Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Attal M, Lauwers-Cances V, Marit G, et al. maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 202;366:782-9.

2 Supplementary Appendix Supplement to: Maintenance Treatment with after Transplantation for Multiple Myeloma. Content Page Part I Collaborators Part II Additional Methods 2-3 Part III Supplementary Figures 4-7 Part IV Supplementary Table 8-9 Attal IFM 2005 Supplementary Appendix 0

3 Supplementary Appendix Part I Collaborators. In addition to the authors, the following investigators listed in alphabetical order participated in the study: P. Agape, Centre Hospitalier Départemental, Saint-Denis; N. Ali-Ammar, Centre Hospitalier, Troyes; D. Assouline, Groupe Hospitalier Mutualiste, Grenoble; B. Audhuy, Centre Hospitalier Louis Pasteur, Colmar; A. Banos, Centre Hospitalier de la côte basque, Bayonne; B. Bareau, Centre Hospitalier Yves Le Foll, Saint-Brieuc; K. Belhadj, CHU Henri Mondor, Créteil; C. Berthou, Hôpital A.Morvan, Brest; F. Boue, Hôpital Antoine Béclère, Clamart; N. Boullanger, Centre Hospitalier, Roanne; D. Bouscary, Hôpital Cochin, Paris; R. Burkhard, Stadtspital Triemli, Zurich; S. Cailleres, Centre Hospitalier du Pays d Aix, Aix en Provence; P. Casassus, Hôpital Avicenne, Bobigny; C. Chateleix, CHU Estaing, Clermont-Ferrand; B. Coiffier, Centre Hospitalier Lyon sud, Pierre-Bénite; R. De Bock, Middelheim, Antwerpen; H. Demuynck, Heilig Hartziekenhuis, Roeselare; M. Dib, Hôpital du Bocage, Angers; V. Dorvaux, Hôpital Notre Dame de Bon Secours, Metz; C. Driessen, Kantonsspital, Saint- Gallen; O. Fitoussi, Polyclinique Bordeaux Nord Aquitaine, Bordeaux; J. Fontan, Hôpital Jean Minjoz, Besançon; C. Fruchart, Centre F.Baclesse, Caen; JG. Fuzibet, Hôpital Archet, Nice; A. Gratwohl, Universitätsspital, Basel; B. Grosbois, Hôpital Sud, Rennes; M. Heizmann, Kantonsspital, Aarau; H. Jardel, Centre Hospitalier P. Chubert, Vannes; J. Jaubert, Institut de Cancérologie de la Loire, Saint-Etienne; N. Ketterer, Centre Hospitalier Universitaire, Lausanne; B. Kolb, Hôpital Robert Debré, Reims; L. Lacotte Thierry, Hôpital Jean Bernard, Poitiers; T. Lamy, Hôpital de Pontchaillou, Rennes; P. Lenain, Centre Henri Becquerel, Rouen ; G. Lepeu, Centre Hospitalier H.Duffaut, Avignon; X. Levaltier, Polyclinique du parc, Caen; B. Lioure, Hôpital de Hautepierre, Strasbourg; M. Maigre, Centre Hospitalier, Chartres; H. Maisonneuve, Centre Hospitalier Départemental, La Roche sur Yon; T. Matthes, HCUG, Genève; N. Meuleman, Institut Jules Bordet, Bruxelles ; P. Mineur, Hôpital Saint-Joseph, Gilly; P. Moreau, Centre Hospitalier Bodélio, Lorient; Orsini-Piocelle, Centre Hospitalier de la région d Annecy, Pringy; T. Pabst, Inselspital, Bern; P. Pierre, Hôpital Saint-Joseph, Arlon; D. Rauch, Spital, Thun; C. Ravoet, Hôpital Jolimont, Haine Saint Paul; T. De Revel, Hôpital d instruction des armées Percy, Clamart; B. Rio, Hôtel Dieu, Paris; P. Rodon, Centre Hospitalier, Blois; V. Salle, CHRU, Amiens; G. Sebahoun, Hôpital Nord, Marseille; C. Sebban, Centre Léon Bérard, Lyon; L. Sutton, Centre Hospitalier Victor Dupouy, Argenteuil; A. Thyss, Centre Antoine Lacassagne, Nice; E. Van Den Neste, UCL Saint-Luc, Bruxelles; A. Vandevelde, UZA, Antwerpen; M. Wetterwald, Centre Hospitalier Général, Dunkerque; P. Zachee, Algemeen Centrumziekenhuis, Antwerpen; E. Zucca, Iosi Ospedale San Giovanni, Bellinzona; P. Zunic, Groupe Hospitalier Sud Réunion, Saint-Pierre. Attal IFM 2005 Supplementary Appendix

4 Supplementary Appendix Part II Additional Methods. Dose modifications During consolidation, the dose of lenalidomide was managed according to established dosemodification guidelines. During maintenance, in case of a grade 3 or 4 adverse event, treatment was withheld and restarted at the next lower daily dose. The dose of lenalidomide was modified as follows: 0 mg (dose level, -), or 5 mg (dose level, -2). Blood counts were performed each week during consolidation, each week during the maintenance cycles to 2, on days and 4 during maintenance cycles 3 to 4, then on day of each subsequent maintenance cycle. Myeloma Working Group Uniform Response Criteria scr = stringent Complete Response CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence CR = Complete Response Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow VGPR= Very Good Partial Response 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 <00 mg per 24 h PR= Partial Response 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg 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, 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 SD= Stable Disease (not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates) Not meeting criteria for CR, VGPR, PR or progressive disease PD= Progressive Disease (to be used for calculation of time to progression and progressionfree survival end points for all patients including those in CR; includes primary progressive disease and disease progression on or off therapy). Any one or more of the following: -Increase of 25% from baseline in *Serum M-component and/or (the absolute increase must be 0.5 g/dl) *Urine M-component and/or (the absolute increase must be 200 mg/24 h *Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be 0 mg/dl. Attal IFM 2005 Supplementary Appendix 2

5 *Bone marrow plasma cell percentage: the absolute % must be 0% -Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas -Development of hypercalcemia (corrected serum calcium.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder Two consecutive assessments made at any time are required; no known evidence of progressive or new bone lesions if radiographic studies were performed is also required. Radiographic studies are not required to satisfy these response criteria. Adapted from: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: Attal IFM 2005 Supplementary Appendix 3

6 Supplementary Appendix Part III Supplementary Figures. Figure S. Progression-Free Survival Hazard Ratio by patient Subgroup. The figure shows that the progression-free survival benefit associated with lenalidomide maintenance is consistent across all subgroups of patients defined by age, gender, type of myeloma, ISS stage, baseline beta-2 microglobulin level, cytogenetic abnormalities, induction regimen, number of transplant, and response at randomization. Subgroup Age < 55 years 55 years Gender Male Female Type of Myeloma IgG IgA Light chain International Staging System Stage I Stage II Stage III Serum beta-2 migroglobulin level 3 mg/liter > 3 mg/liter Cytogenetic abnormalities 3 q deletion No 3 q deletion t(4;4) or 7 p deletion Neither t(4;4) nor 7 p deletion Type of induction therapy VAD VD Number of transplant transplant 2 transplants Response at randomization At least VGPR < VGPR Hazard Ratio for p-value for Progression or Death no. of events / no. of patients interaction 4 / / / / / / 62 5 / 47 3 / / 04 3 / / 34 7 / / 4 44 / 6 2 / / / 4 43 / / / / / 04 6 / / / 8 60 / / / / / / / / / / 6 74 / 67 7 / / / / / / / / better better VAD denotes vincristine, doxorubicin and dexamethasone, VD bortezomib and dexamethasone, VGPR a very good partial response. The position of each square represents the point estimate of the treatment effect and horizontal lines represent 95% confidence intervals. Attal IFM 2005 Supplementary Appendix 4

7 Patients (%) Patients (%) Supplementary Appendix Part III Supplementary Figures. Figure S2. Kaplan-Meier Curves for the Progression-free Survival and Overall Survival according to Treatment Group (Intention-to treat population) as of October 20. Panel A shows the progression-free survival P< N at risk Months of follow-up Panel B shows the overall survival P= N at risk Months of follow-up Attal IFM 2005 Supplementary Appendix 5

8 Patients (%) Supplementary Appendix Part III Supplementary Figures. Figure S3. Cumulative Incidence of Second Primary Malignancy in the and Arms P= N at risk Months of follow-up Attal IFM 2005 Supplementary Appendix 6

9 Patients (%) Supplementary Appendix Part III Supplementary Figures. Figure S4. Kaplan-Meier Curves for the Event-free Survival (including Second Primary Malignancy as an Event) according to Treatment Group (Intention-to treat population) as of October 20. The median event-free survival was 40 months in the lenalidomide group and 23 months in the placebo group (hazard ratio, 0.54; P<0.00) P< N at risk Months of follow-up Attal IFM 2005 Supplementary Appendix 7

10 Supplementary Appendix Part IV Supplementary Tables. Table S. Unadjusted and Adjusted Hazard Ratios for the Risk of Second Primary Malignancy.* Univariate analysis Multivariate analysis Variable HR (95% CI ) p HRa (95% CI ) p Treatment arms 2.36 ( ) ( ) 0.03 Age Less than 55 years years Gender Male Female International Staging System I II III Serum beta-2 microglobulin 3 mg/liter > 3 mg/liter Cytogenetic abnormalities 3 q deletion t(4-4) or 7 p deletion Type of induction therapy VAD VD Others Induction reinforced with DCEP 2.66 ( ) ( ) ( ) 3.96 ( ) 0.76 < ( ) 0..9 ( ).46 ( ).9 ( ).32 ( ).62 ( ) (.9-5.7) ( ) ( ) 3.36 ( ) Number of transplant (0.4-2.) 0.85 *Only the first occurrence of second primary malignancy is taken into account in this analysis (37 events, in the placebo group and 26 in the group). HR and HRa denote unadjusted and adjusted Hazard ratios, CI confidence interval. P values are from a Wald test. The selection of exposure variables for the multivariate analysis was based on preliminary univariate Cox regression analyses. All variables with an alpha level of less than 20 percent according to the Wald test were retained for the multivariate analysis. A manual backward stepwise procedure was used to select explanatory variables with statistically significant effects. Serum beta-2 microglobulin level was not entered in the multivariate analysis because it is already included in the International Staging System classification. Data are from fluorescence in situ hybridization. Attal IFM 2005 Supplementary Appendix 8

11 VAD denotes vincristine, doxorubicin, and dexamethasone, VD bortezomib and dexamethasone, DCEP dexamethasone, cyclophosphamide, etoposide, and cis-platinum. Attal IFM 2005 Supplementary Appendix 9