% 27% 11 Successful harvest therapy) Rajkumar 65 Lenalidomide-D 85% NR 13 Successful harvest Caveat: The overall impact of these novel regimens on survival, long-term transplant outcomes and post transplant complications is not yet defined since these are pilot data. PAD ¼ bortezomib/doxorubicin/dexamethasone; MPT ¼ MEL/prednisone/thalidomide; VDT ¼ bortezomib/dexamethasone/thalidomide; VD ¼ boretzomib/ dexamethasone; V ¼ bortezomib; VDT-PACE ¼ bortezomib/dexamethasone/thalidomide/cisplatin/adriamycin/cytoxan/etoposide; D ¼ dexamethasone; NR ¼ not reported. (465 years) demonstrated superior EFS in the MPT arms. 66,75 Furthermore, the IFM trial includes a third arm: MP, MPT or a tandem HSCT with MEL 100 mg/m 2 (MEL100). With a median follow-up of 28 months, the response rate and EFS to MP was found to be inferior to both MPT and MEL100. Interestingly, the response rates and EFS were similar for the MPT and MEL100 arms, implying that intermediate-dose MEL with HSCT may not improve survival. The additional benefit of HSCT in the setting of patients who have already achieved CR is unknown. Since CR rates are so low with CC, the benefits of CR with CC versus HSCT have not been evaluated. However, as described previously, HSCT did not confer additional survival benefit in patients who responded to initial chemotherapy in the PETHEMA study. Thus, novel induction modalities with higher response rates could conceivably challenge the current standard of planned upfront HSCT by achieving higher CR rates even without transplantation. Tandem autologous transplants After the feasibility of double intensification with HSCT had been reported, the Arkansas group pioneered the tandem planned autologous transplant approach in their TTI program with non-cross-resistant induction chemotherapy regimens culminating in tandem autologous transplantation. 7,79 They observed impressive EFS and OS of 43 and 68 months, respectively, which were superior to historical controls. The results of the TTII trial, which incorporates thalidomide into a tandem transplant ap-

6 6 proach, have also been reported. 80,81 Superior 5-year continuous CR (60%) and improved EFS (50% at 5 years) were shown compared to TTI. The median follow-up of 2.5 years is not yet mature enough to compare the OS. The current Arkansas approach Total Therapy III (TTIII) includes bortezomib in the induction regimen and post transplant consolidation. 73 The French Intergroup trial (IFM 94) comparing single to double HSCT randomized previously untreated MM patients to receive either a single HSCT using MEL 140 mg/ m 2 þ TBI 8 Gy or a double HSCT (MEL 140 mg/m 2 followed by MEL 140 mg/m 2 þ TBI 8 Gy). 82 Patients then received IFN-2a maintenance therapy. The projected 7- year EFS and OS benefits were significant for the double HSCT arm (10 versus 20% for EFS and 21 versus 42% for OS, respectively). There are four additional randomized trials comparing single to double intensive therapy only the French IFM 94 has been published (Table 4). The preliminary data show an EFS benefit for the tandem approach in four out of the five studies. OS benefit has been shown only for the IFM 94 study. However, a recent reanalysis of the MAG 95 trial demonstrated that the subgroup of patients who received non-cd34 þ selected stem cell products had a superior OS in the tandem arm (30 versus 40% at 7 years, P ¼ 0.04) although the EFS was still similar. 85 Benefits of tandem transplantation In the IFM 94 trial, survival for patients undergoing tandem HSCT diverged significantly from the single HSCT arm only after the first 4 years of follow-up. Furthermore, the results of this study show no significant increase in CR with the second HSCT on intent to treat basis, although patients who completed the second transplant did have higher CR compared to patients who only had a single transplant (63 versus 49%, respectively). The subsets of patients who appear to have benefited the maximum from the second planned HSCT are those who do not achieve a CR or a very good PR within 3 months after the first HSCT. In this subset, the probability of 7-year survival was 11% with single transplant versus 43% with the tandem approach. 82 The Bologna 96 data 88 also suggest that tandem HSCT was of particular benefit to patients who failed to respond to first-line therapy and/or are not in CR or near CR following the first transplant. Arkansas data regarding outcomes of patient subsets who achieve CR with one transplant and who do not go on to receive the second planned transplant have never been presented. The authors of the IFM 94 trial suggest that the difference in projected survival with tandem HSCT does not correlate with improved response rates but longer duration of responses. This may explain why differences in survival are not apparent with shorter follow-up in the other randomized studies of tandem transplantation. Also, the IFM results appear inferior to the Arkansas tandem HSCT data in terms of CR, EFS and OS. These differences may be related to differences in patient selection, induction and most likely the transplant conditioning therapy: the IFM 94 utilized MEL 140 mg/m 2 followed by MEL 140 mg/m 2 þ TBI 8 Gy (total MEL dose of 280 mg/m 2 ) while the Arkansas regimen was MEL 200 mg/m 2 followed by MEL 200 mg/m 2 (total dose of 400 mg/m 2 ). The lack of clear OS benefit in any randomized study other than IFM 94 is striking. Short follow-up and improvements in salvage therapy including novel new agents and late second transplants may account for the lack of an OS advantage for the tandem procedure in three out of the five randomized studies (Bologna, HOVON and GMMG). The potential shortcomings of the tandem approach are an increase in hospitalization and overall health care costs, the lack of additional benefit in patients who had already achieved CR with a first HDT, unrealistic expectations of a cure and the lack of any impact on early mortality in the first 4 years. Furthermore, the HOVON investigators reported that quality of life indices were significantly better in the first year post transplant in patients assigned to the single intensive arm as opposed to the double intensive treatment group without any OS benefit. 83 Based on the IFM 94 and Bologna 96 subgroup analyses, a patient who fails to achieve a very good PR after the first HSCT should be offered a tandem second transplant. Routine tandem transplants should otherwise only be considered in the context of well-designed clinical trials and not the standard of care at this time for patients with very good responses to first transplant. Current randomized data on the benefits and risks of tandem autologous transplants are summarized in Table 4 and Figure 1. Table 4 Randomized trials of single versus double autologous HSCT Author N Median age Conditioning regimen, firstsecond CR (%), single versus double EFS (%), single versus double OS (%), single versus double Follow-up (months) IFM MEL 140+TBI-MEL versus versus 30 a 48 versus 58 a 75 HOVON24 MM 47, MEL 140-Cy 120+TBI 13 versus 28 a 20 versus 22 a 55 versus GMMG HD MEL 200-MEL 200 NR 23 versus 29 a No difference NR MAG 95 85, MEL 140+CCNU/VP16/ 39 versus versus versus 73 b 53 CY TBI versus MEL 140- MEL 140+TBI Bologna MEL 200-MEL 120+BU versus versus 35 a 59 versus MEL ¼ melphalan (doses in mg/m 2 ); CY ¼ cyclophosphamide; TBI ¼ total body irradiation; BU ¼ busulfan; NR ¼ not reported. a Statistically significant difference (Po0.05). b OS difference statistically superior for non-cd34 selected tandem transplants only in subset analysis.

7 Overall Survival IFM 94 is the only study to show clear survival benefit. MAG 95 shows OS benefit in non-cd34 selected subgroup. 4 out of 5 studies yet to show OS benefit (too early?) May need longer follow up before OS curves separate. Conditioning Regimens varied between studies (ideal regimen MEL200 x2?) 7 Event Free Survival (EFS) Validity of EFS as an isolated endpoint is debatable without QOL data. Salvage second transplants at relapse have not been formally compared to tandem transplants. EFS advantage for tandem transplants shown in 4 out of 5 studies (MAG 95 is the only one not to show benefit). CR rates HOVON study only study to show improved CR rates with double transplants. Benefit of second transplant from lengthening the duration of CR will not manifest as increased CR rates. Definition of CR and rates of CR with single transplants varied between studies. Who benefits from the second transplant? Patients in less than near CR (at least 90% reduction in paraprotein) more likely to benefit from second transplant (IFM 94 and Bologna 96 based on subgroup analyses). Who does not derive additional benefit from second transplant? Patients already in CR after first transplant Patients with high biologic risk (e.g karyotypic 13) have poor outcome with tandem autologous transplants based on Arkansas data. QOL and cost considerations HOVON the only group to report on QOL for tandem transplants favored single transplants. Cost analysis not prospectively done in any study Figure 1 Recommendations: Outside of a clinical trial, tandem transplants should be limited to patients with good PS who are not in at least a near CR after the first HSCT. Any future trial should have rigorous analysis of QOL. References: 47,82 87 Randomized trials of tandem versus single autotransplants interpreting the evidence. Autologous transplants and biological risk stratification The IFM investigators have designed innovative strategies to offer to patients with predefined adverse biologic risk in their ongoing IFM 99 trials. In the IFM trial, 89 patients with newly diagnosed MM up to the age of 65 years and with two adverse prognostic factors (b-2 microglobulin level 43 mg/l, presence of chromosome 13 deletion by FISH analysis) receive four courses of VAD chemotherapy and a MEL 200 HSCT. Then, according to the availability of an HLA-identical sibling, they receive either an allograft with reduced-intensity conditioning or a second HSCT prepared by MEL 220 mg/m 2 (7antiinterleukin (IL)-6 antibody). Preliminary analysis (median follow-up time 18 months) indicated no significant difference between the two strategies in terms of EFS or OS. 90 Since these patients do not appear to derive benefit from either autologous or nonmyeloablative allogeneic transplants as they are currently administered, it is necessary to devise innovative novel approaches (such as planned donor lymphocyte infusions with/without thalidomide, bortezomibmaintenance therapy, conventional allotransplants) to overcome these adverse biological factors. Optimal timing of a second transplant (salvage or planned) The timing of a second HSCT in patients who have undergone a prior HSCT is an unanswered question. While the IFM 94 and Bologna 96 results suggest that, for patients who are not very good PR or near CR within 3 months after the first transplant, an immediate second HSCT may be optimal, there are reports of the efficacy of salvage second transplants at relapse/progression Tricot et al. 91 have shown that a salvage HSCT at relapse after prior HSCT showed benefit for patients with 412 months remission duration and normal b-2 microglobulin. However, there are no randomized studies that compare a salvage second transplant at relapse to a planned upfront tandem second transplant. A retrospective analysis by the EBMT registry suggested that the completion of a second HSCT before relapse and within 6 12 months of the first transplant resulted in superior outcomes. 94 The Arkansas group performed serial landmark analyses to define the optimal timing of a planned HSCT in TTI: 79 EFS and OS both were longer among the patients who had received a second HSCT within 12 months.

8 8 Cure and operational cure There are no studies that demonstrate a plateau in the relapse curve for MM patients undergoing intense HDT. Thus, virtually all MM patients eventually relapse with disease-free survival at 10 years in the range of 5%. 10,95 In the Arkansas experience, 31 a substantial minority of patients (about 10 15%), defined by lack of adverse cytogenetics, low LDH and low b-2 microglobulin levels, have been considered cured albeit with persistently detectable paraprotein. It is questionable whether these patients represent a low-risk population of myeloma patients who on the basis of their extremely favorable risk profile have excellent survival irrespective of the tandem approach. However, even these patients have detectable paraprotein and are at risk for subsequent relapse. Allogeneic transplantation The obvious advantages of a tumor-free graft source and the proven GVM effect have prompted attempts at allogeneic transplantation in MM. 96,97 Indeed, patients surviving allogeneic transplants frequently have durable molecular CR 24, and a significantly reduced risk of relapse compared to autologous transplants. There is also evidence of a GVM effect and a link between graft-versushost disease (GVHD) and the success of DLI (donor lymphocyte infusions) Despite these benefits, conventional myeloablative allogeneic transplantation is associated with a significantly inferior EFS and OS than autologous transplantation. 105,106 This inferior outcome is related to a significantly higher TRM, reported as high as 50% in some studies, in patients receiving conventional allogeneic transplantation. 92 Nevertheless, some patients may be cured with allogeneic transplant. For example, the aborted allotransplant arm of US Intergroup S9321 study demonstrated a plateau in the survival curve at 25% although associated with a 40% TRM. 107 TRM is related to disease stage at diagnosis, remission status at transplant, donor recipient sex mismatch, number of prior therapies and grade 3 4 GVHD. 108,109 Data from the EBMT indicate that TRM has decreased significantly over the past 10 years to approximately 20%, with improved supportive care and patient selection. 110 Thus, conventional allotransplants, currently rarely considered, should be readdressed as a curative treatment for younger patients with good performance status when administered early in the disease course. Nonmyeloablative or reduced-intensity conditioning allogeneic transplants Nonmyeloablative or reduced-intensity conditioning (NST or RICT) represents an attempt to harness the welldocumented GVM effect while attempting to reduce TRM. This approach proved feasible both in the upfront and salvage settings and has the added benefit of expanding the transplant option to patients who may be ineligible for myeloablative conditioning. The Seattle group, who pioneered the nonmyeloablative (NST) approach, recently reported on their results in three groups of patients: relapsed patients who had failed prior HSCT (n ¼ 14); relapsed patients who had not received prior HSCT (n ¼ 19); and a third group who were candidates for a sequential HSCT followed by NST (n ¼ 84). The predicted 4-year OS were 40, 35 and 70% in the corresponding groups, while TRM was 2% at day 100 and 17% overall. 111 In high-risk or relapsed MM patients, the Arkansas group, using an RICT approach with MEL 100 mg/m 2, had impressive response rates and low early TRM. At 1-year post transplant, the TRM was 38%. 112 However, the OS results remain poor in the salvage setting compared to the upfront tandem approach and no true plateau has yet been documented in EFS. In patient groups composed mainly of progressive/relapsed MM, the OS and EFS at 24 months has been reported to be 25 and 22%, respectively, by Einsele et al. 113 and 30 and 19% by Giralt et al. 114 using RICT approaches. The 1-year TRM has been in the 23 40% range in these studies. In the salvage setting, unless TRM can be reduced or a significant plateau in survival can be shown on follow-up, this approach should only be pursued as part of well-designed clinical trials. A recent EBMT analysis of 229 patients from 33 centers in Europe and Israel is the largest reported series of NST/ RICT in MM. 115 Most of the patients were in CR or PR (67%) prior to transplant, had matched sibling donors (78%) and received fludarabine-based conditioning (96%) with the addition of busulfan or MEL. TRM at day 100, 1 year and 2 years were 10, 22 and 26%, respectively. On multivariate analysis, higher TRM was associated with female donors to male recipients and transplant more than 1 year from diagnosis. The 3-year estimate for OS was 40.6% and for PFS a disappointing 21.3%. The cumulative probability of progression was 50% at 3 years. Transplant in first remission and less than two prior autografts were associated with superior OS on multivariate analysis. Overall, this series suggested a continued decline in PFS with no evidence of a plateau even in patients who developed chronic GVHD. Another RICT series by the Hamburg group in newly diagnosed patients used fludarabine and MEL at doses of mg/m 2 with an option to add anti-thymocyte globulin (ATG). Their TRM was a modest 10 and 13% in the related donor and unrelated donor settings with 3- year OS at 60 and 83% and relapse rates at 46 and 34%, respectively. These results indicate that NST/RICT data need to be interpreted in the context of the conditioning regimen used (NST versus RICT), the setting of the transplant (salvage versus upfront), the type of donor (related versus unrelated) and the approach (planned sequential). Table 5 summarizes the available NST/RICT data in the salvage and upfront tandem setting. Planned sequential autologous followed by NST/RICT allogeneic transplantation The existence of a GVM effect after donor lymphocyte infusion independent of chemotherapy suggested that nonmyeloablative allogeneic transplantation strategies might be useful in MM patients who have minimal disease at the time of allotransplant. This led to the use of initial

9 Table 5 Studies of transplants with reduced intensity or nonmyeloablative conditioning in MM EFS Comment/survival estimate OS % CR % TRM % CGVHD % Conditioning regimen AGVHD % Clinical setting Author N Unrelated donors Kroger Tandem Flu 180+MEL 100+ATG months Giralt Salvage FLU 120+MEL months Maloney NA Tandem TBI 2 Gy months Einsele Salvage FLU 150+Cy 40 TBI months 2 Gy+ATG Kroger Tandem Flu 180+MEL 100+ATG months Badros and Salvage MEL months Lee 119,120 Perez-Simon Salvage FLU 150+MEL months Peggs 122, Upfront FLU+MEL+Campath 35 NR 2 NR months Gerull NR Salvage TBI7FLU 90; some Mel based NR OS and EFS 18 months with 21 month follow-up Moreau Tandem FLU+BU+ATG NR NR NR 6 56 OS 3-year estimate with 18 month follow-up; EFS 21 months Mel ¼ melphalan (doses in mg/m 2 ); ATG ¼ anti-thymocyte globulin; FLU ¼ fludarabine (in mg/m 2 ); BU ¼ busulfan; TBI ¼ total body irradiation; NR ¼ not reported; CY ¼ cyclophosphamide (in mg/m 2 ). autologous transplantation for steep tumor reduction followed by a planned tandem NST/RICT allotransplant aimed at using the GVM effect to eradicate minimal residual disease with a goal of long-term disease control. It is apparent from Table that in a tandem setting where an NST or RICT allograft followed an HSCT, the approach yielded excellent short-term (24 months) EFS and OS with TRM ranging from 11% in the matched related setting to 26% in the unrelated setting. The best results with this strategy seem to be in patients with chemosensitive disease, 116,119 without adverse markers such as D13 defined by FISH 48 or b-2 microglobulin 43 mg/dl 89 and low tumor burden (allograft within 12 months of HSCT). 119,146 In the sequential HSCT/NST data from Seattle too, sensitive disease prior to transplant predicted lower TRM (7 versus 27%). 116 Post transplant, the presence of chronic GVHD predicted better EFS and OS but acute GVHD had a significant adverse impact. 121 The Italian Group for (GITMO) in their planned sequential autologous followed by NST strategy reported a TRM of 13% and overall responses of 83% at a short follow-up of 13 months. 147 The CIBMTR reported a preliminary analysis 148 of a variety of nonmyeloablative regimens in 183 patients who received an initial allograft and 53 who received a tandem auto-allograft. The 1- and 2-year survival estimates were not statistically different in these populations. Thus, this approach appeared to be feasible and superior to conventional myeloablative allografts in terms of TRM. The Spanish PETHEMA/GEM study 149 enrolled patients who were not in at least a near CR after an initial HSCT to a second tandem autograft versus a biologically assigned RICT based on sibling donor availability. Although 56% of patients did not undergo assigned therapy and no significant survival differences were observed, the NST approach produced a significantly higher (26 versus 5%) CR rates achieved at a modest TRM of about 17%. Although it is too early to judge relapse rates in the NST/ RICT setting without longer follow-up data, disappointing relapse rates of 46% were observed in the IFM 9903 risk adapted trial. 89 A recent update of the results suggest that the EFS and OS are not different between the tandem HSCT arm (IFM 9904) and the sequential autograft followed by NST arm (IFM 9903). 150 Furthermore, recent updates of the German 124 and Seattle 151 studies report a continuing risk of relapse with no plateau in relapse curves and a 50 60% PFS at 3 years. Thus, the GVM effect alone may not be sufficient to maintain responses after NST/ RICT. For the present, while randomized trials of NST/ RICT approaches are underway with genetic assignment to the allogeneic arm in both Europe and the USA (BMT Clinical Trials Network 0102), tandem HSCT followed by NST approach remains strictly investigational. Improving the results of reduced-intensity approaches Since acute GVHD and relapse impact survival negatively after NST/RICT, several strategies such as T-depleted grafts, augmented immunosuppression with ATG 113 or 9

10 10 alemtuzumab, 122 pre-emptive DLI, 122 post transplant maintenance therapies have all been proposed to improve the results of allogeneic transplantation in MM. 123 These approaches are still in clinical trials. Allotransplants time for a rethink? As noted previously, NST/RICT strategies for myeloma arose from attempts to reduce the prohibitive TRM with myeloablative allotransplants. However, the reduction in early TRM with this strategy has not translated into a plateau in survival in any of the reported NST/RICT studies. Patients continue to relapse at least within the first 3 years and the relapse risk may be as high as 60% in the first 3 years. 89,124 Intriguingly, conventional myeloablative allotransplant patients seem to have either a plateau in survival and PFS at 6 years as observed by the US Intergroup S or a longer progression free interval described by an EBMT analysis. 105 In another recent analysis by Arora et al., 125 an encouraging 4-year survival of 64% was shown in their ablative allotransplant patients compared to 50% (P ¼ 0.04) in the autologous transplant setting. For patients surviving beyond 1 year after transplant, OS and EFS were significantly superior in the allogeneic setting. Given these promising data and the general advances in HLA typing, antifungal therapy and supportive care, future efforts at improving outcomes after allogeneic transplant should also focus on strategies to make myeloablative regimens safer. It may be premature to abandon myeloablative allotransplants before adequate follow-up data in the NST/RICT setting. The decision to proceed to an allograft approach needs to be made in conjunction with the choices of a wellinformed patient. Initial risk stratification, response to induction therapy, chemosensitivity, presence or absence of defined cytogenetic abnormalities, availability of a donor, performance status as well as the patient s desires need to be taken into account. Even so considering the short follow-up data and the minority who appear to have a probability of a molecular CR or long-term cure, we do not feel that the possibility of cure be used to justify any allograft modality outside of clinical trials. Maintenance therapy IFN Maintenance therapy is a well-recognized strategy to prolong disease-free survival after primary therapy, either chemotherapy or transplant. Ideally, maintenance treatment should bear minimal side effects, be active against myeloma, simple to administer and, ultimately, improve EFS and OS. Among the different maintenance regimens described, single-agent IFN-a has been the most studied after CC where the improvement in EFS and OS is marginal. In the transplant setting, Cunningham et al. 126 studied the role of IFN maintenance after autologous HSCT in patients who responded to transplant. Although initial data showed improved PFS and OS in patients randomized to IFN maintenance, with longer follow-up, no differences in PFS or OS were appreciated. The largest randomized trial is the US Intergroup S9321 study. Upon completion of either HSCT or VBMCP, responding patients were randomized to IFN versus observation. The results showed no significant benefit for IFN maintenance in either arm. 15,107 Finally, a retrospective database analysis from the EBMT registry compared patients who received IFN or observation. IFN appeared to improve PFS and OS (Table 6), with patients who achieved less than a CR after HSCT benefiting the most from IFN maintenance. 127 In summary, there is no basis for the use of IFN maintenance outside of a well-designed clinical trial. Currently, only the GMMG-HD3 trial is continuing to evaluate IFN maintenance. Corticosteroid-based approaches Although there is one published trial and one trial presented in abstract supporting steroid maintenance therapy following CC, 128,129 there are no published trials of maintenance corticosteroids following HSCT. The Arkansas group TTI and TTII 81 use IFN-based maintenance therapy, which is continued until disease relapse. TTII added consolidation chemotherapy after the second autologous transplant including alternating cycles of dexamethasone, cyclophosphamide, etoposide (DCEP) Table 6 Maintenance after primary myeloma therapy Study N Maintenance PFS (months) OS US Intergroup Trial S IFN 25 versus 21 (P ¼ 0.05) 58 versus 53 (P ¼ 0.8) Cunningham IFN NS a NS a EBMT IFN 29 versus 20 (P ¼ 0.006) 78 versus 47 (P ¼ 0.007) HOVON-50 b IFN 13.5 versus 8.5 (P ¼ 0.04) 41 versus 38.4 NS Berenson et al. b Pred 14 versus 5 (0.03) 37 versus 26 (P ¼ 0.05) NCIC MY7 b Dex 33 versus versus 43.8 Arkansas TT2 versus TT1 b (TT2) 231 (TT1) IFN 50 versus 25 (Po0.001) 70 versus 60 (P ¼ 0.06) NCIC MY Thal+Pred % at 1 year IFM , Thal+Pam Pam Obs a Outcomes at 77months. b Studies that include maintenance after a primary treatment other than transplant. PFS ¼ progression-free survival; OS ¼ overall survival; IFN ¼ interferon-a; OR ¼ odds ratio; NS ¼ not statistically significant; Pred ¼ prednisone; Dex ¼ dexamethasone; TT1/TT2 ¼ Total Therapy I and II; Thal ¼ thalidomide; Pam ¼ pamidronate; NR ¼ not reported NS

11 and cisplatin, cyclophosphamide, adriamycin, dexamethasone (CAD) during the first year post transplant. IFN maintenance with monthly pulsed dexamethasone is started after consolidation. In historical comparison to TTI, TTII has improved remission rates and 5-year EFS (50 versus 55%, Po0.0001). However, at 4-year median follow-up, there is not yet a difference in OS. It is unclear whether EFS improvement is secondary to maintenance therapy with dexamethasone and IFN in combination, consolidation chemotherapy, upfront thalidomide or generally therapy intensification. It is important, however, to note that the Total Therapy results are not randomized and represent single institution data achieved in a highly select patient population. Immunomodulators Novel antimyeloma agents are also being evaluated as maintenance therapy. Thalidomide has shown promise as maintenance therapy post-hsct. Preliminary results of the randomized IFM trial demonstrated improved PFS in the thalidomide plus pamidronate arm compared to no maintenance or pamidronate alone (56 versus 37 and 34%, respectively; P ¼ 0.01; median follow-up 36 months). At the time of the interim analysis, there were no differences yet observed in OS. 130 Despite initial good results, the use of thalidomide is associated with significant side effects that are dependent upon dose and treatment duration. For example, in the recently reported NCIC-MY9, which randomized patients to 200 or 400 mg of thalidomide combined with alternate-day 50 mg prednisone, the 400 mg arm was prematurely stopped due to excessive toxicity. However, although 31% of patients in the 200 mg thalidomide arm required dose reductions, 76% of the patients were able to continue maintenance beyond 18 months. 131 Several ongoing trials include immunomodulator maintenance therapies (Table 7). The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0102) trial randomizes patients in the tandem HSCT arm to 1 year of thalidomide 200 mg/day plus dexamethasone 40 mg for 4 days monthly or observation. The joint HOVON- 50/GMMG-HD3 trial randomizes patients to either IFN or thalidomide at a dose of 50 mg daily after tandem HSCT. The NCIC/ECOG MY10 study compares prednisone 50 mg every other day plus thalidomide 200 mg to observation after a single autologous HSCT. The thalidomide analog, lenalidomide, is being evaluated in the CALGB/ECOG post transplant maintenance trial. This trial utilizes lenalidomide at a dose of 10 mg versus placebo after a single HSCT. Lastly, bortezomib has been added as consolidation and maintenance along with thalidomide and dexamethasone in the Arkansas TTIII program. Tables 6 and 7 summarize the role of maintenance therapy after primary treatment and our recommendations for post transplant maintenance. Recovery of target organ dysfunction after transplant The current paradigm for the diagnosis and initiation of therapy in MM is related to myeloma-related organ dysfunction as opposed to paraprotein levels. 132 Consequently, curative intent therapies should ideally go beyond paraprotein responses and address the fate of these organ manifestations. However, such organ assessments have not been part of the major randomized transplant trials in MM. Recovery of myeloma-related organ damage depends, for the most part, on overall response to therapy and extent of pre-existing organ damage. For instance, dialysis duration p6 months, pretransplant creatinine clearance 410 ml/min and a greater than partial remission after HDT significantly increase the possibility of becoming dialysis independent after autologous HCT. 133 Myeloma-induced renal impairment is thus potentially reversible with HDT although this comes with an excess TRM, which may approach 17% Re-establishing skeletal integrity and minimizing fracture risk is the optimal goal for decreasing myeloma-related skeletal morbidity. While autografting may help normalize biochemical markers of bone turnover, 136,137 lytic bone lesions are unlikely to disappear even after successful myeloma treatment. Magnetic resonance imaging evaluations before and after transplants have not added prognostic information or correlated with quality of response. 138 Addition of pamidronate to a maintenance schedule was demonstrated in the IFM trial to significantly decrease bone events post transplant. 130 The 11 Table 7 Post transplant maintenance options recommendations Agent/regimens Dose Pros Cons Currently open trials Interferon 3 mu t.i.w. Marginal improvement in PFS No survival benefit HOVON/GMMG-HD3 Prednisone (Pred) 20 mg q.o.d. Prolong PFS Steroid side effects Thalidomide (Thal) mg Prolong PFS (IFM 99-02) Neuropathy, DVT HOVON/GMMG-HD3 Revlimid 10 mg No available results DVT, myelosuppression ECOG/CALGB Combinations Thal+Pred Thal+dexamethasone (Dex) Recommendations Good tolerability, 76% of patients on maintenance after 18 months (NCIC MY9) Risk for compound side effects ECOG/NCIC MY10 BMT CTN # /50 200/40 1. Clinical trial 2. In absence of a clinical trial, thalidomide 100 mg and Dex 40 mg 4 days (either 4 consecutive days or once a week). If the patient has not been treated with this regimen or responded to this regimen as induction therapy. If no response to Thal/Dex induction, no maintenance. Duration of treatment is still unknown; however, most studies include 1 2 years post transplant or until relapse or disease progression

12 12 length of such biphosphonate therapy post transplant is unknown and should be guided by disease activity and the risk of side effects. Bone mineral density and bone turnover (N- and C-terminal crosslinking telopeptide of type I collagen assays) monitoring might assist in deciding the length of therapy. 137,139,140 There are no large studies addressing post transplant immune reconstitution, specifically in MM. Early lymphocyte recovery after HSCT has been associated with superior outcomes in MM. 141 In addition, high autologous lymphocyte cell doses ( /kg) have been correlated with early lymphocyte recovery and longer survival rates compared to lower lymphocyte doses. 142 As in any transplant setting, immune reconstitution in MM depends on the type of transplant, conditioning regimen and GVHD prophylaxis, graft manipulation and disease response. CD4 þ T-cell recovery kinetics after allogeneic PBSC transplant in MM may be more rapid than in other hematological malignancies. 143 Comparative kinetics of immune reconstitution after single and tandem transplants may have significant implications in terms of post transplant morbidity; however, this has not been the focus of published studies. Conclusions Randomized clinical trials have firmly established the role of upfront autologous HSCT in newly diagnosed MM. While novel agents alone or in combination might result in Newly diagnosed multiple myeloma Patient eligible for high dose therapy Risk stratification: International Staging System Conventional karyotype FISH for high-risk chromosomal abnormalities (esp. 13, IgH locus translocations) Co morbidities and organ function assessment Availability of HLA identical sibling donor Standard risk Biologically defined High risk Consider clinical trial for novel induction therapy, transplant and maintenance Standard of care: Cell collection adequate for 2 HSCT Single autologous HSCT If <90% reduction in paraprotein not achieved at 3 months post transplant - proceed to second HSCT In patients not proceeding to tandem HSCT, consider second transplant at relapse /progression if > 1 year. Strongly recommend clinical trial for induction, transplant and maintenance Allogeneic transplant: conventional or NST on a clinical trial (not as salvage) Questions for clinical trials: Role of novel induction strategies to achieve higher CRs Type of transplant: Tandem auto/auto followed by maintenance or sequential auto/nst Role of conventional myeloablative allogeneic transplant Novel agents for maintenance therapy -single agents or combinations after HSCT -novel therapy with/without empiric DLI after NST -delayed intensification / consolidation after autologous transplant Figure 2 Summary of recommendations.

13 comparable CR rates to single HSCT, there is currently insufficient data to abandon HSCT. With additional time, the newer agents may either supplant transplantation or change our current algorithm by delaying transplants until disease relapse since there is evidence that delayed transplantation is efficacious. Thus, we doubt that transplants will be replaced even by highly active newer therapies and will remain in our treatment armamentarium. Tandem HSCT has consistently shown better EFS compared to single autologous HSCT, but, to date, only the IFM 94 has shown an OS advantage. Given the improvement in salvage therapies, EFS coupled with quality of life end points (not OS) should be the primary outcome measure of transplant trials. Therefore, our recommendations (Figure 2) are to collect sufficient autologous stem cells for at least two transplants and proceed to tandem HSCT if the patient does not enter at least a very good partial remission (defined as a decrease in paraprotein by 490% from diagnosis) after the first HSCT. We consider this the standard of care at this time. For those patients who do achieve a very good partial remission, near CR or CR, a second transplant should be considered at the time of disease progression. Initial disease evaluation should include conventional cytogenetics and interphase FISH that includes a panel of probes directed to chromsome13, the locus of IgH and its translocation partners. Such biologically defined adverse risk factors (D13, t(4;14)) confer an extremely high risk of relapse despite tandem HSCT and other established strategies. Autologous transplants, either single or tandem, should not be routinely utilized in this group of patients owing to their lack of proven efficacy. These patients should be treated aggressively on innovative clinical trials wherever possible. In the absence of a survival plateau in any of the current nonrandomized NST/RICT data, the ongoing randomized trials of sequential nonmyeloablative transplant strategies will define the role of this modality. However, current evidence indicates that this strategy should be reserved only for those patients early in their disease course (not as salvage) with chemosensitive disease who are enrolled on a well-designed clinical trial. It is the physician s responsibility to have in-depth discussions with these patients since the promise of a cure may be too optimistic. Conventional allogeneic transplantation should be considered in younger patients early in their disease course with good performance status and acceptable physiologic organ function: there are data that a minority of these patients may indeed be cured. Allogeneic transplant strategy for MM needs to be continually re-evaluated in the changing context of novel induction strategies, better anti-gvhd prophylaxis, maintenance therapy, minimal residual disease monitoring and improving supportive care. The role for IFN maintenance is ill defined after transplant and we do not recommend its use. Instead, patients should be encouraged to participate in maintenance trials of the newer antimyeloma agents that have shown promise post-hsct. Ultimately, the benefits in terms of time to progression must be proven and balanced against the potential for increased toxicity, which may adversely impact quality of life. 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