Allogeneic stem cell transplantation and targeted immunotherapy for multiple myeloma.

Multiple Myeloma

Allogeneic Stem Cell Transplantation and Targeted Immunotherapy for Multiple Myeloma Ivetta Danylesko, Avichai Shimoni, Arnon Nagler Abstract Multiple myeloma (MM) is a life-threatening hematological malignancy. The graft vs. myeloma effect is the basis of immunological strategies for treatment of MM. Autologous stem cell transplantation causes effective cytoreduction, but most patients subsequently relapse. Allogeneic stem cell transplantation (alloSCT) causes durable responses. The antitumour immunity mediated by lymphocytes of the donor achieves complete remission (CR) and molecular CR for 50% of patients with a long-term freedom from the disease and a cure for 20% to 25% of patients. Early attempts using myeloablative conditioning suffered from high, up to 50%, TRM. With a reduction of the toxicity of the conditioning and introduction of approaches applying reduced intensity conditioning, the results for alloSCT improved. However, they are still deficient because of continued disease progression and relapse after transplantation. Intense research effort concentrates on developing strategies to minimize remission and prevent relapse of MM after alloSCT. This review surveys the results of ongoing and recently published clinical trials. It also includes aspects of immunotherapy in combination with stem cell transplantation. Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. S2, S330-48 ª 2013 Elsevier Inc. All rights reserved. Keywords: Allogeneic transplantation, Donor lymphocytes infusion, Freedom from progression, Molecular remission, Tandem transplantation

Introduction Multiple myeloma (MM) remains a mostly incurable disease despite the recent availability of novel anti-MM agents that, especially when used in various combination regimens, have dramatically improved the initial response rates.1,2 Therefore, new approaches that induce long-term tumor regression and improve the treatment outcome are needed and urgently sought. The concept of high-dose therapy (HDT) supported by autologous stem cell transplantation (ASCT) for treatment of MM results in effective cytoreduction. It was developed in the 1980s,3,4 and since the mid-1990s, has been considered the first-line therapy for younger patients.5 However, the curative outcomes remain elusive because of the persistence of chemotherapy-resistant disease.6 In MM, it is becoming clear that the deeper the response, the longer the survival.7-9 Achievement of complete remission (CR) after ASCT has become an important surrogate marker for prolonged

Division of Hematology, Bone Marrow Transplantation and Cord Blood Bank Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel Submitted: May 6, 2013; Accepted: May 6, 2013 Address for correspondence: Arnon Nagler, MD, MSc, Department of Medicine, Tel Aviv University, Hematology Division and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer Israel Fax: þ972-3-5304792; e-mail contact: [email protected]

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survival in MM.7 Achievement of a better response before ASCT using novel agents might also improve the outcome after transplant.10 Allogeneic stem cell transplantation (alloSCT) is the most effective way to achieve molecular CR for treatment of MM11 leading to a long freedom from the disease and plateau in the overall survival (OS) curve, indicating the ability to cure a subset of patients with MM. Corradini et al demonstrated that a molecular remission achieved after a myeloablative (MA) conditioning was associated with possible cure, whereas patients with persistent minimal residual disease were destined to develop disease recurrence.11 This was determined using a polymerase chain reaction of an immunoglobulin gene rearrangement which generates a clone-specific molecular marker. However MA alloSCT is historically associated with up to 50% transplant-related mortality (TRM).12-14 The reduced intensity conditioning (RIC) approach that is based on the graft-vs. myeloma (GvM) effect rather than on high-dose chemotherapy revolutionized the field because it significantly decreases TRM. These reduced toxicity pre-alloSCT regimens are designed for elderly medically infirm patients with comorbidities.15 They are optimal for patients with a median age at diagnosis of 65 to 70 years and only 7% for patients younger than 55 years.15 RIC alloSCT also induced molecular CR but relapse rates were typically higher than in the MA alloSCT sequence.16 The role and the timing of alloSCT in the course of the disease are still debatable. It is currently still controversial whether the combined auto-alloSCT approach offers an advantage over standard

2152-2650/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.05.021

salvage therapy followed by RIC in the salvage setting, and whether an alloSCT should be offered as a part of a first-line treatment or as a salvage therapy for recurrent/refractory disease. As indicated, despite the debate, alloSCT is currently one of the best treatments for long-term disease control. This could be in part because of the GvM effect, mediated by immune-competent donor lymphocytes, best illustrated by the induction of molecular remissions after donor lymphocyte infusions (DLIs).17 It could also be because of absence of contaminating myeloma cells in the donor graft and thus the documented lower levels of residual disease.18,19 Traditionally, the high risk of TRM (30%-60%) among young, medically fit patients has limited the use of allogeneic transplants.14,20,21

Myeloablative AlloSCT Multiple studies have shown that alloSCT with standard MA conditioning are potentially curative for myeloma. They consistently showed a plateau in the range of 30% to 40% of patients, years after alloSCT.12,14,22-24 In the Southwest Oncology Group SWOG9321 in a randomized trial, patients with a donor received MA alloSCT. The 7-year OS rate was 39% and the progression-free survival (PFS) rate was 22%.12 However, the allogeneic arm was closed prematurely after enrolling only 36 patients because of a 1-year nonrelapse mortality (NRM) of 53%. Similar NRM rates of 30% to 50% have been reported in other studies.13,14 Therefore, although disease recurrence rates with alloSCT were lower than with ASCT, these high rates of NRM resulted in OS that was better, in an earlier European Group for Blood and Marrow Transplantation (EBMT) study, with ASCT.13 Later EBMT studies demonstrated improvement in NRM rates in more recent years, mostly because of better patient selection, but possibly because of improvement in supportive care, yet this has not led to wider use of this approach.22,25

Reduced-Intensity Conditioning AlloSCT Reduced intensity conditioning regimens were developed to reduce NRM and to allow alloSCT for elderly and medically infirm patients.15 Several reduced-intensity regimens have been reported, including melphalan 100 mg/m2 to melphalan 140 mg/m2 (MEL140) with or without fludarabine, 2 Gy total body irradiation (TBI) with or without fludarabine, and intermediate-dose busulfan (BU). Antithymocyte globulin (ATG) or alemtuzumab have also been used for in vivo T-cell depletion to reduce the incidence of graft vs. host disease (GVHD).26-33 A regimen of TBI (800 cGy total) with ATG can decrease the incidence of GVHD after alloSCT to 3% without impairing the graft vs. tumor activity.34 This immunosuppressive protocol might cause a greater reduction in the alloreactivity of donor CD4þ T cells than would a single dose of TBI (200 cGy). Reduced-intensity conditioning rapidly became a promising approach to investigate in relation to myeloma, for which NRM was historically a major limiting factor. A retrospective large study of the EBMT compared the outcome after RIC (320 patients) and MA alloSCT (196 patients).16 RIC was found to reduce NRM (24% vs. 37%), but this rate was offset by an increase in disease recurrence

rates (54% vs. 27%), resulting in similar OS.16 Several studies of RIC allografts from either matched or unmatched donors have shown that the results are generally poor, especially when patients have refractory disease or in whom previous ASCT has failed; the 2-year survival rates range from 26% to 50%.26 Bensinger et al reviewed results of alloSCT for MM beginning in 1975 aiming at identifying factors associated with improvement for disease-free survival and OS because preparative regimens have changed from ablative to non-MA.35 Ablative alloSCT was used as a stand-alone therapy. In contrast, nonablative alloSCTs were performed in most patients, 2 to 4 months after recovery from a standard ASCT. The ASCT was used to provide cytoreduction before the nonablative alloSCT, yet allow the patient time to recover from the effects of HDT used for ASCT. Maintenance therapies were not used after alloSCT. In this retrospective review, significant improvements were observed in the TRM associated with the introduction of non-MA conditioning. The survival at 10 years from transplant was significantly superior for nonablative transplant patients, 35% compared with 15%.35 These analyses are in agreement with other studies showing previous autograft failure as one of the major risk factors for disease progression after non-MA alloSCT.36

Effect of Acute and Chronic GVHD on Relapse and Survival After Reduced Intensity Conditioning AlloSCT In recipients of alloSCT after traditional MA conditioning, the GvM effect is suggested by the fact that chronic GVHD (cGVHD) correlates with CR.37 However, other studies report no correlation.38 Despite the beneficial GvM effect, the high treatment-related mortality, mainly related to GVHD, has made MA-alloSCT unattractive compared with autologous transplants or novel agents.12,39 A retrospective study by Crawley et al showed that cGVHD was associated with superior survival in patients treated with RIC alloSCT.25 Unlike these data, another prospective study suggested no correlation between cGVHD and response in patients undergoing ASCT followed by alloSCT for MM.38 This phenomenon might be because of the non-MA conditioning, which does not favor GVHD yet allows a graft vs. myeloma effect.40 Ringden et al analyzed the effect of acute and cGVHD on outcomes in myeloma patients undergoing tandem auto-RIC alloSCT and the single upfront alloSCT (not preceded by autotransplant) settings.41 Limited cGVHD significantly decreased the risk of myeloma relapse (relative risk [RR], 0.35; P ¼ .035) and was associated with superior event-free survival (EFS) (RR, 0.40; P ¼ .027).41 In the comparison between allo-only and auto-allo cohorts, there were significantly lower early relapses and superior EFS in the auto-allo group, compared with the allo-only group.41

Salvage ASCT Relapse and disease progression are major obstacles for successful MM therapy. Several reports focused on a second salvage ASCT after relapse of the initial ASCT.42-47 These studies demonstrated that second salvage ASCT was feasible and reasonably effective. Results of several studies suggested that the time to progression (TTP) after first ASCT or the interval between transplants is an


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ASCT and Immunotherapy for MM important predictor of the outcome of second ASCT.42,43,45-47 In the retrospective study, Fenk et al reported on 55 patients who were treated with salvage HDT.45 Treatment-related mortality was only 5% and response rates were as follows: 9% CR, 9% very good partial response (VGPR), 56% partial response (PR), 11% minimal response (MR) with stable disease (SD), and 4% progressive disease (PD) (5% not assessable). Toxicity was moderate and the median EFS and OS were 14 months and 52 months, respectively. Patients with an early relapse after their first transplant do not benefit from this treatment modality.45 The retrospective Canadian study showed that the best outcome was observed in patients whose TTP was > 24 months after first ASCT, because these patients had a subsequent PFS lasting more than 1 year and an OS of almost 6 years.42 There is emerging evidence suggesting that novel agent-based systemic chemotherapy might be effective for treating relapsed patients.48-51 Yhim et al investigated the outcomes of second salvage ASCT in patients who relapsed, attempting to identify the effects of a second ASCT compared with salvage systemic chemotherapy alone.52 Forty-eight patients who underwent a second salvage ASCT were compared with 144 patients treated with salvage systemic chemotherapy alone using a matched-pair method.52 Regimens given after relapse of first-line ASCT were similar between the 2 groups; more than 80% of patients received novel therapies, including bortezomib and thalidomide. The PFS and OS of the second ASCT group were significantly better than those of the systemic chemotherapy-alone group (PFS, P ¼ .017; OS, P ¼ .035). The good prognosis subgroup was composed of patients who had TTP of > 18 months after their first ASCT and International Staging System (ISS) I or II, whereas the poor prognosis subgroup was composed of patients with a TTP of 18 months or less after first ASCT or ISS III. In an analysis of the good prognosis subgroup, OS was not different between the second ASCT group and the systemic chemotherapy-alone group (median, 75.3 vs. 77.3 months, respectively; P ¼ .919), whereas in the poor prognosis subgroup, OS was significantly longer in the second ASCT group than in the systemic chemotherapy-alone group (median, 49.9 vs. 17.2 months, respectively; P ¼ .026). As with all other observational studies, this study has limitations. The present analysis is retrospective and is based on a small number of patients. In addition, the choice of therapy after relapse was often governed by a complex list of unmeasured factors that could affect the outcomes. A prospective randomized trial is thus required to compare the different therapies such as second ASCT or systemic chemotherapy for relapsed MM. Second ASCT after a short course of novel induction therapies might be a reasonable option for overcoming the adverse prognosis and the biologic aggressiveness of the tumors after relapse.

Tandem ASCT Although ASCT is safe with a TRM rate of < 2%, it is associated with a continuing risk of disease relapse.53 Disease recurrence is presumably secondary to persistent disease in the bone marrow after transplant because of drug resistance and/or the reinfusion of contaminating malignant plasma cells in the stem cell graft.54 In an effort to reduce minimal residual disease after ASCT, additional therapies have been delivered either with a second ASCT in a tandem fashion or with an RIC followed by alloSCT.

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Several randomized trials have found benefit with tandem vs. single ASCT, with the benefit primarily seen in patients failing to achieve CR or VGPR with the first ASCT.55,56 Two other randomized trials, however, have yet to show significant improvement in OS with double ASCT.57,58 In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with SD and 31 with PD), ie, who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant).59 There were no significant differences in the rates of PR or better between patients with SD or PD. However, 38% of the patients with SD at the time of transplantation remained in a stable condition or achieved an MR after transplantation vs. 7% in the group with PD (P ¼ .0017) and the rate of early progression after transplantation was significantly higher among the group with PD at the time of transplantation (22% vs. 2%; P ¼ .0043). These results show that patients with unresponsive PD do not benefit from ASCT. For this reason, novel treatment approaches, including experimental drugs, should be offered to these patients. In contrast, patients with nonresponding, non-PD have a good outcome with an OS comparable with that of patients with chemosensitive disease.59

Tandem Autologous-AlloSCT A novel treatment modality was designed for patients with newly diagnosed MM in whom an initial ASCT is followed by RICalloSCT approximately 2 to 4 months later. The rationale for the tandem auto-alloSCT approach was to separate in time cytoreduction with standard high-dose melphalan 200 mg/m2 and the graft vs. myeloma effect with the potential for dramatically reducing the TRM. This combination has lowered TRM to approximately 15%.60,61 The initial multicenter prospective trial by the Seattle Consortium enrolled 54 newly diagnosed patients with stage II to III myeloma.60 Half of the patients had refractory or relapsed disease. The CR and TRM rates were 57% and 22%, respectively. After a median follow-up of 60 months, the OS rate was 69% and the PFS rate was 38%.60 The long-term outcomes using the same approach after 6.3 years of follow-up was reported, even though the tandem autoealloSCT was not used in the first-line setting in all patients.62 Grade II to IV acute GVHD occurred in 42% of patients and 74% experienced cGVHD. The TRM rate at 5 years was 18%, primarily because of GVHD and/or infections. The overall response rate was 94% (CR, 65%; PR, 29%). The OS and PFS rates were 64% and 36%, respectively.62 Although RIC-alloSCT induces high rates of CR, even in refractory disease,28 it appears to result in a durable response only if it is applied early in the disease in high-risk patients, when they are still chemosensitive and have an adequate performance status,28 with better results for patients treated early (< 10 months from the start of the initial therapy).62 To evaluate alloSCT for myeloma as a part of first-line therapy, a donor vs. no-donor analysis was performed on patients treated in the HOVON-50 (Hematologie Oncologie Volwassenen Nederland-50) study.63 In this study, the effect of thalidomide combined with ASCT was evaluated.64 In addition, the study allowed patients with a human leukocyte antigen (HLA)- identical

Table 1 Tandem Autologous-allogeneic Stem Cell Transplantation Study/Conditioning Protocol

Type of Study/Follow-Up

Disease Status After ASCT (Before alloSCT)

Response After alloSCT

Survival/Relapse

TRM/GVHD

Rotta et al, 200962 HD melphalan with ASCT followed by 2-Gy TBI, with or without FLU with alloSCT

n ¼ 102 patients; median age 50 (range, 34-70) years

Retrospective; only siblings; median follow-up of 6.3 years

CR, 7 (7%); VGPR, 19 (18%); PR, 52 (50%); RD/SD, 17 (16%); PD, 10 (10%)

Among 83 patients who had detectable disease before allografting, 47 (57%) obtained CR at a median of 208 (range, 28-773) days after allografting

Median OS has not been reached. Median PFS, 3 years. 5-year estimated OS, 64%; PFS, 36%. Median TTR after alloSCT, 5 years

5-year NRM, 18%; Grade 2-4 aGVHD, 42%; extensive cGVHD, 74%

Kroger et al, 200261 1. ASCT with MEL200 2. After an interval of 3 months, RIC: MEL100, FLU 180 mg/ m2, and ATG 3 10 mg/kg BW

n ¼ 17; median age, 51 (range, 32-64) years

Advanced MM, stage II/III; follow-up, 2 years

CR, 3 (18%); PR, 10 (60%); MR 1 (6%)

CR, 11 (73%); PR 3 pts

2-year estimated OS, 74%; DFS, 56%

Lokhorst et al, 201263 1. VAD or TAD 2. MEL200 with ASCT 3. Patients randomized to arm VAD received maintenance therapy with a-interferon 4. Arm B received 50 mg of thalidomide daily starting between 2 and 3 months after MEL200 until progression Patients with a fully matched (10/10) HLA-identical sibling donor could proceed to allo-RIC between 2 and 6 months after ASCT; conditioning TBI 2 Gy

Nondonor group, 138 pts; donor group, 122 pts; median age, 54 (range, 32-65) years

Prospective, donor vs. no donor analysis; HLA-identical sibling only; follow-up, 6 years

AlloSCT group: CR, 16 (16%); VGPR, 42 (42%); PR, 36 (36%); MR, 5 (5%)

CR was 43% in the donor group vs. 37% in the no donor group (P ¼ .67)

Estimated OS, 61%, alloSCT; PFS at 6 years was 28% for patients with a donor vs. 22% for patients without a donor (P ¼ .19); the cumulative incidence of relapse at 6 years was significantly higher in the no donor arm (77% vs. 55%; P ¼ .005)

Conclusions

1. In multivariate analysis, b2MG of more than 3.5 mg/mL at diagnosis and auto/alloHCT more than 10 months after treatment initiation correlated with shorter OS (P ¼ .03 and P ¼ .02) and PFS (P ¼ .04) 2. Karnofsky scores less than 90% at alloSCT correlated with shorter PFS only (P ¼ .005) Severe Grade 3 GVHD, 1. The incorporation of 2 (13%), Grade 4, 0; ATG into the preparative cGVHD, 6 (40%) regimen might have contributed to the low incidence of severe GVHD 2. The rate of CR increased from 0% after induction or salvage therapy to 18% after autografting and to 73% after allografting At 6 years: NRM, 16% in 1. Higher ISS stage (I vs. II the donor group vs. 3% vs. III) and also b2MG more than 3 mg in the no donor group independently affected (P < .001); aGVHD, PFS and OS in the whole 48% pts total; Grade 3, group of patients, 3 pts (4%); Grade 4, whereas the treatment 4 pts (5%); extensive arm in the HOVON-50 cGVHD, 44 pts (55%) study (VAD vs. TAD) or chromosome 13 abnormalities determined using classic cytogenetics or FISH analysis had no influence 2. It is suggested that alloRIC should be performed as part of a clinical trial, preferably including patients with a poor prognosis such as those with a rapid relapse after first-line therapy or having (very) unfavorable features such as the presence of 17p

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Ivetta Danylesko et al


Number of Patients/Age

Abbreviations: b2MG ¼ beta-2 microglobulin; aGVHD ¼ acute graft vs. host disease; allo ¼ allogeneic; alloHCT ¼ allogeneic hematopoietic cell transplantation; alloSCT ¼ allogeneic stem cell transplantation; ASCT ¼ autologous stem cell transplantation; ATG ¼ antithymoglobulin; BW ¼ body weight; cGVHD ¼ chronic graft vs. host disease; CR ¼ complete remission; DFS ¼ disease free survival; FISH ¼ fluorescence in situ hybridization; FLU ¼ fludarabin; GVHD ¼ graft vs. host disease; HD ¼ high-dose; HLA ¼ human leukocyte antigen; HOVON-50 ¼ Hematologie Oncologie Volwassenen Nederland-50; ISS ¼ International Staging System; MEL100 ¼ melphalan 100 mg/m2; MEL200 ¼ melphalan 200mg/m2; MM ¼ multiple myeloma; MR ¼ minimal response; NRM ¼ non-relapse mortality; OS ¼ overall survival; PD ¼ progressive disease; PFS ¼ progression-free survival; PR ¼ partial response; pts ¼ patients; RD ¼ refractory disease; RIC ¼ reduced intensity conditioning; SD ¼ stable disease; TAD ¼ thalidomide, adriamycin, dexamethasone; TBI ¼ total body irradiation; TRM ¼ transplant-related mortality; TTR ¼ time to relapse; VAD ¼ vincristine, adriamycin, dexacortisone; VGPR ¼ very good partial response.

For patients with poor-risk, relapsed, or refractory MM, cytoreductive ASCT followed by nonmyeloablative conditioning and unrelated alloSCT is an effective treatment approach, with low NRM, high CR, and prolonged DFS The 3-year NRM, 21%; aGVHD: Grade 2, 54%; Grade 3, 13%; cGVHD, 75% At 3 years: OS, 61%; PFS, 33% CR, 10 pts (42%); PR, 4 pts (17%) RD, 17 pts (71%); disease relapse or progression after previous ASCT, 14 (58%) Unrelated donor; only poor risk MM; follow-up, 3 years after allografting n ¼ 24 pts; median Georges et al, 2007 FLU 90 mg/m2 and 2 Gy age, 50 (range, 29-66) of TBI years

TRM/GVHD Survival/Relapse Response After alloSCT Disease Status After ASCT (Before alloSCT) Type of Study/Follow-Up Number of Patients/Age

-

Study/Conditioning Protocol

Table 1 Continued

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Conclusions

ASCT and Immunotherapy for MM


sibling donor to proceed to the alloSCT after RIC between 2 and 6 months after ASCT. Only a single ASCT followed by maintenance was applied on nonealloSCT patients. Double ASCT also was allowed in the HOVON-50 study but was only applied on 3 patients.63 No significant differences with respect to CR, PFS, and OS were found after mature follow-up of more than 6 years. However, PFS curves started to diverge after 36 months in favor of the donor group and the cumulative incidence of relapse at 6 years was significantly higher in the no-donor arm (77% vs. 55%; P ¼ .005).63 Tandem auto-RICealloSCT resulted in good response rates with low TRM, but the long-term benefit remains unclear, as does the curative potential. It is also uncertain which patient subgroups are most likely to benefit.16,25,28,29,65 The role of allografting, however, might prospectively be evaluated in selected high-risk patients in whom life expectancy remains very poor despite the use of bortezomib and lenalidomide.66 Table 161-63,65 summarizes several trials of tandem auto-alloSCT in patients with newly diagnosed and relapsed MM after ASCT.

Tandem Autologous Vs. Autologous-AlloSCT Recent trials comparing the platform of tandem auto-alloSCT with a tandem autologous approach are summarized in Table 2.12,40,67-73 The prospective studies with a comparable design were published by the Italian study group led by B. Bruno,40,72 by the EBMT,71 and recently by Blood and Marrow Transplant Clinical Trials Network (BMT CTN).73 A protocol began with induction therapy followed by high-dose (HD) melphalan, with rescue of the hematopoietic system using an ASCT. After recovering from the ASCT, patients with matched related donors subsequently received an allograft.40,71-73 The multicenter phase III trial (BMT CTN 0102) did not show added benefit of the auto-alloSCT approach over tandem ASCT.73 However, the follow-up of this study is probably too short to draw definitive conclusions.73 In contrast, the Italian40 and the EBMT71 studies reported an improved PFS and OS for patients with a sibling donor. Transplant-related mortality did not differ significantly between the double-autologous transplant group (46 patients) and the autografteallograft group (58 patients, P ¼ .09), but disease-related mortality was significantly higher in the double-autologous transplant group (43% vs. 7%; P < .001) in the Italian group.40 Overall, 21 of 58 patients (36%) were in CR after a median follow-up of 38 months (range, 10 to 72) after allograft.40 The inter-groupe francophone du myeloma (IFM) study treated 284 newly diagnosed myeloma patients with high-risk features (elevated b2-microglobulin and chromosome 13 deletion) in 2 protocols: IFM99-03 and IFM99-04.67,68 ATG was part of the conditioning regimen. At a median follow-up of 2 years, the OS and EFS rates were 35% and 25%, respectively, in the tandem autoalloSCT cohort and 41% and 30% in the tandem ASCT cohort. These findings suggest that patients with high risk features did not benefit from a RIC alloSCT. It is possible that the administration of high-dose ATG might have hindered, to some extent, the potentially curative GvM effects because the incidence of cGVHD was only 7%.

Table 2 Tandem Auto-Auto Vs. Tandem Auto-Allogeneic Stem Cell Transplantation

Study Bruno et al, 200740 Prospective study; de novo MM; median follow-up of 46 months; HLA-identical sibling

Number

Age

Response TRM

CR

Survival

PR

RD/SD

Tandem ASCT: 1. VAD 2-3; 2. HDM with ASCT; 3. Second ASCT

Total, 82 pts; 54 (range, completed 33-65) protocol, years 46 pts

After induction (before the first ASCT): CR, 1; PR, 22 pts; before the second ASCT: CR, 4; PR, 31; RD, 11 pts

At 2 years, 2%

12 (26%) pts

29 (63%) pts

11%

54 months

29 months

Auto-alloSCT: 1. VAD 2-3; 2. HDM with ASCT; 3. TBI 200 cGy


At 2 years, 10%

32 (55%) pts; 18 (31%) pts 21 (36%) were in CR after a median follow-up of 38 months

14%

80 months

35 months

Tandem auto 1. VAD 2-3; 2. HDM with ASCT; 3. IntermediateDose, 100 mg/ m2 or HD: MEL140-200


After induction (before the first ASCT): CR, 3; PR, 29 pts; at the time of allografting: CR, 8; PR, 36 pts After induction (before the first autograft): CR, 1; PR, 22 pts; before the second autograft: CR, 4; PR, 31; RD, 11 pts

11%

5.3 years

Median At a median follow-up of 7.1 EFS, 2.4 years, OS and EFS were years; EFS, significantly longer in patients 33 months with HLA-identical siblings than those without

Median follow- 12 pts (26%) up of 6.5 years from ASCT,1(2%)

29 pts (63%)

OS, Median PFS, Median

Conclusions 1. The rate of CR was significantly higher in the autografte allograft group than in the double autologous-transplant group 2. Among patients with newly diagnosed myeloma, survival in recipients of an ASCT followed by a stem cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem cell autografts 3. Among patients who completed their assigned treatment protocols, TRM did not differ significantly between the double-autologous transplant group and the autograftallograft group, but diseaserelated mortality was significantly higher in the double-autologous transplant group (43% vs. 7%; P < .001)

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Giaccone et al, 201172 Long-term (median follow-up, 7 years (Bruno et al, 200740) (Clinicaltrials.gov number, NCT00415987)12; newly diagnosed MM; HLA-identical sibling

Transplant

Disease Status Before Transplant

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Study

Garban et al, 200667 Prospective; de novo MM; high-risk MM (b2MG greater than 3 mg/L and chromosome 13 deletion); median follow-up, 24 months. AlloSCT: HLAidentical sibling

Transplant

Number

Age

Auto-allo: 1. VAD 2-3; 2. HDM with ASCT; 3. TBI 200 cGy

Total 80 pts; completed protocol: 58 pts

54 (range, 33-65) years

Tandem Auto 1. VAD x 4 2. MEL200 þ ASCT 3. ASCT MEL220 þ/anti-L6. IFM 9904 trial

Total 219 pts 58 (range, Completed 28-65) protocol years 166 pts

Auto-allo: Total, 65 pts; 54 (range, 1. VAD 4; complete 36-65) 2. ASCT MEL200; protocol, years 3. Mini-allo 46 pts BU-FlU-high dose ATG; IFM 9903 trial Moreau et al, 200868 Median follow-up, 56 months

Tandem auto IFM 9904 trial

Total, 219 pts; completed protocol, 166 pts

Auto-allo IFM 9903 trial




Response TRM

After induction Median follow(before the first up of 6.5 autograft): CR, years from 3; PR, 29 pts; RIC:9(16%) at the time of allografting: CR, 8; PR, 36 pts Response rates 5%: 6 pts (CR þ VGPR) during VAD, -16% after VAD, 2 pts during 34% after the 1st ASCT, 3 pts - 2nd first ASCT ASCT

1 month after ASCT: CR, 5; VGPR, 12; combined, 17 (37.8%) pts; PR 46.6%, SD or PD, 7 (15.5%) pts Response rates (CR and VGPR): 16% after VAD; 34% after the first ASCT

1 month after ASCT: CR, 5; VGPR, 12; combined, 17 (37.8%) pts; PR, 46.6%; SD or PD, 7 (15.5%) pts

5 pts (10.9%)

CR

PR

32 pts (55%) 18 pts (31%)

CRþVGPR 51%

-

CR, 15 pts; 9 pts (20%) VGPR, 13 pts; total, 28 pts (62.2%)

Survival RD/SD


14%

Not reached; P ¼ .02

-

47.2 months

8 pts (17.8%) 35 months

Conclusions

Median EFS, 2.8 years; P ¼ .005; EFS, 39 months; P ¼ .02 EFS 35 1. The EFS of the patients in the months tandem ASCT protocol was similar to the EFS of the patients in the auto-allo protocol, with a trend for a better OS in patients treated with tandem ASCT (median, 47.2 vs. 35 months; P ¼ .07). 2. In patients with high-risk de novo MM, the combination of ASCT followed by dosereduced allogeneic transplantation was not superior to tandem doseintensified, melphalan-based ASCT EFS, 31.7 months

6 pts (5%) during VAD; 2 pts during first ASCT; 3 pts, second ASCT

e

e

e

48 months

EFS, 22 months

5 pts (10.9%)

e

e

e

34 months

EFS, 19 months

1. There was a trend for a superior OS in the double ASCT trial (median, 48 vs. 34 months; P ¼ .07) 2. The EFS did not significantly differ from tandem ASCT to single autograft followed by allo-RIC


Table 2 Continued

Table 2 Continued

Study Rosinol et al, 200869 A prospective PETHEMA study; the patients with MM failing to achieve at least an nCR after a first ASCT. AlloSCT: HLAidentical sibling; median follow-up: 5.2 years

Response

Survival

Transplant

Number

Age

TRM

CR

PR

RD/SD

Tandem auto: 1. VBMCP/ VBAD 6; 2. First ASCT; 3. Second ASCT

85 pts

55 8 years

Suboptimal response (< nCR) to the first ASCT were considered for a second transplantation

5%

11%

e

e

58 months

31 months

Auto-allo: 1. VBMCP/ VBAD 6; 2. First ASCT; 3. FLU 25 mg/m2 for 5 days with MEL70 for 2 days Tandem auto : 1. Anthracycline/ DEX induction; 2. HDM with ASCT; 3. Tandem ASCT

25 pts

52 6 years

Suboptimal response (< nCR) to the first ASCT were considered for a second transplantation

16%

40%

e

e

Not reached

Not reached

73 pts


e

e

32%

ORR 86%

14%

Projected 3-year OS, 72%

e

Auto-allo: 1. Anthracycline/ DEX induction; 2. HDM with ASCT; 3. FLU 30 mg/m2 for 3 days with MEL140; ATG (for UD)

126 pts

59%; P ¼ .003

ORR, 91%; P ¼ .003

9%

Projected 3-year OS, 60%; P ¼ .22

e

e

At 2 years, 16 pts (12.7%)


Conclusions 1. The significantly higher CR rate in the allo-RIC group; 2. There was a trend toward a higher TRM with allo-RIC; 3. With a long follow-up after the second transplantation (median, 5.2 years), there was a trend toward a longer PFS in favor of allo-RIC; 4. The EFS and the OS were not significantly different between second ASCT and allo-RIC

1. ORR was significantly higher with alloSCT; 2. Interim results show a higher CR rate in FISH 13q subjects undergoing alloSCT when compared with tandem HDM; 3. Despite most allografts in the study being delivered from unrelated donors, TRM was comparable with trials confined to sibling transplants; 4. At a relatively short follow-up, there is not yet a difference between both arms regarding OS

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Knop et al, 200970 German DSMM V trial; prospective; only pts with 13q; related and Unrelated donors (1 mismatch allowed); median follow-up, 25 months for tandem HD MEL and 34 months for alloSCT



Study

Transplant

Bjorkstrand et al, Tandem auto- or 201171 single ASCT; Prospective study; 1. VAD or previously untreated; VAD-like; HLA-identical 2. HDM with sibling; follow-up 5 ASCT; years 3. Second ASCT

Krishnan et al, 201173 Phase III study; HLA-identical sibling; follow-up, 3 years

Number 249 pts; single ASCT, 145 pts; tandem, 104 pts

Age 57 (range, 31-69) years

108 pts; 54 (range, Auto-allo: completed, 34-66) 1. VAD or VAD91 pts years like; 2. HDM with ASCT; 3. TBI 2 Gy with FLU 30 mg/m2/ d for 3 days Tandem auto: 366 pts 55 (range, 1. Induction; 22-70) 2. MEL200 with years ASCT; 3. Second, MEL200 with ASCT; 4. Observation vs. TD maintenance


Response TRM

CR, 20 (8%) pts; At 2 years 3% PR, 199 (80%) pts; SD, 30 (12%) pts

CR, 7 (6%); PR, 83 (77%); SD, 8 (17%) pts

Standard risk group: CR, 41 (9%) pts; nCR, 65 (15%) pts; VGPR, 79 (18%); PR, 158 (36%); MR, 31 (7%); SD, 21 (5%)

CR

PR

RD/SD

41%

50%

9%

43%

6%

e

e

At 2 years, 12%; 51%; P ¼ .02 P < .001

4%

Survival

164 (45%) pts; achieved CR after second ASCT: 102/ 295 (35%)


Conclusions

58%

18%; del 1. In patients with previously (13), untreated multiple myeloma, PFS at 60 long-term outcome with respect months, to PFS, OS, and RR is superior 11% after auto-allo compared with auto only; 2. Importance of prolonged follow-up; difference favoring this group did not emerge until after 2 to 3 years 65%; P ¼ .047 35%; P ¼ .001; 13q, PFS at 60 months, 31% (P ¼ .002)

OS, 95% at 1 Estimated 3year; 2 years, year PFS, 89%; 3 46% years, 80%

1. The study did not show a benefit in 3-year PFS or OS compared with tandem auto transplantation; 2. Indirect evidence of a graft vs. myeloma effect with a 60% reduction in risk of relapse in patients diagnosed with cGVHD; 3. Although much the same proportion of patients in both groups had VGPR or better, more patients in the auto-allo group upgraded their response to a CR; 4. The cumulative incidence of disease relapse or progression at 3 years was 38% (95% CI, 22-54) in patients with highrisk disease in the auto-allo group and 57% (95% CI, 42-71) in the auto-auto group (P ¼ .079)


Table 2 Continued

156 pts

Abbreviations: b2MG ¼ beta-2 microglobulin; alloSCT ¼ allogeneic stem cell transplantation; ASCT ¼ autologous stem cell transplantation; ATG ¼ antithymoglobulin; auto ¼ autologous; auto-allo ¼ autologous stem cell transplantation followed by allogeneic stem cell transplantation; BCNU ¼ adriamycin, dexamethasone; BU ¼ busulfan; cGVHD ¼ chronic graft vs. host disease; CR ¼ complete remission; DEX ¼ dexamethasone; DSMM ¼ deutsche studiengruppe multiples myelom; EFS ¼ event-free survival; FlU ¼ fludarabin; FISH ¼ fluorescence in situ hybridization; FLU ¼ fludarabin; HD ¼ high-dose; HDM ¼ high-dose melphalan; HLA ¼ human leukocyte antigen; IFM ¼ intergroupe français du myélome; MEL ¼ melphalan; MEL70 ¼ melphalan 70 mg/m2; MEL140 ¼ melphalan 140 mg/m2; MEL200 ¼ melphalan 200 mg/m2; MM ¼ multiple myeloma; MR ¼ minimal response; nCR ¼ near complete remission; ORR ¼ overall response rate; OS ¼ overall survival; PD ¼ progressive disease; PETHEMA ¼ programa para el estudio de la terapéutica en hemopatía maligna; PFS ¼ progression-free survival; PR ¼ partial response; pts ¼ patients; RD ¼ refractory disease; RIC ¼ reduced intensity conditioning; RR ¼ response rate; SD ¼ stable disease; TBI ¼ total body irradiation; TD ¼ thalidomid, dexamethason; TRM ¼ transplant-related mortality; UD ¼ unrelated donor; VAD ¼ vincristine, adriamycin, dexacortisone; VBAD ¼ vincristine, BCNU, adriamycin, dexamethasone vincristine; VBMCP ¼ vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone; VGPR ¼ very good partial response.

OS 91% at Estimated 1year (P ¼ 3-year PFS .085), 2years 43% 85% (P ¼ P ¼ .67 .176), 3years 77% (P ¼ .191)

OS, Median PFS, Median RD/SD

e e

PR CR TRM Number Transplant Study

Auto-allo 1. Induction. 2. MEL200þ ASCT. 3. TBI þ 200cGy

Age

Disease Status Before Transplant Table 2 Continued

53 (range, 29- Standard risk group: CR 11% P < .0001 90 (58%) pts. 68) years 24 (13%) pts, nCR P ¼ .007 22 (12%) pts, VGPR Achieved CR 32 (17%), PR 76 after alloSCT: (40%), MR 17 (9%), 58/120 SD 6 (3%). (48%) P ¼ .009

Survival Response

Conclusions

Ivetta Danylesko et al In the Spanish Pethema study,69 only patients that did not achieve a CR after a first ASCT were included and MEL140 was part of the conditioning regimen. The CR rate was higher in the tandem auto-alloSCT arm (40% vs. 11%; P ¼ .001).69 There were no statistically significant differences in OS and EFS. Although there was a trend toward a longer PFS (median, 31 months vs. not reached; P ¼ .08) in the RIC group,69 which is in line with the result reported by the Italian group showing lower relapse rates after tandem auto-alloSCT than after tandem ASCT.40 It is known that the possible favorable effect of alloSCT might become apparent only after a long follow-up. Several studies demonstrated that the true benefit of the tandem auto-alloSCT approach over tandem ASCT might appear beyond 5 years from the time of transplant.71,72 The US Intergroup trial (S9321) demonstrated a PFS plateau of 22% at 7 years in the 36 patients undergoing alloSCT, which was superior to the 7-year PFS of patients in the trial who received ASCT.12 The purpose of the Australian study was to examine whether factors predictive for favorable outcome could be identified.74 In multivariate Cox regression models, immunoglobulin (Ig) G myeloma, an HLA-identical sibling, and less than 1 year between diagnosis and transplant were independently significant favorable risk factors for OS and PFS. The 4-year survival probability of patients who underwent RIC alloSCT 1 year or more after autograft (40%) was significantly lower than that of patients who underwent RIC allogeneic transplant as the first stem cell transplant (SCT) used for treatment of their disease (53%) or those who underwent RIC alloSCT within a year of their ASCT (58%; P ¼ .04), indicating poorer survival for rescue procedures.74 Therefore, several studies compared tandem auto and autoRIC regimens and showed different results. These conflicting results might be explained by different patient populations, different regimens, and different GVHD prophylaxis. Among several reports comparing ASCT with alloSCT, at least 5 have shown survival advantages for the non-MA approach when compared with tandem autologous transplantation.12,40,71,72,74

Salvage AlloSCT Treatment of relapsed MM remains a challenge, even in the era of novel drugs. Although different drug treatment options are available, the duration of a second or third response is often limited. The novel agents are administered after relapse are associated with significant improvement in OS from 17 to 30 months.49,50,75 AlloSCT offers an additional treatment option in these patients using the proven graft vs. myeloma effect to control disease burden.25,27,76-79 Despite evidence to support alloSCT as upfront therapy, the use of alloSCT as salvage therapy has been less studied. Several studies assessed the benefit of RIC transplantation as salvage therapy in MM patients with chemotherapy-refractory disease and/or failure of ASCT.27,80,81 These trials are summarized in Table 3.25,27,29,76-79,82 Osman et al studied the outcomes of 20 heavily pretreated MM patients after non-MA allogeneic transplantation. Thirteen of these 20 patients had active disease at the time of transplant and thus received alloSCT as salvage therapy after several previous attempts at cure. CR was achieved in


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Study/Conditioning Protocol


Einsele et al, 2003 n ¼ 22; 53 RIC: I.V. FLU 30 mg/ (range, 33-63) 2 m for 5 days with I.V. years CY 20 mg/kg for 2 days; ATG 10 mg/kg for 3 days followed by TBI 2 Gy n ¼ 229; 52 Crawley et al, 200525 RIC: heterogeneous (range, 32-66) conditioning, most years were FLU-based and T-cell depleted with ATG or alemtuzumab 27

n ¼ 50; 53 Shimoni et al, 201076 RIC: FLU at a total (range, 32-64) dose of 90-150 mg/ years 2 m with MEL100MEL150; patients with an unrelated or mismatched donor and some of the patients with a sibling donor were also given ATG; total dose 1560 mg/kg

Type of Study/ Follow-Up

Previous Treatment

Phase I/II study; follow-up, 2 years

Progression after ASCT (1 or 2)

33 centers, EBMT; follow-up, 3 years

Retrospective analysis; median follow-up of 6.4 years (range, 5-7.9 years)

Disease Status Before AlloSCT PR/MR, n ¼ 8 (36%); no response to chemotherapy administered previously (SD/PD, n ¼ 14; 64%)

AlloSCT Response At least an MR, 15 (75%) pts; PR, 7 pts; CR, 6 pts

Survival

TRM/GVHD

Conclusions

Whole patient group: TRM, 23%; Grade 2 Chemorefractory 2-year OS, 25.5%; aGVHD, 7 (33%) pts; disease before EFS, 22%; patients Grade 3/4 aGVHD, 1 alloSCT (P ¼ .0182) with chemosensitive (5%) patient; cGVHD, and absence of disease before 7 pts cGVHD (P ¼ .069) allograft: OS, 62.5%; were associated with EFS, 57.1% shorter EFS Most pts at least 1 63% responded CR, 25%; PR, 48%; SD, 3-year OS, 41%; TRM, 22% at 1 year; Adverse OS was previous ASCT; 10% (10% CR) 12%; PD, 7%; 10% PFS, 21%, Grade 2-4 aGVHD, associated with: in CR before alloSCT; with 2 or more 31%; limited cGVHD, chemoresistant disease, 87% remained in CR; 25%; extensive more than 1 previous 20% in PR, attained cGVHD, 25% transplantation, and a CR after alloSCT; male pts with female 66% remained in PR, donors; and 7%, PD; 18% 2. Adverse PFS was with PD achieved CR; associated with: 27% PR; and 34% SD chemoresistance, alemtuzumab; 3. cGVHD was associated with better OS and PFS 47 (94%) pts in whom 30 (60%) pts, remission; At day 100, CR, 46%; 7-year OS, 34%; NRM 5-year; 26%, 1. OS and PFS were a previous ASCT had 20 (40%) pts SD PR, 34%; 9 pts were 7-year PFS, 26% aGVHD; Grade 2-4, better in pts with failed, or if previous or PD given thalidomide 51%; cGVHD, 63% sensitive MM at the lines of chemotherapy after SCT to convert time of SCT (to either had failed and ASCT PR to CR; 5 of these chemotherapy or was not feasible patients achieved CR novel agents); because of failed SCC 2. The independent factors found to be predictive of worse OS: RD, SCT from a female donor to a male recipient; 3. The pretransplantation factors found to be predictive of worse PFS: RD, SCT from a female donor to a male recipient, and disease duration of > 5 years


Table 3 Salvage Allogeneic Stem Cell Transplantation

Table 3 Continued Study/Conditioning Protocol


Type of Study/ Follow-Up

Previous Treatment

Disease Status Before AlloSCT

AlloSCT Response

Survival

TRM/GVHD

Conclusions

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n ¼ 19; 54 (range, 37-65) A single center, de Lavallade et al, 1. Induction mainly VAD; 44% disease response; PFS, 46% at 3 years 4 pts (22%), PD at a TRM, 33% at a median of In multivariate analysis for years retrospective analysis; 2. At least 1 course of 200877 56% chemoresistant significantly higher in median of 215 (range, 83 (range, 65-464) PFS, actual RIC: only match related HDT (MEL200) with disease after salvage the ‘donor’ group 90-1044) days after days after alloSCT; performance of RIC 1. FBA: FLU 30 mg/ donor; median follow-up ASCT; treatment (SD and PD) compared with the ‘no- alloSCT; 10 pts (56%) aGVHD, Grade 2-4, alloSCT was the m2 for 5 days, oral BU of 36 (range, 21-60) 3. After relapse, salvage donor’ group (P ¼ .01; are still alive: 4 pts, CR; 56%; Grade 3-4, 33%; strongest factor 4 mg/kg/d for 2 days, months therapy with VTD, 46 vs. 8% at 3 years); 5 PR or VGPR extensive cGVHD, 57% significantly associated ATG 2.5 mg/kg/d for additional ASCT, as a OS 95% at 6 months, with better PFS 1 day; single-agent therapy or 49% at 3 years 2. FT: FLU 30 mg/m2 in association for 3 days in combination with lowdose TBI (2 Gy) n ¼ 48; median age 50 A prospective multicenter 24 pts, 1 previous ASCT; Chemosensitivity to PFS at 5 years, 20%; OS,ORR at day 100 was 95%; NRM at 1 year, 25%; 1. The only significant Kroger et al, 201078 RIC: FLU total 90 mg/ (range, 34-64) years trial; unrelated donor 23 pts, 2 previous salvage therapy before 26% CR, 46%; cumulative grade 2-4 aGVHD, 25% factor for increased 2 m with MEL140; only autografts; 1 patient, 3 alloSCT in 26 pts; 13 incidence of relapse at of pts; 35% had cGVHD NRM was HLAGVHD prophylaxis, previous autografts pts refractory to 3 years, 55% mismatched ATG 20 mg/kg for 3 salvage; 7 pts were transplantation, which days treated with alloSCT resulted in a 1-year without salvage after cumulative increase of relapse following an NRM of 53 in autograft comparison with only 10% for patients transplanted from a fully (10/10) matched donor (P ¼ .001); 2. Patients who achieved CR at day 100 had a significantly prolonged PFS at 5 years in comparison with the non-CR patients (56% vs. 16%) A total of 33 pts (87%) At the time of alloSCT, 3 The median PFS was 1.4 In 16 pts (42%), the TRM, 8% at 1 year, 17% 1. CR after alloSCT or Minnema et al, 201179 n ¼ 38; median age, 56 Retrospective study; RIC: low-dose TBI of (range, 36-68) years median follow-up, 2.3 after MEL200 with pts were in CR, 11 in (range, 0.1-4.9) years; response improved after at 3 years; aGVHD cGVHD were associated 2 Gy only; I.V. FLU 30 years ASCT; after relapse and VGPR, 23 in PR, and 1 median OS, 3.1 (range, alloSCT; 15 pts (39%), Grade 2 or 4%, 3with a better OS; mg/m2 was before alloSCT, salvage had PD 0.2-7.2) years CR; 8 pts (21%) rapidly year cGVHD, 28%, 42. The use of ATG or additionally (variable): VAD, TD, VD, progressive within 6 year, 38% having an HLA administered for 3 RD in 15 pts (40%) months after alloSCT mismatch was days to patients who after salvage ASCT negatively associated had not undergone with OS; ASCT a minimum of 6 3. The presence of months earlier; cGVHD and reaching CR patients with a MUD after alloSCT was also or patients who associated with a better planned to receive PFS preemptive DLI after alloSCT with ATG, 2 mg/kg, for 4 days


Study/Conditioning Protocol 82


Kroger et al, 2013 33 pts; median age, 50 MAB toxicity-reduced (range, 36-67) years allograft: I.V. BU 14 0.8 mg/kg (11.2 mg/kg) for 3 days and I.V. CY 120 mg/kg for 2 days; after a median interval of 168 days, 24 patients started with R without

Type of Study/ Follow-Up Retrospective study; median follow-up, 3 years

Previous Treatment

Disease Status Before AlloSCT

AlloSCT Response

Survival

TRM/GVHD

Failure of a previous Before alloSCT: CR, 1; PR, The 3-year estimated Before relapse (R): CR, 7 Severe Grade 3 aGVHD, autograft or refractory 21; SD, 3; RD, 3 pts; 5 probability of PFS, 52% (29, PR 13 (54, SD 4 6%; overall Grade 2-3 disease with failure to pts were treated with and OS, 79% (17. After R: 7 pts with GVHD was 34 yield ASCT alloSCT without salvage PR and 1 with SD treatment after relapse converted to CR; 1 to ASCT patient with SD converted to PR; overall CR, 46; PR, 48(21 VGPR); SD, 3

n ¼ 41; median age, 52 Prospective; HLA-identical 34 patients (83%) received PR, 29 (70%) pts; CR, 1 The 2-year estimate OS, CR, 10; PR, 11; SD, 2 pts TRM, 17%; Grade 2-4 Mohty et al, 200429 RIC: FLU: 30 mg/m2 (range, 35-61) years siblings only; median at least 1 ASCT; after patient; SD or PD, 11 62%; PFS, 41% aGVHD, 36%; Grade 3for 6 or 5 consecutive follow-up of 389 (range, progression, salvage (27%) pts 4, 7%; cGVHD, 41% days; oral BU 4 mg/ 74-1270) days kg/d for 2 consecutive days with ATG; median ATG dose, 7.5 (range, 2.512.5) mg/kg

Conclusions 1. Lenalidomide post allografting has acceptable toxicities and may have contributed to the encouraging overall and PFS; 2. Trigger of GVHD should be considered; 3. No effect on survival was seen for chemosensitivity to salvage therapy before alloSCT; 4. A more intensive MAB toxicity-reduced allograft is feasible in heavily pretreated patients 1. PFS and OS were significantly higher in pts with cGVHD compared with pts without cGVHD (P ¼ .006 for PFS and P ¼ .01 for OS); 2. An objective GVM effect can be achieved without an increased risk of GVHD-related mortality

Abbreviations: aGVHD ¼ acute graft vs. host disease; alloSCT ¼ allogeneic stem cell transplantation; ASCT ¼ autologous stem cell transplantation; ATG ¼ antithymoglobulin; BU ¼ busulfan; cGVHD ¼ chronic graft vs. host disease; CR ¼ complete remission; CY ¼ cytoxan; DLI ¼ donor lymphocyte infusion; EBMT ¼ European Bone Marrow Transplantation; EFS ¼ event-free survival; FLU ¼ fludarabin; GVHD ¼ graft vs. host disease; GVM ¼ graft vs. myeloma; HDT ¼ high dose therapy; HLA ¼ human leukocyte antigen; MAB ¼ myeloablative conditioning; MEL100 ¼ melphalan 100 mg/m2; MEL140 ¼ melphalan 140 mg/m2; MEL200 ¼ melphalan 200 mg/m2; MM ¼ multiple myeloma; MR ¼ minimal response; MUD ¼ match unrelated donor; NRM ¼ nonrelapse mortality; ORR ¼ overall response rate; OS ¼ overall survival; PFS ¼ progression-free survival; PD ¼ progressive disease; PR ¼ partial response; pts ¼ patients; R ¼ revlimid; RD ¼ refractory disease; RIC ¼ reduced intensity conditioning; SCC ¼ stem cell collection; SCT ¼ stem cell transplantation; SD ¼ stable disease; TBI ¼ total body irradiation; TD ¼ thalidomid, dexamethason; TRM ¼ transplant-related mortality; VAD ¼ vincristine, adriamycin, dexacortisone; VD ¼ vincristine, dexacortisone; VGPR ¼ very good partial response; VTD ¼ vincristine, thalidomide, dexacortisone.


Table 3 Continued

Ivetta Danylesko et al 5 (38%) of these 13 patients, with the median duration of response 10.1 months.80 Similar results were reported by Efebera et al.81 The authors showed that RIC alloSCT offers long-term survival in a subset of patients with relapsed or refractory MM with PFS and OS at 2 years of 19% and 32%, respectively.81 This fact is very encouraging because patients in these series were heavily pretreated and their median time from diagnosis to alloSCT was 34 months81 compared with 18 months in the EBMT study.25 We retrospectively analyzed a relatively heavily pretreated 50 patients who received RIC for recurrent/refractory myeloma between the years 2001 and 2004 with a median of 3 years from the time of diagnosis. AlloSCT earlier in the disease course was associated with better outcome. The cutoff was 5 years from diagnosis.76 Most other studies demonstrated similar trends but used an earlier cutoff of 1 to 2 years.25,36,62 Nonrelapse mortality in our study76 was, as might be expected, higher than in the upfront approach, reaching 26%, which is similar to other studies in the same setting.16,25,31,36,77 With a median follow-up of > 6 years, there was a clear plateau in the PFS curve after 3 years, with 34% of patients alive and 26% free of disease progression, 7 years after alloSCT.76 We found that alloSCT is associated with a high CR rate.76 The depth of remission is related to the prolonged response. The achievement of VGPR was associated with longer responses than PR; however, long-term PFS was possible almost exclusively in patients achieving CR. These data suggest that RIC alloSCT might salvage a subset of myeloma patients with relapsed/refractory disease for whom conventional therapeutic options are otherwise limited. It is currently unknown whether the auto-allo approach offers an advantage over standard salvage therapy followed by RIC in the salvage setting. Whether an alloSCT should be offered as part of a first-line treatment or as salvage therapy for recurrent/refractory disease is a matter of debate. As discussed, upfront therapy is associated with a lower NRM, but long-term outcome still requires better confirmation. In at least one trial comparing second ASCT with RIC allografting after relapse from a previous ASCT there were no significant differences in PFS and OS.47 One concern of alloSCT is the high incidence of relapse that exceeds 55% at 3 years in a cohort of 32 relapsed MM patients, using a reduced-intensity melphalan (140 g/m2)/fludarabine regimen.77 To lower the risk of relapse, Kroger et al used a MA toxicity-reduced allograft consisting of intravenous (I.V.) BU (11.2 mg/kg) infusion and cytoxan I.V. infusion of 120 mg/kg followed by lenalidomide maintenance therapy in 33 patients with MM who relapsed after an autograft after a median of 12 months.82 Before lenalidomide was started, the remission status in those patients was CR 29%, PR 54%, and SD 17%. After lenalidomide treatment, 7 patients with PR and 1 patient with SD converted to CR and 1 patient with SD converted to PR. Overall, for all 30 response-evaluable patients, CR, PR, and SD was noted in 46%, 48% (21% VGPR), and 3%, respectively. The cumulative incidence of NRM at 1 year was only 6% (95% confidence interval [CI], 0-14). Overall, this study shows that a more intensive MA toxicity-reduced allograft is feasible in heavily pretreated patients with myeloma who already experienced relapse after an autograft. Furthermore, lenalidomide after allograft might have contributed to the encouraging overall and PFS but triggering of GVHD should be considered.82

Hence, the choices of transplant option after failed ASCT remain subject to further research.

Predictors of Prolonged Survival After AlloSCT for MM In the study by Bruno et al,38 deletion (del) 13q was detected in 13 of 39 patients studied. There was no difference in OS; however, the EFS was better in patients without del 13q. Kroger et al83 retrospectively compared the outcomes of 31 patients with del 13q, and 37 patients without del 13q. At 2 years, patients with del 13q had significantly lower EFS (18% vs. 42%) and OS (18% vs. 67%). In addition, the relapse rate was higher in patients with del 13q (77% vs. 44%), but the TRM at 1 year was similar (24% vs. 18%).83 A large study from M.D. Anderson Cancer Center evaluated the outcome of all patients with MM who received alloSCT between November 1985 and June 2010, with the exception of the patients treated in a tandem auto-auto vs. auto-alloSCT trial.84 In this heavily pretreated patient population (81% with relapsed or refractory disease), several factors that affect alloSCT outcome and might help in identifying patients who might benefit the most from this treatment modality were identified. In a multivariate analysis, alloSCT for first remission consolidation was associated with longer PFS (hazard ratio [HR], 0.35; 95% CI, 0.18-0.67; P ¼ .0016) and OS (HR, 0.29; 95% CI, 0.15-0.55; P ¼ .0002), whereas absence of high-risk cytogenetic features was associated with longer PFS only (HR, 0.59; 95% CI, 0.37-0.95; P ¼ .03).84 Patients with 1 or more of the known high-risk cytogenetic features (t(4;14), t(14;16), del 17p, del 13q, 1q amplification, or hypodiploidy) had significantly lower 5-year PFS and OS compared with the patients without these features.84 This was particularly true for the patients who had either del 13q or del 17p abnormalities.84 Age, immunoglobulin subtype, b2 microglobulin level, serum albumin level, serum lactate dehydrogenase level, hemoglobin level, serum calcium level, interval between diagnosis and alloSCT, interval between ASCT and alloSCT, number of previous ASCTs, development of cGVHD, and administration of DLIs did not emerge as significant predictors of PFS or OS.84 Whereas Efebera et al showed that the major differences between the long-term survivors (12 patients) and others were a lower b-2 microglobulin (median 2.45 vs. 3.5, P ¼ .01) and more previous ASCT (92% vs. 64%, P ¼ .08) in the long-term survivor group.81 Taken together, these data suggest that cytogenetics continue to play an important role in determining the outcome, and it remains uncertain whether RIC alloSCT can overcome the risk posed by these high-risk cytogenetic abnormalities.85

Targeted Immunotherapy After SCT Immunotherapy After ASCT in MM A major area of investigation is to develop strategies to elicit myeloma-specific immune responses that will selectively eliminate malignant cells and eradicate residual disease after ASCT. HD melphalan induces severe and persistent immunosuppression characterized by a delayed recovery of CD4 T-cells that remain below normal counts for months to years after ASCT,86,87 a restricted T-cell repertoire88 and impaired T-cell functions including an increased susceptibility to apoptosis,89 a reduced proliferation


- S343

ASCT and Immunotherapy for MM intensity on stimulation with mitogens or defined antigens and a default in Th1 cytokine production that lasts at least 1 year after ASCT in patients with MM.90,91 The B cell immune response is also altered after ASCT because levels of plasma antibodies after 1 recall vaccination are less than those found in healthy donors.87 Tcell functions are impaired after transplantation in patients with MM despite a recovery of normal numbers of T lymphocytes.89-91 In theory, the posttransplantation phase should be highly amenable to the application of immunotherapy because of a lower tumor burden. However, after HDT, the immune system is characterized by immune cell depletion and impaired function that might last for years.86 On the other hand, lymphocyte levels in patients after stem cell transplantation correlate with clinical outcomes.92-95 Therefore Rapoport et al have developed a strategy for inducing an effective antitumor immune response during the posttransplantation period to control or eliminate residual disease.96 The authors hypothesized that enhanced numeric and functional recovery of T-cells might provide a platform for posttransplantation tumor vaccine immunotherapy. The autologous T-cells were costimulated with paramagnetic beads that deliver CD3 and CD28 signals designed to reverse T-cell anergy.97-100 Patients with myeloma received costimulated autologous T cells after autotransplantation, along with immunizations with a 7-valent pneumococcal conjugate vaccine (Prevnar; Wyeth).96,101 In addition, patients who were positive for HLA-A2 received a multipeptide tumor antigen vaccine that was based on peptides derived from human telomerase reverse transcriptase and survivin, 2 “universal” tumor antigens that are often overexpressed in myeloma and might have prognostic relevance.102-104 In this study, adoptive transfer of vaccine-primed and costimulated autologous T cells generates a rapid and scheduledependent recovery of the cellular and humoral immune system in patients with myeloma. Immune responses to a cancer vaccine occur in a substantial proportion of patients early after autotransplantation.96 Some studies have shown high interleukin (IL)-6 plasma levels after ASCT.105,106 Condomines et al showed that IL-7 and IL-15 plasma levels increase and peak at a median day 8 after high-dose melphalan and ASCT in patients with MM,107 supporting results found in mice by Restifo and coworkers.108 Increasing data support the idea that the early period after lymphodepletion is propitious to promote in vivo amplification of adoptively transferred T cells and to enhance their functions. Several studies in mice and humans showed that homeostatic expansion is associated with faster and more efficient immune response and that immunization with tumor antigens during lymphopenia generates CD8 T-cells with enhanced antitumor capacities.109-112 IL-7, produced by stromal cells, is required for homeostatic expansion of naive and memory CD4 and CD8 T-cells and is critical for their survival.113 IL-15 drives antigen-independent homeostatic memory CD8þ abT cell proliferation.113,114 IL-7 and IL-15 are also required for gdT cell homeostatic expansion.115 The g9d2T cells exert antimyeloma-specific cytotoxicity and can be expanded 100fold with IL-2 and biphosphosphonate ex vivo116 and are present in mobilized autografts.117 These g9d2T cells could be expanded ex vivo and then grafted after ASCT. CD8 T cells recognizing several myeloma antigens such as mucin-1,118 cancer-testis antigens,119-121 or IgG epitopes,122 detected in peripheral blood of patients might also be present in hematopoietic stem cell harvests.

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When stimulated ex vivo with antigen pulsed dendritic cells (DCs),123 these antimyeloma cell CD8þ T-cells are able to kill myeloma cells.

Immunotherapy After AlloSCT Allogeneic transplantation results in long-term disease-free survival for a subset of patients with MM. The unique efficacy of allogeneic transplantation is because of the GvM effect that is mediated by alloreactive donor T cells.16,20,21 As discussed already, compared with autologous transplantation, allogeneic transplantation results in lower rates of disease relapse and higher rates of molecular remission.16,18,124,125 Standard MAalloSCT for myeloma is associated with a rather high treatmentrelated mortality. One approach to reduce TRM is the use of RIC regimens76 in which the primary antimyeloma cytoreductive agent is the donor lymphocytes contained in the graft or administered as part of DLI at a subsequent time point. The CR rate of alloSCT after standard MA and dose-reduced conditioning ranged between 27% and 81%.22,61,67,76,126 The ability of DLI to eradicate posttransplant disease relapse demonstrates the potency of the GvM effect. This finding was first described by Tricot et al, who described a MM patient with PD 2.5 months after a MA Tecell-depleted transplantation from an unrelated donor.17 Because only patients who achieved molecular remission have a high probability of longterm freedom from disease and cure,11 a higher number of CRs, especially molecular CRs, must be reached. For upgrading non-CR into CR, DLI might be used as adoptive immunotherapy after alloSCT. In most reports on DLI in myeloma, DLI was given for relapse127-129 and only a few reported on prophylactic DLI.30,130 Most studies to date have used relatively high T-cell doses, resulting in a high rate of aGVHD up to 55%.129 DLI given after RIC in a dose-escalating manner resulted in less acute and cGVHD.30 Ayuk et al thus considered it important to find DLI doses that might induce a GvM effect without GVHD.129 Their data show that it is possible to achieve remission in myeloma patients who have relapsed, or with persistent or PD after RIC allografting with much lower T-cell numbers with relatively low starting doses (1.0 106 CD3þ/kg body weight [BW] for unrelated grafts and 4.7 106 CD3þ/kg BW for sibling grafts). The incidence and severity of aGVHD and cGVHD was relatively low.129 Achieving molecular CR after alloSCT is a major goal. Because novel agents have been shown to be effective not just for induction therapy but also in relapsed disease, novel agents are being recently introduced after alloSCT aiming to improve molecular CR rates and prevent relapse and disease progression. Some of these agents are combined with DLI. Combination of thalidomide and DLI has been shown to increase response rate achieving CR in approximately 70% of the patients.131 A theoretic attractive option is lenalidomide that has been shown to potentiate natural killer (NK) activity.132,133 NK mismatch has been shown to correlate with outcome after alloSCT and reduce relapse rate after transplantation in MM.134 However, lenalidomide might increase incidence of GVHD135 and death from GVHD after alloSCT in MM.136 Low-dose lenalidomide (5 mg/d) might be a solution.135 Lenalidomide-mediated increase in NK and NK killer inhibitor receptor mismatch subsets were correlated with lower MM disease progression after alloSCT.135 Finally, Kroger et al investigated the effect of DLI alone or in combination with

Ivetta Danylesko et al thalidomide, bortezomib, and lenalidomide in patients with MM who achieved only PR or VGPR after alloSCT.19 Fifty-nine percent of patients achieved CR, and this CR resulted in significantly improved PFS at 5 years (58% vs. 35%). CR determined using flow cytometry could be achieved in 63%, and this resulted in an even more favorable EFS at 5 years (74% vs. 15%).19

Combined Donor Vaccination and AlloSCT A special aspect of active immunotherapy in MM is the combination of alloSCT with the induction of myeloma-specific immunity in the donor’s immune system. The donor immune system is presumably naive for the patient’s myeloma idiotype and therefore not tolerated or anergic. Therefore, induction of tumor-specific immunity in donors of hematopoietic stem cells for myeloma patients using idiotype immunization, followed by adoptive transfer of specific immune cells into the transplanted patient, might render alloSCT from a nonspecific form of active immunotherapy into a tumor-specific therapy. In the 38C13 mouse lymphoma model, mice receiving marrow from a donor immunized with the 38C13 idiotype had a statistically significant survival advantage after a lethal challenge with 38C13 lymphoma cells compared with animals transplanted with control marrow.137 When preimmunized marrow transplantation was combined with a subsequent booster immunization, even tumor-bearing mice could evidently be cured of their disease. The protective effect was mediated by donor-derived T-cells. More recently, results from a formal clinical trial of donor idiotype immunization were reported. Five patients and their related donors received 3 subcutaneous vaccinations with idiotype (coupled to keyhole limpet hemocyanin (KLH) at the first vaccination) and granulocyte-macrophage colony-stimulating factor (GM-CSF) before alloSCT. All donors developed cellular and humoral antiidiotype immune responses. After bone marrow transplantation, the 3 patients who survived longer than 30 days received 3 booster vaccinations with KLH-coupled idiotype and GM-CSF. Remarkably, these patients survived without evidence for disease recurrence for 5.5 to more than 8 years, and all had evidence for idiotypespecific immunity after alloSCT.138 One recipient suffered from cGVHD and was taking chronic steroid therapy, and the other 2 recipients and all of the donors were medically well, without any significant complications. To avoid immunization of the healthy donor, attempts have been made to generate myeloma idiotype-specific donor immunity through in vitro stimulation of donor T-cells with monocytederived, idiotype-presenting DC.139 Implementation of this approach would permit extension of the principle of transfer of tumor-specific immunity to the vast pool of unrelated stem cell donors for alloSCT.

Conclusion Major progress has been made in the treatment of MM in recent years, including the introduction of novel agents and transplant strategies. Many studies stress the importance of constructing better predictive factors for improved survival, ie, VGPR or better and molecular CR. However, even with significant advances in the field, multiple MM remains incurable for most patients.

Allogeneic transplantation is a therapeutic approach resulting in 5% molecular CR in 50% of patients and most probably still the only curative modality in MM. Allogeneic stem cell transplantation with standard MA conditioning has been shown in multiple studies to be potentially curative in myeloma.12,14,22-24 However, the high NRM rates of 30% to 50% have been reported in those studies.12-14 RIC has significantly reduced the NRM to 10% to 20%.16,25,31,36,40,62,68,69,77 Two strategies were developed for RIC in the course of the disease. RIC could be used in the initial treatment program for newly diagnosed patients or as a salvage approach for patients in whom previous therapy has failed, which in modern therapy, most often includes single or tandem autologous transplants. The therapy for newly diagnosed patients could use an auto-allo approach. Although the ASCT is used for cytoreduction, the allogeneic part is administered to provide the possibly curative GvM effect. The temporal separation between the 2 parts allows reduction in NRM. Several studies compared tandem auto and auto-RIC regimens and showed different results. These conflicting results might be explained by different patient populations studied, different regimens, and different GVHD prophylaxis regimens used. Collectively, they demonstrate, with a long follow-up of > 5 years, an NRM of 11% to 18% and similar survival rates. Although most of the studies have shown lower relapse rates and survival advantages for the non-MA approach when compared with tandem autologous transplantation.12,40,71,72,74 Until there are definitive answers from well designed studies, this approach might only be recommended within clinical studies and for the high-risk MM group. Alternatively, alloSCT can be used as a salvage therapy for patients in whom previous therapies have failed, which includes ASCT.76 The advantages of alloSCT might become apparent after a long follow-up, whereas most of the studies in the salvage setting might not have had sufficient follow-up.31,77 However, outcome after alloSCT of patients who develop disease recurrence after ASCT is significantly worse than in patients who received the auto-allo upfront approach.36 After disease recurrence, patients might harbor highly resistant myeloma cells that might also not respond to the GvM effect. Nonrelapse mortality is still significant when considering the possible long-term survival of newly diagnosed patients with modern anti-MM therapy. Nevertheless, if not given early, alloSCT can still effectively salvage a subset of patients especially because the conventional therapeutic options for patients who develop disease recurrence after an ASCT are rather limited. The 2-year OS rate after disease recurrence in the IFM study was 36%55; and the median OS in the other study was < 3 years.140 Identifying prognostic factors for predicting outcome after alloSCT is thus of major importance. Chemosensitivity at the time of SCT is one of the most important factors in alloSCT for all hematologic malignancies including myeloma.141 In addition, achievement of a CR and reduction of disease progression and relapse is usually associated with cGVHD in most,25,36 but not all studies.40,62 The association of cGVHD with reduced recurrence risk supports the existence of GvM; however, it might also occur in its absence. The EBMT study demonstrated that patients with PD do not benefit from alloSCT with RIC.25 The GvM effect might not be potent enough to overcome bulky or highly resistant disease.


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ASCT and Immunotherapy for MM This observation must be taken with caution because the worse outcome of patients with long disease duration might be related to poor prognostic characteristics such as refractory disease and heavy previous therapy. Cytogenetics has become an important tool in determining prognosis of myeloma. Although alloSCT can overcome the adverse prognostic effect of del 13 as a sole fluorescence in situ hybridization finding and even when associated with t(4;14); del 17p remains a poor prognostic factor after alloSCT.62,142 Patients who develop disease recurrence after alloSCT might respond to DLI.129 Furthermore, they might still demonstrate remarkable responses to the novel agents alone or in combination with DLI.131,143 These observations led to the use of novel agents in conjunction with DLI in patients achieving only PR after SCT, not waiting until the inevitable disease progression in these patients, in an attempt to upgrade remission depth and improve survival.19 Future studies will continue to explore the integration of novel agents and novel cellular therapies with RIC, in an attempt to reduce the incidence of disease recurrence, which is the major obstacle for cure after RIC. Perhaps the most interesting field for active immunotherapy in myeloma lies in the combination with alloSCT. This setting offers the advantage of an immune system that is unaffected by potential negative influences exerted by the tumor on the immune system. Transfer of tumor antigen-specific immunity from the donor to the myeloma patient might help to enhance the antimyeloma immunological efficacy of alloSCT and to separate GvM from graft vs. host activity. One of the most crucial questions in developing this concept further is whether the donor has to be immunized personally or whether efficacious, specific antitumor immunity can be induced ex vivo or in the transplanted patient. Major progress in understanding the interactions between the immune system or the donor, recipient, and the malignant cells will strongly augment the design of clinically more efficient study protocols for MM.

Acknowledgments The authors thank the Naor family for their support memorializing their dear son-in-law, Mr Guy Weinshtock, with the Guy Weinshtock Multiple Myeloma Foundation, which supports research in the field of MM at the Division of Hematology at Chaim Sheba Medical Center (Tel Hashomer, Israel) and the Jacqueline Seroussi Grant Award (AN).

Disclosure The authors have stated that they have no conflicts of interest.

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