title: Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.
abstract: BACKGROUND
  Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma.
  
  
  METHODS
  This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up.
  
  
  RESULTS
  222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated.
  
  
  CONCLUSIONS
  Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile.
  
  
  BACKGROUND
  Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.
authors.affiliation: University Hospital, Nantes, France. philippe.moreau@chu-nantes.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: Halyna
authors.initials: H
authors.lastname: Pylypenko
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grosicki
authors.forename: Ievgenii
authors.initials: I
authors.lastname: Karamanesht
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Maria
authors.initials: M
authors.lastname: Grishunina
authors.forename: Grigoriy
authors.initials: G
authors.lastname: Rekhtman
authors.forename: Zvenyslava
authors.initials: Z
authors.lastname: Masliak
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Anna
authors.initials: A
authors.lastname: Shubina
authors.forename: Bertrand
authors.initials: B
authors.lastname: Arnulf
authors.forename: Martin
authors.initials: M
authors.lastname: Kropff
authors.forename: James
authors.initials: J
authors.lastname: Cavet
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Huaibao
authors.initials: H
authors.lastname: Feng
authors.forename: Suzette
authors.initials: S
authors.lastname: Girgis
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: William
authors.initials: W
authors.lastname: Deraedt
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001208:Asia; D001773:Blood Cells / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects*; D000069286:Bortezomib; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology / Q000473:pathology; D009367:Neoplasm Staging; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects*; D012008:Recurrence; D013020:South America; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib