Effect of cumulative bortezomib dose on survival in multiple myeloma. patients receiving bortezomib-melphalan-prednisone in the phase III

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1 Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study María-Victoria Mateos, 1 Paul G. Richardson, 2 Meletios A. Dimopoulos, 3 Antonio Palumbo, 4 Kenneth C. Anderson, 2 Hongliang Shi, 5 Jennifer Elliott, 6 Edward Dow, 6 Helgi van de Velde, 7 Liviu Niculescu 6 and Jesús F. San Miguel 8 1 Hospital Universitario Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Spain, 2 Dana-Farber Cancer Institute, Boston, MA, USA, 3 Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, 4 Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria (AOU) S. Giovanni Battista, Torino, Italy, 5 Takeda Pharmaceuticals International Co., Cambridge, MA, USA, 6 Millennium: The Takeda Oncology Company, Cambridge, MA, USA, 7 Janssen Research & Development (Division of Janssen Pharmaceutica NV), Beerse, Belgium and 8 Clinica Universidad de Navarra, Centro Investigación Medica Aplicada, Pamplona, Spain Correspondence: María-Victoria Mateos, Servicio de Hematología, Hospital Universitario de Salamanca, Instituto Biosanitario de Salamanca (IBSAL), Paseo San Vicente , Salamanca 37007, Spain; Tel: ; Fax: ; mvmateos@usal.es. Article type: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an Accepted Article, doi: /ajh.23933

2 American Journal of Hematology Page 2 of 32 Abstract word count: 225 words. Word count: 3,425 words (inc. Acknowledgments: 94 words; Disclosure information: 132 words) [Max: XXX]. Tables: 3. Figures: 3. References: 24. Running short title: Effect of cumulative bortezomib dose on survival Keywords: hematology, clinical trials, long-term survival 2

3 Page 3 of 32 American Journal of Hematology Abstract This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m 2 ; this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher ( 39 mg/m 2 ) versus lower (<39 mg/m 2 ) cumulative bortezomib dose group (median 66.3 vs months; hazard ratio [HR] 0.533, P < ; age-adjusted HR 0.561, P = ). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27% vs 4% of patients discontinued due to adverse events in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs months; HR 0.709, P = ). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive adverse event management. 3

4 American Journal of Hematology Page 4 of 32 Introduction Bortezomib (VELCADE ) is a therapeutic proteasome inhibitor that has a key role in the treatment of both previously untreated and relapsed/refractory multiple myeloma (MM) 1. In the USA, bortezomib is approved for the treatment of MM 2 ; in the EU, bortezomib is indicated in different combination regimens for previously untreated MM patients not eligible for high-dose chemotherapy, as an induction regimen for previously untreated MM patients eligible for high-dose chemotherapy, and for relapsed MM 3. The results of the pivotal Phase III VISTA study on which approval in the frontline non-high-dose chemotherapy setting was based showed that intravenous (IV) bortezomib (administered on a twice-weekly schedule for four 6-week cycles, followed by a once-weekly schedule for five 6-week cycles) combined with melphalan and prednisone (VMP) was superior to melphalan-prednisone (MP) in terms of response rates, time to progression (TTP), and overall survival (OS) in transplant-ineligible patients with previously untreated MM 4-6. However, VMP was associated with increased toxicity compared with MP, including higher rates of peripheral neuropathy (PN) 5. Subsequent national cooperative group studies conducted in Spain (PETHEMA study GEM2005MAS65) 7;8 and Italy (GIMEMA study MM-03-05) 9-11 have attempted to optimize bortezomib dosing within combination regimens (including using weekly bortezomib administration during induction and prolonging therapy through maintenance approaches) to reduce toxicity without compromising efficacy. Recent research suggests that the paradigm of extended treatment leads to better outcomes for MM patients This is particularly relevant to bortezomib as 4

5 Page 5 of 32 American Journal of Hematology recent developments in the administration of bortezomib, specifically the introduction of subcutaneous (SC) bortezomib 14;15, may allow for a longer duration of therapy and hence may provide an opportunity for improved patient outcomes 14;15. Although clinical trials provide some guidance on the duration of bortezomib therapy, there is currently no widely accepted clinical guidance on the optimal duration of bortezomib treatment. However, treatment duration itself is not always a reflection of the actual dose of drug received by patients, as dose/schedule modifications during the course of treatment can impact on the planned dose; another measure for the concept of extended therapy may therefore be the cumulative dose, which takes into account both the actual dose of drug received and time on therapy. In the VISTA study, the protocol-specified duration of VMP treatment was up to 54 weeks (nine 6-week cycles) 5, corresponding to the standard duration of MP therapy. However, it is not known whether the full duration of VMP therapy at the planned bortezomib dose is required for optimal clinical outcomes. Similarly, determining the optimal duration of therapy beyond attainment of complete response (CR) remains an important clinical goal to maximize the benefits of therapy and reduce undue exposure or risk of treatment-related toxicity. While an earlier study with MP indicated little or no benefit of continued treatment post-attainment of CR 16, other studies have suggested a role for extended treatment in helping patients to achieve superior long-term outcomes 8;10;

6 American Journal of Hematology Page 6 of 32 In this retrospective analysis, patient-level data from the VMP arm of the VISTA study were analyzed to determine whether a higher cumulative bortezomib dose (obtained by longer treatment duration, more intensive therapy or both) is associated with improved OS. An additional exploratory objective was to assess the impact of continued treatment post-attainment of CR on OS. Methods Patients and study design Patient eligibility for the VISTA study has been reported previously 5. Briefly, patients with previously untreated, symptomatic, measurable MM who were ineligible for high-dose therapy, and stem cell transplantation due to age ( 65 years) or comorbidities were enrolled. Exclusion criteria included grade 2 PN or neuropathic pain, and a serum creatinine level >2 mg/dl. Following stratification by β 2- microglobulin level, serum albumin level, and geographic region, patients were randomly assigned 1:1 to receive nine 6-week cycles (54 weeks) of VMP (n = 344; IV bortezomib 1.3 mg/m 2 of body surface area per day on days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 4, and on Days 1, 8, 22, and 29 during Cycles 5 9, with melphalan 9 mg/m 2 and prednisone 60 mg/m 2 of body surface area per day on days 1 4 of each cycle) or MP alone (n = 338). Patients initially received two treatment cycles beyond achieving a CR; however, following a protocol amendment, patients received a maximum of 9 cycles, discontinuing only due to withdrawal of consent, disease progression or development of unacceptable toxicity. The primary end point of the VISTA study was TTP; OS was a prespecified secondary end point. 6

7 Page 7 of 32 American Journal of Hematology Review boards at all participating institutions approved the study, which was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guideline for Good Clinical Practice. All patients provided written informed consent. Assessments Response and progression were assessed according to European Group for Blood and Bone Marrow Transplantation criteria 20 through central laboratory M-protein assessment 5. Per protocol, patients were observed at least every 12 weeks for up to 4.5 years after the last-patient-in date for OS and initiation of subsequent MM therapy. Adverse events (AEs), which were assessed throughout the trial and for 30 days after administration of the last dose of study medication, were graded according to the National Cancer Institute s Common Terminology Criteria for Adverse Events version 3.0. Serious AEs were monitored monthly by an independent data and safety monitoring committee. Bortezomib exposure The planned duration of VMP therapy was 54 weeks. At 100% dose intensity, the maximum planned cumulative dose of bortezomib was 67.6 mg/m 2, including 41.6 mg/m 2 during Cycles 1 4 and 26 mg/m 2 during Cycles 5 9. Statistical analyses 7

8 American Journal of Hematology Page 8 of 32 Differences in baseline characteristics between groups were analyzed using the Student s t-test for continuous variables and the chi-square test for categorical variables. Distributions were estimated using the Kaplan Meier method, with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated using the Cox proportional hazards model. Differences in OS between groups were then analyzed using the likelihood ratio or log-rank tests. To account for potential differences in baseline characteristics between groups, a preplanned sensitivity analysis was conducted, whereby the Cox proportional hazards model was adjusted for discordant characteristics. A landmark analysis was also planned a priori at 180 days after randomization to account for potential biases introduced by early deaths or discontinuations. One hundred and eighty days was chosen as the cut-off to approximately align with the end of Cycle 4 (last of the twice-weekly bortezomib cycles), which was considered a clinically relevant time point to exclude early deaths and discontinuations; a much later cut-off would have resulted in the inclusion of too few patients in the lower cumulative bortezomib dose group for a clinically meaningful comparison. Additional landmark analyses were performed at 90 days and 40 days after randomization to further account for early deaths and discontinuations. Lastly, analyses of OS were performed for patient groups defined by the number of cycles of VMP received following attainment of CR. In particular, OS was calculated for patients who received 2 versus >2 cycles of VMP post-attainment of CR. For all statistical comparisons, differences between groups were tested at a 2-sided alpha level of Results 8

9 Page 9 of 32 American Journal of Hematology Cumulative bortezomib dose received A total of 340 patients randomized to the VMP arm in VISTA received at least one dose of bortezomib. Among all 340 patients, cumulative bortezomib dose ranged from 1.3 to 71.2 mg/m 2, and treatment duration from 0.13 to 13.9 months. Seven patients received more than the maximum planned cumulative bortezomib dose (67.6 mg/m 2 ) due to non-protocol-specified dose adjustments following slight body weight changes (<5%). The observed median cumulative bortezomib dose received was 39 mg/m 2, which approximately equates to the planned dose during the first four treatment cycles (41.6 mg/m 2 ). A cumulative bortezomib dose of 39 mg/m 2 was thus selected as the cut-off for defining the two cumulative bortezomib dose groups for the OS analyses. Patient characteristics by cumulative bortezomib dose group Patient characteristics were generally well balanced between the higher ( 39 mg/m 2 ; n = 170) and lower (<39 mg/m 2 ; n = 170) cumulative bortezomib dose groups (Table I), except with respect to age; patients in the higher cumulative bortezomib dose group were significantly younger than those in the lower cumulative bortezomib dose group (mean age 71 vs. 74 years, respectively; t-test, P < ). Due to this difference, the Cox proportional hazards model was adjusted for age in the preplanned sensitivity analysis of OS. A total of 118 patients (69%) in the higher cumulative dose group and 97 (57%) patients in the lower cumulative dose group received subsequent therapy following VMP. Dexamethasone was the most common agent used in subsequent therapy in both 9

10 American Journal of Hematology Page 10 of 32 higher and lower cumulative bortezomib dose groups (72% and 66% of patients, respectively), followed by thalidomide (51% and 46%, respectively), cyclophosphamide (50% and 41%, respectively) and lenalidomide (39% and 40%, respectively). OS by cumulative bortezomib dose group The survival analysis showed that OS was significantly longer in patients in the higher ( 39 mg/m 2 ) versus lower (<39 mg/m 2 ) cumulative bortezomib dose group (Fig. 1). Median OS in the higher and lower cumulative bortezomib dose groups was 66.3 and 46.2 months, respectively (HR [95% CI ]); likelihood ratio test, P < ). When adjusted for age (sensitivity analysis), the HR was (95% CI ), which also represented a statistically significant difference in OS between the two groups (P = ). In addition to the difference in OS, there were also substantial differences between the two groups with respect to reasons for treatment discontinuation. Patients in the higher cumulative bortezomib dose group had a lower incidence of early treatment discontinuations due to AEs, patient choice, disease progression or death compared with patients in the lower cumulative bortezomib dose group (Table II). To address the confounding effects of these deaths and discontinuations, a landmark analysis of OS was conducted at 180 days post-randomization among patients on study at this time point and according to whether they received a total cumulative bortezomib dose of 39 or <39 mg/m 2 (Fig. 2). This analysis included all 170 patients in the 39 mg/m 2 dose group and 130 of 170 patients in the <39 mg/m 2 dose group. Median OS 10

11 Page 11 of 32 American Journal of Hematology from the 180-day landmark remained significantly longer in patients who received a cumulative bortezomib dose of 39 versus <39 mg/m 2 (60.4 vs months, respectively; HR [95% CI ]); likelihood ratio test, P = ; Fig. 2A). Of note, OS was longer in patients who received a lower cumulative bortezomib dose versus those who received MP and achieved the 180-day landmark (median 50.3 vs months). Similar results were seen with the 90-day and 40-day landmark analyses. In the 90-day landmark analysis (which included 170 versus 145 patients in the 39 versus <39 mg/m 2 dose groups, respectively), median OS was 63.4 versus 50.8 months in the 39 versus <39 mg/m 2 dose groups (HR [95% CI ], likelihood ratio test, P = ; Fig. 2B). Median OS in patients who received MP and achieved the 90-day landmark was 42.4 months. Similarly, in the 40-day landmark analysis (which included 170 and 163 patients, respectively), median OS was 65.0 versus 49.3 months in the 39 versus <39 mg/m 2 dose groups (HR [95% CI ], likelihood ratio test, P = 0.002). AEs by cumulative bortezomib dose group Treatment-emergent AEs reported for patients in the higher ( 39 mg/m 2 ) and lower (<39 mg/m 2 ) cumulative bortezomib dose groups are summarized in Table III. The overall incidence of treatment-related AEs was similar in the higher and lower cumulative bortezomib dose groups (99% vs. 96%, respectively); however, as expected, fewer patients in the higher cumulative bortezomib dose group had serious AEs (35% vs. 58%), including treatment-related serious AEs (21% vs. 37%). There were 3 (2%) 11

12 American Journal of Hematology Page 12 of 32 and 26 (15%) deaths due to AEs in the higher and lower cumulative dose groups, respectively, of which 1 and 6, respectively, were considered treatment related). Six (4%) patients in the higher ( 39 mg/m 2 ) cumulative bortezomib dose group and 46 (27%) in the lower (<39 mg/m 2 ) cumulative bortezomib dose group discontinued treatment due to AEs; these were treatment-related AEs in 4% and 20% of patients, respectively. In the higher cumulative dose group, treatment discontinuation was most commonly due to thrombocytopenia (n = 6); in the lower cumulative bortezomib dose group it was most commonly due to peripheral sensory neuropathy (n = 11), neuralgia, thrombocytopenia (each n = 6), and fatigue (n = 5). In the 180-day landmark analysis (excluding patients who discontinued treatment prior to 180 days), 4% and 26% of patients in the higher and lower cumulative bortezomib dose groups, respectively, discontinued treatment due to AEs, including 4% and 23%, respectively, due to treatment-related AEs. Analysis of OS by additional treatment cycles received following attainment of complete response In the 102 patients who achieved CR during VMP treatment, median OS was 55.5 months for those who received 2 additional treatment cycles post-attainment of CR and 64.6 months for those who received >2 additional cycles (HR 0.71; 95% CI ; log-rank test, P = 0.25) (Fig. 3). Median duration of CR was 16.9 months among patients who received 2 additional cycles post-attainment of CR (n = 35) and 20.3 months among those who received >2 additional cycles (n = 67) (log-rank test P = 12

13 Page 13 of 32 American Journal of Hematology ). Median cumulative bortezomib dose was 40.0 mg/m 2 (range, mg/m 2 ) among patients who received 2 additional cycles post-attainment of CR, and 48.8 mg/m 2 (range, mg/m 2 ) among those who received >2 additional cycles. Discussion Using data from the VMP arm of the Phase III VISTA study, this retrospective analysis investigated the relationship between cumulative bortezomib dose and OS in transplant-ineligible patients with previously untreated, symptomatic MM. The results of this analysis suggest that higher cumulative bortezomib doses, reflecting prolonged treatment duration and/or greater dose intensity, can lead to improved OS. Patients who received a cumulative bortezomib dose of 39 mg/m 2 had a median OS of 66.3 months, whereas patients who received a cumulative dose of <39 mg/m 2 had a median OS of 46.2 months. The difference in OS between the two groups equated to a 47% reduction in the risk of death (HR 0.533; P < ) in favor of higher cumulative bortezomib doses. Of note, and further supporting the suggestion that increased cumulative dose can lead to improved OS, median OS in the higher cumulative dose group was 10 months longer than that previously reported for the entire VMP cohort in the VISTA trial (56.4 months) 6. In addition, although the sample size was limited, there was some preliminary, albeit non-significant, evidence to suggest that continued VMP treatment following attainment of CR may be associated with a trend toward improved OS. While this analysis was retrospective in nature and subject to the limitations inherent to this type of analysis, the results were robust when adjusted for the difference 13

14 American Journal of Hematology Page 14 of 32 in patient age, which was the only discordant baseline characteristic between the two cumulative bortezomib dose groups: patients in the lower cumulative bortezomib dose group were significantly older than those in the higher cumulative bortezomib dose group. More patients in the lower cumulative dose group had high-risk cytogenetic abnormalities, but cytogenetic information was only available for a small number of patients in each group, limiting any possible analysis. Prior medical history, comorbidities and performance status were similar between the two groups so, although some differences in patient populations cannot be discounted, the lower cumulative bortezomib dose group did not seem to represent an appreciably more frail patient population. Notably, the data were also shown to be robust in the 180-day landmark analysis. This analysis accounted for all patient deaths (except for one in the higher cumulative bortezomib dose group) and all early discontinuations (including those due to AEs), and thereby minimized the impact of confounding factors on the OS analysis. Although the 180-day landmark analysis cannot completely account for all possible differences in patient characteristics, or indeed factors such as subsequent therapy received, the results are supported by the 90-day and 40-day landmark analyses, conducted to further counter the confounding effects of patients dying or discontinuing therapy before receiving a significant cumulative dose of bortezomib. The observed association between cumulative bortezomib dose and OS is consistent with previous suggestions of improved clinical outcomes with increased bortezomib exposure 7;10;19;21;22. In an analysis of the Total Therapy 3 trial in previously untreated MM patients receiving the combination of bortezomib, thalidomide, and 14

15 Page 15 of 32 American Journal of Hematology dexamethasone, premature discontinuation of bortezomib was independently associated with poorer OS in a multivariate analysis (HR 6.44; P < 0.001) 22. Also, in the APEX trial of single-agent bortezomib in patients with relapsed/refractory MM, prolonged therapy beyond initial response led to continued improvement in the overall quality of response (defined as the proportion of patients with 100% M-protein reduction), which in turn was associated with a longer duration of response 21. Additionally, several studies in patients with previously untreated MM have suggested that prolonged bortezomib administration as maintenance therapy is associated with improved long-term outcomes 7;10;19. In the Spanish PETHEMA GEM2005MAS65 and Italian GIMEMA MM cooperative group trials, prolongation of therapy through bortezomib-based maintenance after induction with weekly bortezomib resulted in improvements in CR rate, and notable progression-free survival and OS 7;8;10;11. Similar results have been seen with other MM therapies, such as the benefit of continuous lenalidomide-dexamethasone maintenance therapy until disease progression rather than for only day cycles 13. These data point to an emerging paradigm in MM treatment in which patient outcomes are improved by finding ways to administer currently used drugs for longer durations. Although the sample size was limited in this analysis, the results presented here suggest that continued VMP treatment following attainment of CR, and a corresponding increase in cumulative bortezomib dose, is associated with a longer duration of response and a trend towards improved OS. Several therapeutic approaches could be used to achieve a high cumulative bortezomib dose. For example, as SC administration of bortezomib is associated with 15

16 American Journal of Hematology Page 16 of 32 noninferior efficacy and an improved safety profile compared with IV bortezomib 14;15, SC bortezomib has the potential to improve compliance and, in so doing, may result in increased cumulative dose. Alternatively, a less intensive, better-tolerated VMP regimen, with limited or no twice-weekly dosing followed by a less dose-intense bortezomib schedule as prolongation of the induction therapy, could also be used to achieve a similar cumulative bortezomib dose and so maximize treatment duration and outcomes, as shown in the PETHEMA GEM2005MAS65 7;8 and GIMEMA MM ;10 trials. These alternative, less intensive VMP regimens (which included weekly bortezomib induction) delivered a similar median cumulative dose (as reflected in the comparable efficacy) 7;9;10;23 largely due to the impact of fewer bortezomib dose modifications, which in VISTA occurred primarily during Cycles 1 4 (the initial twiceweekly bortezomib cycles). Safety analyses revealed an increased incidence of serious AEs, deaths, and discontinuations due to AEs in the lower versus higher cumulative bortezomib dose group. This difference was expected due to the protocol-defined dose modification guidelines, and indicates that, in the VISTA trial, investigators were following the protocol guidance for the management of AEs. As drug tolerability is among the factors known to influence whether a patient remains on therapy, proactive management of AEs is required to prolong treatment duration and thus maximize cumulative bortezomib dose; this may be especially important for elderly patients, who are more likely to experience AEs. 16

17 Page 17 of 32 American Journal of Hematology In conclusion, the results of this analysis suggest that a higher cumulative dose of bortezomib may result in improved OS in transplant-ineligible patients with previously untreated, symptomatic MM receiving VMP. Our data also suggest that continued VMP treatment following attainment of CR may be associated with a trend toward more favorable OS. Several strategies could be used to achieve a higher cumulative bortezomib dose in clinical practice (mainly through ensuring patients remain on therapy), including the use of SC bortezomib administration, bortezomib administration only once per week, continued therapy in patients benefiting from treatment (e.g., through bortezomib maintenance), and proactive AE management. 17

18 American Journal of Hematology Page 18 of 32 Acknowledgments All authors designed and/or performed the research reported in this analysis. Collection of data: M-VM, PGR, HS, ED, HvdV, JFSM. Interpretation of the cumulative dosing data: M-VM, HS, LN, JE, ED, HvdV, JFSM. Manuscript writing: M-VM. Review and approval of the manuscript: M-VM, PGR, MAD, AP, KCA, HS, JE, ED, HvdV, LN, JFSM. The authors would like to acknowledge the writing assistance of Jane Saunders of FireKite, part of KnowledgePoint360, an Ashfield Company, during the development of this publication, which was funded by Millennium: The Takeda Oncology Company, and Janssen Global Services, LLC. Disclosure and competing interests statement M-VM discloses consultancy for Millennium: The Takeda Oncology Company and Janssen. PGR discloses advisory board roles for Celgene, Janssen and Millennium: The Takeda Oncology Company, and research funding from Celgene and Millennium: The Takeda Oncology Company. MAD discloses consultancy for, and honoraria from, Ortho-Biotech. AP discloses consultancy/advisory role and honoraria for Celgene and Janssen-Cilag. KCA discloses consultancy for Celgene, Onyx Pharmaceuticals, Gilead, Millennium: The Takeda Oncology Company and Sanofi-Aventis, and equity ownership in Acetylon and OncoPep. HS discloses employment with Takeda Pharmaceuticals International Co. JE, ED and LN disclose employment with Millennium: The Takeda Oncology Company. HvdV discloses employment with Janssen Pharmaceutica NV and holds stock with Johnson & Johnson. JFSM discloses consultancy for Bristol-Myers 18

19 Page 19 of 32 American Journal of Hematology Squibb, Celgene, Janssen, Millennium: The Takeda Oncology Company, Novartis and Onyx Pharmaceuticals. References 1. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011;11:p Millennium Pharmaceuticals Inc. VELCADE (bortezomib) for Injection. Prescribing information. October 2012 (revision 15). Cambridge, MA, USA Janssen-Cilag International N.V. VELCADE (bortezomib). Summary of Product Characteristics. Beerse, Belgium 2013;p published December 2009, updated October Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van d, V, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 2010;28:p San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van d, V, Richardson PG. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:p

20 American Journal of Hematology Page 20 of San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van d, V, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 2013;31:p Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de PR, Garcia-Larana J, Bengoechea E, Martin A, Mediavilla JD, Palomera L, de AF, Gonzalez Y, Hernandez JM, Sureda A, Bello JL, Bargay J, Penalver FJ, Ribera JM, Martin-Mateos ML, Garcia-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalban MA, Lahuerta JJ, Blade J, Miguel JF. 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. Lancet Oncol 2010;11:p Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, Lopez dlg, Lopez J, Bengoechea E, Perez M, Polo M, Palomera L, de AF, Gonzalez Y, Hernandez JM, Granell M, Bello JL, Bargay J, Penalver FJ, Ribera JM, Martin-Mateos ML, Garcia-Sanz R, Lahuerta JJ, Blade J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012;120:p Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De RL, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, 20

21 Page 21 of 32 American Journal of Hematology Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010;116:p Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28:p Palumbo A, Bringhen S, Larocca A, Rossi D, Di RF, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omede P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomibthalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol 2014;32:p Niesvizky R, Flinn I, Rifkin RM, Essell J, Gaffar Y, Warr T, Neuwirth R, Ba-Mancini A, Zhu Y, Niculescu L, Reeves J. Efficacy and Safety Of Three Bortezomib-Based Induction and Maintenance Regimens In Previously Untreated, Transplant-Ineligible Multiple Myeloma (MM) Patients (Pts): Final Results From The Randomized, Phase 3b, US Community- Based UPFRONT Study (NCT ). Blood 2013;122:p Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee 21

22 American Journal of Hematology Page 22 of 32 JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van OJ, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014;371:p Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van d, V, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncol 2011;12:p Rifkin R, Chen C, Dhanda R, embert D, a-mancini A, a E, hu Y, ow E, iculescu L. Impact Of Route Of Bortezomib (B) Administration On Dose Intensity and Time To Dose Reduction In Previously Untreated Patients (Pts) With Multiple Myeloma (MM). Blood 2013;122:p Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, Willan A. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57:p Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De S, V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A. Bortezomibthalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012;120:p

23 Page 23 of 32 American Journal of Hematology 18. Offidani M, Corvatta L, Polloni C, Gentili S, Mele A, Rizzi R, Catarini M, Caraffa P, Samori A, Blasi N, Ferranti M, Malerba L, Brunori M, Leoni P. Thalidomide, dexamethasone, Doxil and Velcade (ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed-refractory multiple myeloma. Ann Hematol 2011;90:p Sonneveld P, Schmidt-Wolf IG, van der Holt B, El JL, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van d, V, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 2012;30:p Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102:p Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Blade J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007;110:p van RF, Szymonifka J, Anaissie E, Nair B, Waheed S, Alsayed Y, Petty N, Shaughnessy JD, Jr., Hoering A, Crowley J, Barlogie B. Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD 23

24 American Journal of Hematology Page 24 of 32 maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood 2010;116:p Mateos MV, Bringhen S, Richardson PG, Lahuerta JJ, Larocca A, Oriol A, Boccadoro M, Garcia-Sanz R, Di RF, Esseltine DL, van d, V, Desai A, Londhe A, San Miguel JF, Palumbo A. Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy. Haematologica 2014;99:p

25 Page 25 of 32 American Journal of Hematology TABLE I. Baseline patient characteristics in the lower (<39 mg/m 2 ) and higher ( 39 mg/m 2 ) cumulative bortezomib dose groups Cumulative bortezomib dose Characteristic <39 mg/m 2 (n = 170) 39 mg/m 2 (n = 170) Mean age, years (SD) 74 (6.2) 71 (4.6) Male, n (%) 85 (50) 87 (51) White/Asian, n (%) 146 (86) / 20 (12) 154 (91) / 14 (8) Karnofsky performance status, n (%) 60 70% 58 (34) 64 (38) 80 90% 89 (52) 81 (48) 100% 23 (14) 25 (15) β 2 -microglobulin level, n (%) <2.5 mg/l 17 (10) 25 (15) mg/l 99 (58) 88 (52) >5.5 mg/l 54 (32) 57 (34) Albumin level 3.5 g/dl, n (%) 70 (41) 72 (42) International Staging System stage, n (%) I 31 (18) 33 (19) II 85 (50) 75 (44) III 54 (32) 62 (36) High-risk cytogenetics, # n (%) 26 (15) 12 (7) SD, standard deviation. *High-risk cytogenetics were defined as: hypoploidy by karyotype (defined as <45 chromosomes, i.e., at least 2 monosomy findings); deletion 13 by karyotype (defined as

26 American Journal of Hematology Page 26 of 32 either true deletion of 13 or monosomy 13); t(14,16) by FISH; t(4,14) either by FISH or by karyotype; deletion 17p defined as deletion of 17p (by FISH or by karyotype) or monosomy 17 by karyotype.

27 Page 27 of 32 American Journal of Hematology TABLE II. Treatment completion rates, treatment duration, and reasons for treatment discontinuation in the lower (<39 mg/m 2 ) and higher ( 39 mg/m 2 ) cumulative bortezomib dose groups Cumulative bortezomib dose <39 mg/m 2 (n = 170) 39 mg/m 2 (n = 170) P Patients completing planned 53 (31) 146 (86) < # course of treatment, n (%) Median treatment duration, months 2.5 ( ) 12.1 ( ) < (range)* Number of patients who 117 (69) 24 (14) discontinued treatment, n (%) Reasons for treatment discontinuation, n (%) AE 46 (27) 6 (4) Patient choice 29 (17) 3 (2) Disease progression 16 (9) 8 (5) Death 13 (8) 1 (1) Other 13 (8) 6 (4) AE, adverse event. *The maximum values are the same in the two groups due to certain patients continuing with MP treatment after discontinuing bortezomib. Patients for whom death was reported as the reason for treatment discontinuation; this does not include all patients who died during the study. Other reasons include maintenance of confirmed immunofixation-negative CR (n = 9), physician s decision due to poor state of patient (n = 2), medical decision for stable disease and start of subsequent treatment (each n = 1). # Chi-square P-value. t-test of difference of mean P-value.

28 American Journal of Hematology Page 28 of 32 TABLE III. Treatment-emergent AEs in the lower (<39 mg/m 2 ) and higher ( 39 mg/m 2 ) cumulative bortezomib dose groups. Cumulative bortezomib dose P* <39 mg/m 2 (n = 170) 39 mg/m 2 (n = 170) Any AE, n (%) 170 (100) 168 (99) treatment-related 164 (96) 167 (99) None treatment-related 6 (4) 1 (1) Any serious AE, n (%) 99 (58) 59 (35) < treatment-related 63 (37) 35 (21) None treatment-related 36 (21) 24 (14) Maximum severity of any AE, n < (%) Grade 1 1 (1) 1 (1) Grade 2 12 (7) 15 (9) Grade 3 81 (48) 100 (59) Grade 4 50 (29) 49 (29) Grade 5 26 (15) 3 (2) Treatment discontinuation due to 46 (27) 6 (4) < AE, n (%) 1 treatment-related 34 (20) 6 (4) None treatment-related 12 (7) 0 AE, adverse event. *Fisher s exact test P-value.

29 Page 29 of 32 American Journal of Hematology Figure 1 85x54mm (300 x 300 DPI)

30 American Journal of Hematology Page 30 of 32 Figure 2a 85x58mm (300 x 300 DPI)

31 Page 31 of 32 American Journal of Hematology Figure 2b 85x58mm (300 x 300 DPI)

32 American Journal of Hematology Page 32 of 32 Figure 3 85x54mm (300 x 300 DPI)