Evolving strategies with immunomodulating drugs and tandem autologous/allogeneic hematopoietic stem cell transplantation in first line high risk multiple myeloma patients
2013; Elsevier BV; Volume: 41; Issue: 12 Linguagem: Inglês
10.1016/j.exphem.2013.08.003
ISSN1873-2399
AutoresMauricette Michallet, Mohamad Sobh, Jean El Cheikh, Stéphane Morisset, Anne Sîrvent, Oumédaly Reman, Jérôme Cornillon, Reza Tabrizi, Nöel Milpied, Jean‐Luc Harousseau, Hélène Labussière, Franck‐Emmanuel Nicolini, Michel Attal, Philippe Moreau, Mohamad Mohty, Didier Blaise, Hervé Avet‐Loiseau,
Tópico(s)Cancer Treatment and Pharmacology
ResumoWe prospectively evaluated in high-risk myeloma patients the efficacy and toxicity of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) followed by reduced-intensity conditioning (RIC) and allogeneic (allo)-HSCT with bortezomib and donor lymphocyte infusions introduction after allo-HSCT (group 1). Results were compared with results from tandem auto-RIC-allo-HSCT without bortezomib (group 2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the Intergroupe Francophone du Myélome prospective studies. Allo-HSCT groups included 25 patients (12 in group 1, 13 in group 2). All patients engrafted. There were 8 acute GVHD (7 grade II [3 in group 1], 1 grade III in group 1)] and 11 chronic GVHD (3 limited [in group 1], 8 extensive [1 in group 1]). Matched population included 36 controls for group 1 and 39 for group 2. After a median follow-up of 55 months (range, 3–142 months), median overall survival was not reached in group 1 versus 65 months (51-not reached [NR]) in its matched group (p = 0.027); it was 96 months (49-NR) in group 2 versus 91 months (32-NR) in its matched group (p = 0.77). Median progression-free survival was 49 months (29-NR) in group 1 and was 25 months (range, 21–35 months) in its matched group (p = 0.0045); it was 31 months (22-NR) in group 2 and 28 months (range, 21–40 months) in its matched group (p = 0.0776). Tandem auto-RIC–allo-HSCT including new molecules and immunomodulation after transplantation could be used as a first-line treatment for high-risk myeloma patients. We prospectively evaluated in high-risk myeloma patients the efficacy and toxicity of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) followed by reduced-intensity conditioning (RIC) and allogeneic (allo)-HSCT with bortezomib and donor lymphocyte infusions introduction after allo-HSCT (group 1). Results were compared with results from tandem auto-RIC-allo-HSCT without bortezomib (group 2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the Intergroupe Francophone du Myélome prospective studies. Allo-HSCT groups included 25 patients (12 in group 1, 13 in group 2). All patients engrafted. There were 8 acute GVHD (7 grade II [3 in group 1], 1 grade III in group 1)] and 11 chronic GVHD (3 limited [in group 1], 8 extensive [1 in group 1]). Matched population included 36 controls for group 1 and 39 for group 2. After a median follow-up of 55 months (range, 3–142 months), median overall survival was not reached in group 1 versus 65 months (51-not reached [NR]) in its matched group (p = 0.027); it was 96 months (49-NR) in group 2 versus 91 months (32-NR) in its matched group (p = 0.77). Median progression-free survival was 49 months (29-NR) in group 1 and was 25 months (range, 21–35 months) in its matched group (p = 0.0045); it was 31 months (22-NR) in group 2 and 28 months (range, 21–40 months) in its matched group (p = 0.0776). Tandem auto-RIC–allo-HSCT including new molecules and immunomodulation after transplantation could be used as a first-line treatment for high-risk myeloma patients. The development of new agents with potent anti-tumor activity has considerably improved the survival of patients with multiple myeloma (MM) [1Anderson K.C. The role of immunomodulatory drugs in multiple myeloma.Semin Hematol. 2003; 40: 23-32Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 2Kumar S.K. Rajkumar S.V. Dispenzieri A. et al.Improved survival in multiple myeloma and the impact of novel therapies.Blood. 2008; 111: 2516-2520Crossref PubMed Scopus (1805) Google Scholar, 3Palumbo A. Anderson K. Multiple myeloma.N Engl J Med. 2011; 364: 1046-1060Crossref PubMed Scopus (1770) Google Scholar]. However, there is still a high risk of relapse mainly because of the inability of these agents to cure and eliminate the MM cells definitively. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only available potentially curative treatment, particularly for patients with high risk factors, but its use is still controversial because of discordant results from different studies with different treatment and conditioning modalities and because of different patient and donor characteristics [4Blade J. Rosinol L. Cibeira M.T. Rovira M. Carreras E. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010.Blood. 2010; 115: 3655-3663Crossref PubMed Scopus (123) Google Scholar]. Conventional myeloablative conditioning regimens are associated with a high mortality and morbidity and are lacking evidence of survival benefit [5Bensinger W.I. Buckner C.D. Anasetti C. et al.Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.Blood. 1996; 88: 2787-2793PubMed Google Scholar]. In the last decade, reduced-intensity conditioning (RIC) followed by allo-HSCT has gained in popularity because of significantly reduced transplant-related mortality (TRM) that has decreased to 10%–20%, whereas the complete response (CR) rate has reached approximately 50% [6Lokhorst H. Einsele H. Vesole D. et al.International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.J Clin Oncol. 2010; 28: 4521-4530Crossref PubMed Scopus (141) Google Scholar]. The most important predictors of outcome are the low tumor burden at the time of transplant and the management of chronic graft-versus-host disease (GVHD). In this regard, the use of autologous HSCT to reduce tumor burden followed by RIC allo-HSCT to obtain a benefit from the graft-versus-myeloma effect has been investigated and has shown interesting long-term results [7Garban F. Attal M. Michallet M. et al.Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.Blood. 2006; 107: 3474-3480Crossref PubMed Scopus (325) Google Scholar, 8Rotta M. Storer B.E. Sahebi F. et al.Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting.Blood. 2009; 113: 3383-3391Crossref PubMed Scopus (92) Google Scholar, 9Giaccone L. Storer B. Patriarca F. et al.Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma.Blood. 2011; 117: 6721-6727Crossref PubMed Scopus (104) Google Scholar, 10Bjorkstrand B. Iacobelli S. Hegenbart U. et al.Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up.J Clin Oncol. 2011; 29: 3016-3022Crossref PubMed Scopus (146) Google Scholar], but the results regarding this type of strategy remain controversial [4Blade J. Rosinol L. Cibeira M.T. Rovira M. Carreras E. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010.Blood. 2010; 115: 3655-3663Crossref PubMed Scopus (123) Google Scholar]. The new antimyeloma drugs, such as bortezomib, are susceptible to improve the outcomes if used before allo-HSCT as demonstrated [2Kumar S.K. Rajkumar S.V. Dispenzieri A. et al.Improved survival in multiple myeloma and the impact of novel therapies.Blood. 2008; 111: 2516-2520Crossref PubMed Scopus (1805) Google Scholar] and early after allo-HSCT to eliminate the residual disease and decrease the GVHD incidence and severity related to its immunomodulatory potency [11Richardson P.G. Weller E. Lonial S. et al.Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.Blood. 2010; 116: 679-686Crossref PubMed Scopus (721) Google Scholar]. Lenalidomide is also of interest in this setting, but at the price of GVHD activation or reactivation [12Kneppers E. van der Holt B. Kersten M.J. et al.Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial.Blood. 2011; 118: 2413-2419Crossref PubMed Scopus (149) Google Scholar, 13Wolschke C. Stubig T. Hegenbart U. et al.Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: Results from a phase I/II dose-finding study.Exp Hematol. 2013; 41: 134-142.e133Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. On the other hand, adoptive immunotherapy with donor lymphocyte infusion (DLI) using a prophylactic or curative is one of the approaches used to reduce the risk of relapse and to improve the outcome by enhancing the graft-versus-myeloma effect that can also cause a GVHD reaction and should be administered carefully [14Beitinjaneh A.M. Saliba R. Bashir Q. et al.Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant.Leuk Lymphoma. 2012; 53: 1525-1529Crossref PubMed Scopus (23) Google Scholar]. In view of the need to continue investigations into RIC regimens and pre- and post-allogeneic transplant strategies, we decided: (1) to conduct a prospective, multicenter study to evaluate the efficacy and toxicity of tandem auto-RIC–allo-HSCT with the introduction of bortezomib and DLI in patients categorized with a high-risk prognosis (group 1); (2) to compare results observed in group 1 to those observed after traditional tandem auto-RIC–allo-HSCT without bortezomib after allo-HSCT (group 2); and (3) to perform a matched-control analysis of patients from groups 1 and 2 with matched patients who were not receiving allo-HSCT from the Intergroupe Francophone du Myélome (IFM) and were enrolled in previous prospective studies. The prospective multicenter study (group 1) included MM patients aged 65 years or younger and categorized as poor-prognosis patients. Patients were preselected at diagnosis; the treatment consisted of tandem autologous HSCT and RIC followed by allogeneic HSCT. Patients previously received four cycles of either vincristine, doxorubicin, and high-dose dexamethasone (VAD) or bortezomib plus dexamethasone (VD) as induction treatment followed by melphalan 140 or 200 mg/m2 and autologous HSCT. Concerning disease response, all patients were evaluated according to the European group for Bone and Marrow Transplantation (EBMT) criteria [15Blade J. Samson D. Reece D. et al.Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant.Br J Haematol. 1998; 102: 1115-1123Crossref PubMed Scopus (1474) Google Scholar]. Only patients who achieved at least a partial response (PR) to autotransplantation were eligible to be enrolled for RIC allo-HSCT. Patients must have an HLA-identical donor either from siblings or unrelated 10/10 HLA donors, and at least one of the following factors: β2 microglobulin level > 3 mg/L, deletion of chromosome 13 (del 13), translocation (t) (4; 14) or deletion of chromosome 17p (del 17p). Patients with substantial renal failure (glomerular filtration rate < 50 mL/min), liver impairment with bilirubin more than twofold the upper limit of normal, severe cardiac failure (left ventricular ejection fraction < 40%), or other major organ system dysfunction were considered ineligible for inclusion. The main objective of the prospective study (group 1) was to improve the 15% event-free survival at 3 years after allo-HSCT (i.e., decrease the number of deaths and progressions), and it was designed to include 105 patients. However, the initiation occurred during other concurrent nonallogeneic strategies and maintenance protocols, and the accrual was difficult; therefore, for economic reasons we decided to stop the study and 12 patients were included. As a consequence, with this low accrual, we were not able to evaluate and draw conclusions from additional different planned objectives, such as immunologic graft recovery, quality of life, and bortezomib tolerance. For this reason, we planned to compare the results of the group 1 with outcomes of patients who could have benefited from the new all-HSCT strategy. A query was sent to centers that performed allo-HSCT as used in group 1, but not included in the protocol. Next, we obtained group 2 patients with the same characteristics (MM, treatment before allogeneic HSCT including autotransplant, and transplant procedures) as group 1 and the only difference concerned the post-allo-HSCT strategy, patients did not receive bortezomib. Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the IFM enrolled in previous prospective studies (IFM-2005-01 [n = 57], IFM-99-02 [n = 9], IFM-99-04 [n = 9]). Matching variables were: diagnosis date, age, gender, β2 microglobulin, cytogenetics, induction treatment, achieved at least a PR to autotransplantation. The matching ratio was 1:3. All unrelated donors were 10/10 HLA identical on HLA-A, -B, -C, -DRB1 and -DQB1 on allelic level. Donors were mobilized for peripheral blood stem cell (PBSC) collection after recruitment by G-CSF given at the dose of 10 μg/kg/day during 5 consecutive days. The conditioning regimen in groups 1 and 2 combined fludarabine 30 mg/m2/day (day 5→day 1), intravenous (IV) busilvex (Pierre Fabre, Paris, France) 3.2 mg/kg/day (day 4, day 3) and anti-thymoglobulin (ATG; Genzyme, Lyon, France) 2.5 mg/kg/day (day 2, day 1). Graft-versus-host disease prophylaxis consisted of cyclosporine A at a dose of 3 mg/kg from day −1 associated with methotrexate given at days 1 (15 mg/m2), 3, and 6 (10 mg/m2) in case of ABO incompatibility. In group 1, by day 90 after transplantation, a disease response assessment was completed, patients not in CR received four cycles of IV bortezomib given at the dose of 1.3 mg/kg on days 1, 4, 8, and 11 during a 21-day cycle. After bortezomib, if the CR was not achieved or if a progressive disease appeared, increasing doses of DLIs were administered with a starting dose of 1 × 107 CD3+ cells/kg and the following infusions will be at 6-week intervals with a dose of half log higher. The study flowchart for group 1 is shown in Figure 1. Response rate was evaluated according to the EBMT criteria as described previously [15Blade J. Samson D. Reece D. et al.Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant.Br J Haematol. 1998; 102: 1115-1123Crossref PubMed Scopus (1474) Google Scholar]. GVHD was reported and graded according to published criteria [16Glucksberg H. Storb R. Fefer A. et al.Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.Transplantation. 1974; 18: 295-304Crossref PubMed Scopus (3115) Google Scholar]. Chronic GVHD was diagnosed according to standard criteria in patients who survived at least 90 days after transplantation [5Bensinger W.I. Buckner C.D. Anasetti C. et al.Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.Blood. 1996; 88: 2787-2793PubMed Google Scholar]. TRM was defined as death from any cause other than relapse occurring after transplantation. Relapse was defined based on morphologic evidence of hematopoietic disease in bone marrow or other sites. Overall survival (OS) was defined as the time from transplantation to any cause of death, and progression-free survival (PFS) was defined as survival from transplantation to disease progression. Cumulative incidence curves were used to estimate incidence over time of acute and chronic GVHD, TRM, and relapse. OS and PFS were estimated using the Kaplan-Meier method with a log-rank test for univariate analysis [17Kaplan E.L. Meier P. Non parametric estimationfrominomplete observations.J Am Stat Assoc. 1958; 53: 457Crossref Scopus (47473) Google Scholar]. Cox proportional-hazards regression models were used to assess the influence of disease- and transplant-related variables on OS and PFS [18Cox D.R. Regression models and life tables.J Royal Stat Soc B. 1972; 34: 187-220Google Scholar]. Statistical analysis was performed with R statistical software (version 2.9.2). Allo-HSCT groups included 25 patients (12 in group 1 and 13 in group 2), 18 men and 7 women with a median age of 51 years (range, 28–67 years), there were 15 IgG (11 kappa, 4 lambda), 7 IgA (5 kappa, 2 lambda), and 3 light-chain MMs. Thirteen (52%) patients had del13, 8 (32%) had del17, and 16 (64%) had a β2 microglobulin level greater than 3mg/L. Induction treatment was VAD based in 18 (72%) patients and bortezomib based in 7 (28%) patients. Twenty-one (84%) patients received high-dose melphalan (200 mg/m2), and the rest received a dose of 140 mg/m2; auto-HSCT was performed after a median time of 5.5 months (range, 3.6–15.3 months) from diagnosis. The median time between auto-HSCT and allo-HSCT was 3.8 months (range, 2.5–8.5 years). The stem cell source was PBSC in 22 (88%) cases, and the median number of infused CD34+ cells was 6.1 × 106 cells/kg (range, 2–13 cells/kg) from 16 identical siblings and 9 HLA (10/10) matched unrelated donors. Sex matching was as follows: F→M:9, F→F:3, M→F: 4 and M→M:9. For ABO compatibility, 18 (72%) were compatible, 1 had a minor incompatibility, and 6 had major incompatibilities. At allo-HSCT, one patient was in CR, four patients were in very good partial response (VGPR), and 20 patients were in PR. The matched population included 36 controls for group 1 and 39 for group 2, each patient had three controls with the same matched characteristics according to diagnosis date, age, gender, β2 microglobulin, cytogenetics, and induction treatment. Detailed patient characteristics of groups 1 and 2 separately with their controls are shown in Table 1.Table 1Group 1 and 2 patients and controls: characteristicsCharacteristicGroup 1 (n = 12)Controls for group 1 (n = 36)Group 2 (n = 13)Controls for group 2 (n = 39)Sex Male10 (83%)23 (64%)8 (61%)18 (46%) Female2 (17%)13 (36%)5 (39%)21 (54%)Age, years Median46565454 Range40–6027–6727–6528–66Subtype IgG9 (75%)30 (83%)6 (46%)21 (54%) IgA3 (25%)6 (17%)4 (31%)13 (33%) Light chains003 (23%)5 (13%)International staging system I010 (28%)06 (15%) II3 (25%)13 (36%)1 (8%)16 (41%) III9 (75%)13 (36%)12 (92%)17 (44%)β2 microglobilin > 3 mg/L7 (58%)23 (64%)9 (69%)30 (77%)Cytogenetics Del (13)8 (67%)28 (78%)5 (39%)14 (36%) t(4;14)4 (33%)13 (36%)2 (16%)6 (15%) Del (17p)5 (38%)11 (31%)3 (23%)9 (23%)Auto-HSCT induction VAD based9 (75%)27 (75%)9 (69%)27 (69%) Bortezomib based3 (25%)9 (25%)4 (31%)12 (31%)Disease status at allo-HSCT Partial response10 (83%)—10 (77%)— Better than partial response2 (17%)—3 (23%)—Interval diagnosis-allo-HSCT, months Median12—9— Range8–20—8–12—Cell source Peripheral blood12 (100%)—10 (77%)— Bone marrow0—3 (23%)—CD34+-injected cells × 106 cells/kg Median6.5—4.5— Range2.6–10.7—2.0–7.9—HSCT = hematopoietic stem cell transplantation; IG = immunoglobulin. Open table in a new tab HSCT = hematopoietic stem cell transplantation; IG = immunoglobulin. At day 90 after allo-HSCT, all patients were engrafted, 10 patients were in CR, and 15 patients were in less than CR. Patients not in CR should receive bortezomib according to the protocol in group 1, whereas while only nine patients received it; the six other patients did not have it following local investigator's decision because of VGPR status after transplant. Among patients who received bortezomib (n = 9), three reached a CR, and the six others remained in PR and received increasing doses of DLI (median number of infusions = 2; range, 1–5 doses). After transplantation, there were eight acute GVHD cases (seven grade II [three in group 1] and one grade III in group 1). There were 11 chronic GVHD cases (three were limited [all in group 1] and eight extensive [one in group 1]); no GVHD was observed after DLI. The cumulative incidence of acute GVHD grade II–IV at 3 months for the two allo-HSCT groups was 24% (95% confidence interval [CI], 16–32%), with a cumulative incidence of chronic GVHD that reached 11% (95% CI, 8–14%) at 1 year. At the last follow-up, 10 patients were in durable CR1 post–allo-HSCT (5/12 in group 1 [no GVHD] and 5/13 in group 2 [4 with chronic GVHD]) and four patients were in PR, all after having received bortezomib and DLI (all in group 1). At the last follow-up, 14 of 25 patients were alive (10 in CR, 4 in PR; 9/12 in group 1 and 5/13 in group 2) and 11 patients died—3 in group 1 (all from progression) and 8 in group 2 (5 from progression and 3 from TRM). Among the 11 dead patients (5 had del 17p), 8 died from progression and 3 died from TRM causes (infections after GVHD). After a median follow-up of 55 months (range, 3–142 months), the median OS was not reached in group 1, compared with 65 months (51-NR) in its matched patients (p = 0.027) with a 5-year probability of 83% (95% CI, 65–100%) versus 54.5% (95% CI, 40–75%); it was 96 months (49-NR) in group 2 versus 91 months (32-NR) in its matched patients (p = 0.77) with a 5-year probability of 54% (95% CI, 33–89%) versus 62% (95% CI, 48–80%). The median PFS was 49 months (29-NR) in group 1 versus 25 months (range, 21–35 months) in its matched patients (p = 0.0045) with a 5-year probability of 50% (95% CI, 28–88%) versus 25% (95% CI, 14–44%); it was 31 months (22-NR) in group 2 versus 28 months (range, 21–40 months) in its matched patients (p = 0.0776), with a 5-year probability of 38.5% (95% CI, 19–76%) versus 21% (95% CI, 11–40%) Figure 2. The cumulative incidence of TRM was 8% at 2 years and reached 12% at 4 years. Allogeneic HSCT remains controversial in the MM setting, and it seems fundamental to collect all data concerning this therapeutic strategy to draw strong recommendations especially, for patients with a poor prognosis. In our study, the interesting results observed in group 1 regarding survival and toxicity were probably related to (1) the introduction of IV busilvex in place of oral busulfan in the conditioning regimen (better pharmacokinetics and less toxicity especially on liver) [19Nath C.E. Shaw P.J. Busulphan in blood and marrow transplantation: dose, route, frequency and role of therapeutic drug monitoring.Curr Clin Pharmacol. 2007; 2: 75-91Crossref PubMed Scopus (38) Google Scholar], (2) the timing and the dose of ATG that was demonstrated to influence GVHD incidence and severity [20Mohty M. Boiron J.M. Damaj G. et al.Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation.Bone Marrow Transplant. 2004; 34: 77-84Crossref PubMed Scopus (70) Google Scholar], and (3) the role of bortezomib used after transplantation as an immunomodulating agent associated with DLI. Currently, autologous hematopoietic stem cell transplantation remains the gold standard for young patients with MM eligible for high-dose therapy [21Bird J.M. Owen R.G. D'Sa S. et al.Guidelines for the diagnosis and management of multiple myeloma 2011.Br J Haematol. 2011; 154: 32-75Crossref PubMed Scopus (239) Google Scholar, 22Fermand J.P. Katsahian S. Divine M. et al.High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe.J Clin Oncol. 2005; 23: 9227-9233Crossref PubMed Scopus (335) Google Scholar, 23Barlogie B. Kyle R.A. Anderson K.C. et al.Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321.J Clin Oncol. 2006; 24: 929-936Crossref PubMed Scopus (434) Google Scholar]. In association with novel agents during induction, consolidation, or maintenance therapy, the 3-year OS is reaching 80% [24Attal M. Lauwers-Cances V. Marit G. et al.Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1782-1791Crossref PubMed Scopus (874) Google Scholar, 25McCarthy P.L. Owzar K. Hofmeister C.C. et al.Lenalidomide after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1770-1781Crossref PubMed Scopus (886) Google Scholar, 26Kumar S.K. Lacy M.Q. Dispenzieri A. et al.Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma.Cancer. 2012; 118: 1585-1592Crossref PubMed Scopus (97) Google Scholar]. The emergence of new antimyeloma drugs has produced high response rates when used at different treatment points. In our study, more than half of patients received VAD as induction treatment, whereas the new drug and its different associations have been demonstrated to be superior in reducing the tumor burden before allo-HSCT. This observation is also applicable in the post–allo-HSCT setting by having an action on the residual disease [27Cavo M. Di Raimondo F. Zamagni E. et al.Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.J Clin Oncol. 2009; 27: 5001-5007Crossref PubMed Scopus (47) Google Scholar, 28Benson Jr., D.M. Panzner K. Hamadani M. et al.Effects of induction with novel agents versus conventional chemotherapy on mobilization and autologous stem cell transplant outcomes in multiple myeloma.Leuk Lymphoma. 2010; 51: 243-251Crossref PubMed Scopus (15) Google Scholar]. However, our view is that the introduction of the new drugs in the same way into the auto-allo setting followed by our new tandem strategy, including immunomodulation after transplant with bortezomib with or without DLI, might still improve the outcome even further with this approach. In a previous study, we showed promising results for bortezomib use for relapse after allogeneic HSCT with GVHD enhancement [29El-Cheikh J. Michallet M. Nagler A. et al.High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma.Haematologica. 2008; 93: 455-458Crossref PubMed Scopus (55) Google Scholar], in contrary to lenalidomide in the same indication [13Wolschke C. Stubig T. Hegenbart U. et al.Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: Results from a phase I/II dose-finding study.Exp Hematol. 2013; 41: 134-142.e133Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. In a recent study, bortezomib combined with tacrolimus and methotrexate proved to be an effective regimen to prevent GVHD after allo-RIC with mismatched unrelated donors [30Koreth J. Stevenson K.E. Kim H.T. et al.Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors.Blood. 2009; 114: 3956-3959Crossref PubMed Scopus (77) Google Scholar]. In our prospective group 1 study, the use of bortezomib after allo-HSCT showed acceptable GVHD rates and has considerably improved the overall response and disease control after allogeneic HSCT. There is still a debate concerning the best time to propose allogeneic transplantation for patients with MM. The prognosis of MM has improved substantially in the last decade, and the majority of younger patients can achieve and maintain remissions of excellent quality for a median of 3 years. However, it is hotly debated whether patients should be subjected to the morbidity and mortality of allo-HSCT as part of first-line therapy, even when a late survival benefit is further proven by the outcome of the expected donor versus no-donor comparisons [31Gahrton G. Iacobelli S. Bjorkstrand B. et al.Autologous/reduced-intensity allogeneic stem cell transplantation versus autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study.Blood. 2013; 121: 5055-5063Crossref PubMed Scopus (150) Google Scholar]. In the updated, randomized Italian study by Bruno et al. [32Bruno B. Rotta M. Patriarca F. et al.A comparison of allografting with autografting for newly diagnosed myeloma.N Engl J Med. 2007; 356: 1110-1120Crossref PubMed Scopus (435) Google Scholar], RIC allogeneic HSCT was proposed to MM patients with an HLA-identical sibling donor using a tandem approach versus a double-autologous transplantation [32Bruno B. Rotta M. Patriarca F. et al.A comparison of allografting with autografting for newly diagnosed myeloma.N Engl J Med. 2007; 356: 1110-1120Crossref PubMed Scopus (435) Google Scholar]. Although this study showed a significant improvement in terms of quality of response and OS, the TRM rate was only 11%. A recent Spanish study and an update of a previous IFM study failed to show a significant advantage of tandem auto-allogeneic approach as compared with double-autologous transplantation [7Garban F. Attal M. Michallet M. et al.Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.Blood. 2006; 107: 3474-3480Crossref PubMed Scopus (325) Google Scholar, 33Rosinol L. Perez-Simon J.A. Sureda A. et al.A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma.Blood. 2008; 112: 3591-3593Crossref PubMed Scopus (233) Google Scholar]. The IFM study has been updated recently, and long-term follow-up shows an advantage in the autologous transplantation arm [34Moreau P. Garban F. Attal M. et al.Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma.Blood. 2008; 112: 3914-3915Crossref PubMed Scopus (96) Google Scholar]. Nevertheless, the analysis of the IFM study was done with the intention to treat, and a nonnegligible number of patients did not proceed to allo-HSCT. In addition, this study was criticized for the inclusion of high-dose ATG 12.5 mg/kg in the conditioning regimen that might have negatively influenced the desired GVM effect, as measured by a relatively low CR rate of 23% and a high frequency of relapses [35Lokhorst H. No RIC in high-risk myeloma?.Blood. 2006; 107: 3420-3421Crossref Scopus (9) Google Scholar]. Recently, the EBMT has published the results of a large, prospective tandem auto-RIC–allo-HSCT versus auto-HSCT alone; the conditioning for the allo-HSCT arm was total-body irradiation (2 Gy) plus fludarabine (30 mg/m2/day for 3 days). Progression-free survival at 60 months was significantly better with auto-allo than with auto alone (33% vs 18%; p < 0,003), as was the risk of death and of relapse in the long term (p < 0.047 and p < 0.003, respectively) while the OS was not statistically different at 60 months (64% vs 57%. p = 0.204). However, at 96 months auto-allo was statistically superior (49% vs 36%, p = 0.030) [10Bjorkstrand B. Iacobelli S. Hegenbart U. et al.Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up.J Clin Oncol. 2011; 29: 3016-3022Crossref PubMed Scopus (146) Google Scholar, 31Gahrton G. Iacobelli S. Bjorkstrand B. et al.Autologous/reduced-intensity allogeneic stem cell transplantation versus autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study.Blood. 2013; 121: 5055-5063Crossref PubMed Scopus (150) Google Scholar]. Krishnan et al. [36Krishnan A. Pasquini M.C. Logan B. et al.Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial.Lancet Oncol. 2011; 12: 1195-1203Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar] compared 226 patients randomized to tandem auto/allo- SCT and 484 patients who received double auto-SCT. In the double–auto-SCT arm, 233 patients were randomly allocated to thalidomide plus dexamethasone, and 234 patients were allocated to observation. The 3-year PFS and OS were 43% and 77%, respectively, for the auto/allo-SCT group versus 46% and 80% for the double auto-SCT group. However, for the allo-arm in this study, a total body irradiation–based reduced intensity conditioning was used and 83% of patients received a second transplantation, which adds more toxicity to these patients and affects outcomes. When classifying patients into standard and high risk, none of the most important risk criteria were used, namely t(4;14) and del(17p) as recently demonstrated [37Avet-Loiseau H. Attal M. Campion L. et al.Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival.J Clin Oncol. 2012; 30: 1949-1952Crossref PubMed Scopus (166) Google Scholar], which makes it difficult draw conclusions about the results of this study in high-risk MM patients. Lokhorst et al. also evaluated in the HOVON-50 study the results of donor versus no-donor MM patients. The 99 patients who received the allo-SCT showed a significantly prolonged PFS compared with the 115 patients who proceeded to a second auto-SCT, without a survival benefit; this might be related to the use of novel agents after relapse. Moreover, cytogenetics included only del(13q) that in absence of other abnormalities, t(4;14) and del(17p), is no longer considered a high-risk feature [38Lokhorst H.M. van der Holt B. Cornelissen J.J. et al.Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study.Blood. 2012 Jun 28; 119: 6219-6225Crossref PubMed Scopus (88) Google Scholar]. In our group 1, despite all patients being considered poor risk for cytogenetics or high β2 microglobulin levels, the median OS was not reached and the PFS showed a median of 49 months. Moreover, the more interesting finding in our study is that those patients were matched with previous patients treated in the IFM studies, showing the important benefit of these patients from the new treatment strategy. In the 1990s and early 2000s, the use of DLI after myeloablative allo-HCT was associated with a high incidence of TRM and GVHD [39Lokhorst H.M. Wu K. Verdonck L.F. et al.The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma.Blood. 2004; 103: 4362-4364Crossref PubMed Scopus (159) Google Scholar, 40Salama M. Nevill T. Marcellus D. et al.Donor leukocyte infusions for multiple myeloma.Bone Marrow Transplant. 2000; 26: 1179-1184Crossref PubMed Scopus (158) Google Scholar]. More recent use of DLI after RIC allo-HCT in gradually escalating doses was associated with a lower risk of GVHD and improved overall survival [41Peggs K.S. Thomson K. Hart D.P. et al.Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.Blood. 2004; 103: 1548-1556Crossref PubMed Scopus (184) Google Scholar, 42van de Donk N.W. Kroger N. Hegenbart U. et al.Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma.Bone Marrow Transplant. 2006; 37: 1135-1141Crossref PubMed Scopus (86) Google Scholar, 43Peggs K.S. Mackinnon S. Williams C.D. et al.Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity.Biol Blood Marrow Transplant. 2003; 9: 257-265Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. Our results for group 1 were consistent with earlier reports showing the benefit of escalating doses of preemptive DLI in achieving good disease control with minimal GVHD. In addition, we showed a good GVM effect, especially after DLI with a durable stability of the disease without any important GVHD complication. Finally, there is no clear positioning of International Myeloma Working Group consensus regarding the statement [6Lokhorst H. Einsele H. Vesole D. et al.International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.J Clin Oncol. 2010; 28: 4521-4530Crossref PubMed Scopus (141) Google Scholar] that allo-HSCT in MM should be recommended only in the context of clinical trials. RIC allo-HSCT should be considered part of a whole strategy from diagnosis to the end of immunomodulation in comparison with the state of the art in the auto-HSCT settings, with a possible consolidation after autologous transplant followed by a maintenance therapy, which seems useful in relapse prevention [24Attal M. Lauwers-Cances V. Marit G. et al.Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1782-1791Crossref PubMed Scopus (874) Google Scholar]. According to our promising results, the use of tandem auto-RIC–allo-HSCT, including new agent combinations and immunomodulation after transplantation, could be reconsidered in the context of first-line treatment for MM, especially for patients with poor prognostic factors. Results need to be confirmed in prospective randomized clinical trials. The prospective study was registered on ClinicalTrial.gov (no. NCT00466674). Author contributions: M.M. and M.M. designed the protocol; all coauthors contributed to patient enrolment and data collection and approved the final report; M.M., M.S., and M.M. wrote the manuscript. No financial interest/relationships with financial interest relating to the topic of this article have been declared.
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