title: Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.
abstract: BACKGROUND
  The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial.
  
  
  METHODS
  We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363.
  
  
  RESULTS
  Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070).
  
  
  CONCLUSIONS
  This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future.
  
  
  BACKGROUND
  Pethema (Spanish Program for the Treatment of Hematologic Diseases).
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer, Salamanca, Spain. Electronic address: mvmateos@usal.es.
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Mateos
authors.affiliation: Hospital Universitario de Canarias, Tenerife, Spain.
authors.forename: Miguel-Teodoro
authors.initials: MT
authors.lastname: Hernández
authors.affiliation: Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
authors.affiliation: Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: de la Rubia
authors.affiliation: Hospital Morales Messeguer, Murcia, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: de Arriba
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer, Salamanca, Spain.
authors.forename: Lucía López
authors.initials: LL
authors.lastname: Corral
authors.affiliation: Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosiñol
authors.affiliation: Clínica Universidad de Navarra, CIMA, IDISNA, Pamplona, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Paiva
authors.affiliation: Hospital Lozano Blesa, Zaragoza, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Palomera
authors.affiliation: Hospital Sont Llatzer, Palma de Mallorca, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bargay
authors.affiliation: Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Clínica Universidad de Navarra, CIMA, IDISNA, Pamplona, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.affiliation: Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: López
authors.affiliation: Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: José-María
authors.initials: JM
authors.lastname: Arguiñano
authors.affiliation: Celgene, Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Quintana
authors.affiliation: Celgene, Madrid, Spain.
authors.forename: José-Luis
authors.initials: JL
authors.lastname: García
authors.affiliation: Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Juan-José
authors.initials: JJ
authors.lastname: Lahuerta
authors.affiliation: Clínica Universidad de Navarra, CIMA, IDISNA, Pamplona, Spain.
authors.forename: Jesús-F San
authors.initials: JS
authors.lastname: Miguel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016022:Case-Control Studies; D003907:Dexamethasone / Q000008:administration & dosage; D005500:Follow-Up Studies; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D003907:Dexamethasone; D000077269:Lenalidomide; D013792:Thalidomide