www.thelancet.com/oncology Vol 12 May 2011 431 Articles Lancet Oncol 2011; 12: 431–40 Published Online April 19, 2011 DOI:10.1016/S1470- 2045(11)70081-X This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on XX XX, 2011 See Comment page 410 University Hospital, Nantes, France (Prof P Moreau MD); Cherkassy Regional Oncology Dispensary, Cherkassy, Ukraine (H Pylypenko MD); Oddzial Hematologiczny ZSM, Chorzow, Poland (S Grosicki MD); Kiev BMT Centre, Kiev, Ukraine (I Karamanesht MD); Hôpital Huriez, CHRU, Lille, France (X Leleu MD); Nizhniy Novgorod Region Clinical Hospital, Nizhniy Novgorod, Russia (M Grishunina MD); Khmelnitskiy Regional Hospital, Khmelnitskiy, Ukraine (G Rekhtman MD); SI Institute of Blood Pathology and Transfusion Medicine UAMS, Lviv, Ukraine (Z Masliak MD); Medical University of Lodz, Lodz, Poland (Prof T Robak MD); SP Botkin Moscow City Clinical Hospital, Moscow, Russia (A Shubina MD); Hôpital Saint-Louis, Paris, France (B Arnulf MD); University of Munster, Munster, Germany (M Kropff MD); The Christie NHS Foundation Trust and University of Manchester, Manchester, UK (J Cavet MBBS); Millennium Pharmaceuticals, Cambridge, MA, USA (D-L Esseltine MD); Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ, USA (H Feng PhD, S Girgis PhD); Janssen Research and Development, Beerse, Belgium (H van de Velde MD, Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study Philippe Moreau, Halyna Pylypenko, Sebastian Grosicki, Ievgenii Karamanesht, Xavier Leleu, Maria Grishunina, Grigoriy Rekhtman, Zvenyslava Masliak, Tadeusz Robak, Anna Shubina, Bertrand Arnulf, Martin Kropff, James Cavet, Dixie-Lee Esseltine, Huaibao Feng, Suzette Girgis, Helgi van de Velde, William Deraedt, Jean-Luc Harousseau Summary Background Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the eicacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m² 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/m², 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, stratiied 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 deined as retaining 60% of the intravenous treatment efect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. Findings 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 diference –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 signiicant diferences 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 signiicantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Interpretation Subcutaneous bortezomib ofers non-inferior eicacy to standard intravenous administration, with an improved safety proile. Funding Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals. Introduction The introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide have contributed to improvements in overall survival in patients with multiple myeloma. 1 Bortezomib-based therapies are suggested as standards of care in patients with newly diagnosed and relapsed multiple myeloma, 2,3 including the approved indication of bortezomib plus melphalan and prednisone for previously untreated patients who are ineligible for stem-cell transplantation, 4,5 bortezomib-based induction regimens for transplant patients, 6,7 and the approved indication of bortezomib alone or in combination with pegylated liposomal doxorubicin for patients with relapsed multiple myeloma. 8–10 The recommended dose and schedule of bortezomib is 1·3 mg/m² administered as a 3–5-s bolus intravenous injection on days 1, 4, 8, and 11 of 21-day cycles. 11,12 This regimen is active and well tolerated in patients with relapsed multiple myeloma. 8,9,13–15 As an alternative to