title: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial.
abstract: BACKGROUND
  Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects.
  
  
  METHODS
  Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235.
  
  
  RESULTS
  In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy.
  
  
  CONCLUSIONS
  Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma.
  
  
  BACKGROUND
  Pethema (Spanish Program for the Treatment of Hematologic Diseases).
authors.affiliation: University Hospital of Salamanca, Salamanca, Spain. mvmateos@usal.es
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Mateos
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.forename: Joaquín
authors.initials: J
authors.lastname: Martínez-López
authors.forename: Norma
authors.initials: N
authors.lastname: Gutiérrez
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Teruel
authors.forename: Raquel
authors.initials: R
authors.lastname: de Paz
authors.forename: José
authors.initials: J
authors.lastname: García-Laraña
authors.forename: Enrique
authors.initials: E
authors.lastname: Bengoechea
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín
authors.forename: Joaquín Díaz
authors.initials: JD
authors.lastname: Mediavilla
authors.forename: Luis
authors.initials: L
authors.lastname: Palomera
authors.forename: Felipe
authors.initials: F
authors.lastname: de Arriba
authors.forename: Yolanda
authors.initials: Y
authors.lastname: González
authors.forename: Jose-Mariano
authors.initials: JM
authors.lastname: Hernández
authors.forename: Ana
authors.initials: A
authors.lastname: Sureda
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Bello
authors.forename: Joan
authors.initials: J
authors.lastname: Bargay
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Peñalver
authors.forename: José-María
authors.initials: JM
authors.lastname: Ribera
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Martín-Mateos
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.forename: María-Teresa
authors.initials: MT
authors.lastname: Cibeira
authors.forename: María-Luisa Martín
authors.initials: ML
authors.lastname: Ramos
authors.forename: María-Belén
authors.initials: MB
authors.lastname: Vidriales
authors.forename: Bruno
authors.initials: B
authors.lastname: Paiva
authors.forename: María-Angeles
authors.initials: MA
authors.lastname: Montalbán
authors.forename: Juan-José
authors.initials: JJ
authors.lastname: Lahuerta
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
authors.forename: Jesús-Fernando San
authors.initials: JF
authors.lastname: Miguel
mesh_terms: D000367:Age Factors; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011480:Protease Inhibitors / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain; D013792:Thalidomide / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D008558:Melphalan; D011241:Prednisone