title: 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.
abstract: BACKGROUND
  Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT.
  
  
  METHODS
  In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1:1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and β2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829.
  
  
  RESULTS
  Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0·671); overall survival also did not differ at 3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0·191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group).
  
  
  CONCLUSIONS
  Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach.
  
  
  BACKGROUND
  US National Heart, Lung, and Blood Institute and the National Cancer Institute.
authors.affiliation: City of Hope Cancer Center, Los Angeles, CA, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Krishnan
authors.forename: Marcelo C
authors.initials: MC
authors.lastname: Pasquini
authors.forename: Brent
authors.initials: B
authors.lastname: Logan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: David H
authors.initials: DH
authors.lastname: Vesole
authors.forename: Edwin
authors.initials: E
authors.lastname: Alyea
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Raymond
authors.initials: R
authors.lastname: Comenzo
authors.forename: Stacey
authors.initials: S
authors.lastname: Goodman
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.forename: Ginna
authors.initials: G
authors.lastname: Laport
authors.forename: Muzaffar H
authors.initials: MH
authors.lastname: Qazilbash
authors.forename: Scott
authors.initials: S
authors.lastname: Rowley
authors.forename: Firoozeh
authors.initials: F
authors.lastname: Sahebi
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Marian
authors.initials: M
authors.lastname: Ewell
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Geller
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.forename: David G
authors.initials: DG
authors.lastname: Maloney
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D020350:Graft vs Tumor Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000601:surgery*; D019653:Myeloablative Agonists / Q000627:therapeutic use; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage; D013997:Time Factors; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D019653:Myeloablative Agonists; D013792:Thalidomide; D003907:Dexamethasone