Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Cook G, Williams C, Brown JM, et al, on behalf of the National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; published online JUne 17. http://dx.doi.org/10.1016/s1470-2045(14)70245-1.
Supplementary Appendix Content Page Part I Collaborators 2 Part II Additional Methods 4 Part III Supplementary Figures 5 Part IV Supplementary Tables 6 1
Supplementary Appendix Part I Collaborators In addition to the authors, the following investigators (listed in alphabetical order) participated in the study: Recruiting centre Principal Investigator Number of participants registered Nottingham University Hospital Dr Cathy Williams 30 University College London Hospital Dr Kwee Yong 17 Royal Hallamshire Hospital Dr John Snowden 14 Leeds Teaching Hospitals Prof Gordon Cook 14 Derriford Hospital Dr Hannah Hunter 11 Christie Hospital Dr Jim Cavet 10 St. Bartholomew's Hospital Dr Heather Oakervee 10 Bristol Haematology & Oncology Centre Dr Jenny Bird 9 Birmingham Heartlands Hospital Dr Guy Pratt 8 Gloucestershire Royal Hospital Dr Sally Chown 8 Glan Clwyd Dr Earnest Heartin 7 Manchester Royal Infirmary Dr Eleni Tholouli 7 Addenbrookes Hospital Dr Jenny Craig 7 Ipswich Hospital Dr A J Ademokun 7 Royal Derby Hospital Dr David Allotey 7 Castle Hill Hospital Dr Haz Sayala 7 Medway Maritime Hospital Dr Vivienne Andrews 6 Southampton University Hospital Dr Matthew Jenner 6 Guy s & St Thomas NHS Foundation Trust Dr Majid Kazmi 5 Frenchay Hospital Dr Alastair Whiteway 5 Singleton Hospital Dr Hamdi Sati 5 Kings College Hospital Prof Steve Schey 5 Leicester Royal Infirmary Dr Claire Chapman 5 James Cook Hospital Dr Angela Wood 4 St Helier & Epsom Hospitals Dr Simon Stern 4 Queen Elizabeth Hospital, Birmingham Dr Mark Cook 4 Aberdeen Royal Infirmary Dr Jane Tighe 4 Colchester Hospital Dr Gavin Campbell 4 Rotherham General Hospital Dr Helen Barker 4 Beatson West of Scotland Cancer Centre Dr Grant McQuaker 4 Belfast City Hospital Dr Mary Drake 4 2
Ysbyty Gwynedd Dr Melinda Hamilton 3 Stafford Hospital Dr Paul Revell 3 Royal Berkshire NHS Foundation Trust Dr Henri Grech 3 Chesterfield Royal Hospital Dr Emma Welch 3 Doncaster Royal Infirmary Dr Youssef Sorour 3 St Georges Hospital Dr Fenella Willis 3 Ninewells Hospital Dr Duncan Gowans 2 Bradford Royal Infirmary Dr Samuel Ackroyd 2 Crosshouse and Ayr Hospitals Dr Julie Gillies 2 Norfolk & Norwich Hospital Dr Martin Auger 2 Diana Princess of Wales Hospital Dr Susan Levison Keating 2 Raigmore Hospital Dr Peter Forsyth 2 Royal Devon & Exeter Hospital Dr Malcolm Hamilton 2 Sandwell & West Birmingham Hospitals Dr Farooq Wandroo 2 University Hospital Coventry Dr Syed Bokhari 2 University Hospital of Wales, Cardiff Dr Keith Wilson 2 Dorset County Hospital Dr Akeel Moosa 2 Queens Hospital, Burton Dr Hamayun Ahmed 2 Torbay Hospital Dr Deborah Turner 2 Cheltenham General Hospital Dr Sally Chown 1 The Great Western Hospital, Swindon Dr Norbert Blesing 1 United Lincolnshire Hospitals Dr Kandeepan Saravanamuttu 1 Peterborough District Hospital Dr S Kumar Nagumantry 1 Salisbury Hospital Dr Jonathan Cullis 1 Mid Yorkshire Hospitals NHS Trust Dr John Ashcroft 1 Russells Hall Hospital Dr Savio Fernandes 1 Countess of Chester Hospital Dr Salaheddin Tueger 1 Royal Oldham Hospital Dr Vivek Sen 1 Warwick Hospital Dr Anton Borg 1 Royal Bournemouth Hospital Dr Helen McCarthy 1 3
Supplementary Appendix Part II Additional Methods International Myeloma Working Group uniform response criteria Response subcategory scr CR VGPR PR SD e Response criteria a CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrow b by immunohistochemistry or immunofluorescence c Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow b Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 h 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200mg per 24 h If the serum and urine M-protein are unmeasurable, a 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria If serum and urine M-protein are unmeasurable d, and serum free light assay is also unmeasurable, 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was 30% In addition to the above listed criteria, if present at baseline, a 50% reduction in the size of soft tissue plasmacytomas is also required Not meeting criteria for CR, VGPR, PR or progressive disease CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; scr, stringent complete response; VGPR, very good partial response. a All response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. b Confirmation with repeat bone marrow biopsy not needed. c Presence/absence of clonal cells is based upon the / ratio. An abnormal / ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is / of >4:1 or <1:2. d Definitions of measurable disease Response criteria for all categories and subcategories of response except CR are applicable only to patients who have measurable disease defined by at least one of the following three measurements: Serum M-protein 1 g/dl ( 10 gm/l)[10 g/l] Urine M-protein 200 mg/24 h Serum FLC assay: Involved FLC level 10 mg/dl ( 100 mg/l) provided serum FLC ratio is abnormal e Not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates. 4
Supplementary Appendix Part IIII Supplementary Figures Figure 1: Reasons for patients nott being included in the randomization 40 35 33.8 30 25 22.5 255 Percent 20 15 13.8 10 7.5 5 0 Withdrew consent Insufficient HPC Co-morbidity PD DeathD 5
Supplementary Appendix part IV Supplementary Tables Table 1: Status of patients in the trial at trial closure (21 November 2012) Total (n=297) Participants have completed PAD treatment (not undergone randomization and never going to knew pre-21 November 2012) 106 (35.7%) Participants have not yet completed PAD treatment 17 (5.7%) Participants have completed ASCT (>100 days post-asct) 86 (29.0%) Participants have undergone randomization but not yet started treatment (ASCT) 3 (1.0%) Participants have completed cyclophosphamide-weekly (>30 days post-end of cyclophosphamide-weekly) 80 (26.9%) Participants have undergone randomization but not yet started treatment (cyclophosphamide-weekly) 5 (1.7%) Table 2: Response to induction and ASCT front-line and at relapse in randomized patients % Response to front-line induction (n=174) Response to frontline ASCT (n=174) Response to PAD induction (n=297) Response to salvage ASCT (n=89) scr/cr 27.6 52.9 16.5 39.3 VGPR/PR 65 40.1 62.6 43.8 SD 4.4 4.7 14.8 4.5 Table 3: Response to salvage ASCT by response to first-line ASCT Response rates to first-line ASCT Response rates to salvage ASCT % scr/cr VGPR/PR SD Total scr/cr 31.5 16.9 1.1 49.4 VGPR/PR 5.6 24.7 3.4 33.7 SD 2.3 2.3 0 4.5 Total 39.3 43.8 4.5 Table 4: Unadjusted Cox regression analysis for time to progression (TTP), progression-free survival (PFS) and overall survival. Parameter DF Estimate Hazard Ratio 95% CI for HR Test statistic p-value Estimate (HR) TTP 1-0.97 0.38 [0.26, 0.55] 25.37 <.0001 PFS 1-0.99 0.37 [0.26, 0.54] 27.23 <.0001 OS 1-0.43 0.65 [0.32, 1.33] 1.40 0.24 6