controlled study of siltuximab - Wiley Online Library

RESEARCH ARTICLE

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A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma Robert Z. Orlowski,1* Liana Gercheva,2 Cathy Williams,3 Heather Sutherland,4 Tadeusz Robak,5 Tamas Masszi,6 Vesselina Goranova-Marinova,7 Meletios A. Dimopoulos,8 James D. Cavenagh,9 Ivan Spicˇka,10 Angelo Maiolino,11 Alexander Suvorov,12 Joan Blade,13 Olga Samoylova,14 Thomas A. Puchalski,15 Manjula Reddy,15 Rajesh Bandekar,15 Helgi van de Velde,16 Hong Xie,15 and Jean-Fran1ois Rossi17 We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) 1 B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S 1 B and plc 1 B was 8.0 and 7.6 months (HR 0.869, P 5 0.345), overall response rate was 55 versus 47% (P 5 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P 5 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S 1 B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade 3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S 1 B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory C 2014 Wiley Periodicals, Inc. multiple myeloma. V C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 90:42–49, 2015. V

䊏 Introduction Studies have long shown that the pleiotropic cytokine interleukin (IL)-6 plays an important role in the pathogenesis of multiple myeloma (MM), with proliferative and anti-apoptotic effects in neoplastic plasma cells [1]. Elevated serum IL-6 levels are associated with poor prognosis and short survival in advanced MM [2]. Interleukin-6 promotes myeloma cell survival via phosphorylation of signal transducers and activators of transcription (STAT)-3 and upregulation of antiapoptotic molecules, such as myeloid cell leukemia-1 (Mcl-1) and c-Myc [3–5]. Interleukin-6 also induces vascular endothelial growth factor expression in myeloma cells [6–8], contributing to the enhanced angiogenesis seen in myeloma. Although the recent development of the proteasome inhibitor bortezomib has improved survival in patients with MM [9,10], its efficacy is limited by a number of resistance mechanisms. One of the most important is the heat shock protein (HSP) and stress response pathways which, through members such as HSP-70 and mitogen-activated protein kinase (MAPK) phosphatase, oppose the pro-apoptotic activities of bortezomib [11,12]. IL-6 inhibition was hypothesized to enhance the activity of bortezomib by interfering with the induction of the HSP response and Mcl-1. IL-6 activates STAT-1 [13], which in turn interacts with heat shock transcription factor (HSF)-1 to facilitate transcription of HSP-70 and HSP-90 [14]. Preclinical studies demonstrated that the addition of siltuximab (formerly CNTO 328), a chimeric (human-murine), anti-IL-6 monoclonal antibody, to bortezomib had an additive effect in inducing apoptosis in IL-6-dependent and IL-6-independent MM cell lines [11]. Treatment with

Additional Supporting Information may be found in the online version of this article. 1 Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2University Hospital for Active Treatment “St. Marina,” Varna, Bulgaria; 3Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; 4Vancouver General Hospital, Vancouver, Canada; 5Medical University of Łodz and Copernicus Memorial Hospital, Ł odz, Poland; 6St. Istvan and St. Laszlo Hospital of Budapest and Semmelweis University, Budapest, Hungary; 7University Multiprofile Hospital for Active Treatment “St. George,” Plovdiv, Bulgaria; 8National and Kapodistrian University of Athens, Athens, Greece; 9St. Bartholomew’s and the London Hospital, London, United Kingdom; 10Charles University in Prague, Prague, Czech Republic; 11Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 12First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; 13Hospital Clinic i Provincial and Institut d’Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain; 14Nizhniy Novgorod Region Clinical Hospital, Nizniy Novgorod, Russia; 15Janssen Research & Development, Spring House, Pennsylvania; 16Janssen Research & Development, Beerse, Belgium; 17University Hospital CHU Saint Eloi and INSERM U1040, Montpellier, France.

Trial registration: NCT00401843. *Correspondence to: Robert Z. Orlowski; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit Number 429, Houston, TX 77030. E-mail: [email protected] Received for publication: 1 October 2014; Accepted: 3 October 2014 Am. J. Hematol. 90:42–49, 2015. Published online: 8 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23868 C 2014 Wiley Periodicals, Inc. V

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American Journal of Hematology, Vol. 90, No. 1, January 2015

doi:10.1002/ajh.23868

RESEARCH ARTICLE siltuximab reduced bortezomib-induced HSP-70 and potently attenuated bortezomib-mediated increases in Mcl-1 by inhibiting IL-6mediated downstream signaling pathways via STAT-1, STAT-3, and p44/42 MAPK. A large, open-label, dose-finding phase 1 study of single-agent siltuximab was conducted in 67 patients with B-cell non-Hodgkin’s lymphoma, Castleman’s disease (CD), or relapsed MM. Siltuximab could be given up to 12 mg/kg once every 2 or 3 weeks without dose-limiting toxicity and over prolonged dosing with no evidence of cumulative toxicity [15]. The most frequently reported possibly drugrelated adverse events (AEs) were transient and reversible thrombocytopenia, neutropenia, hypertriglyceridemia, leukopenia, hypercholesterolemia, and anemia. Twelve of 36 evaluable CD patients showed radiologic response, most of whom were treated at 12 mg/kg. Two of 13 MM patients achieved complete response, and 1 MM patient had prolonged disease stabilization. The purpose of this current study was to evaluate the safety and efficacy of the combination of siltuximab (S) and bortezomib (B) in patients with relapsed or refractory MM.

䊏 Methods Patients. Patients were at least 18 years old and had a confirmed diagnosis of MM with measurable secretory disease (i.e., serum M-protein 1 g/dL or urine Mprotein 200 mg/24 h). Patients must have had 1–3 prior lines of therapy, relapsed or refractory disease, and had undergone or were unsuitable for autologous hematopoietic stem cell transplantation (SCT). Other eligibility criteria included an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 2 and adequate organ function. Key exclusion criteria were prior bortezomib use, allogeneic transplantation, and chemotherapy washout of 1). During the randomized treatment phase, patients received blinded treatment in 42-day cycles for 4 cycles, with S 6 mg/kg or plc infused over 2 hr every 2 weeks (q2w) and B 1.3 mg/m2 injected intravenously twice weekly (days 1, 4, 8, 11, 22, 25, 29, 32). Patients with stable disease (SD) or better could continue to receive maintenance therapy: S 6 mg/kg or plc q2w and weekly B (days 1, 8, 15, 22 every 5 weeks) until progressive disease (PD). For the first 113 patients enrolled, those with PD on B treatment were permitted, at the investigator’s discretion, to continue on assigned treatment with the addition of low-dose dexamethasone (dex; 20 mg on the day of and day after each B administration). To align the study protocol with clinical practice, it was thereafter amended to require B discontinuation at the time of PD or intolerable B-related toxicity (i.e., after 2 B dose reductions), with optional high-dose dex salvage (on days 124, 9212, 17220 for 4 28-day cycles, then on days 1–4 for subsequent cycles) while blinded S/plc was continued. Treatment-related toxicities were managed by protocol-specified dose delays (up to 14 days) for S and dose modifications for B and dex and, ultimately, treatment discontinuation. The focus of this report is the pre-dex portion of the blinded randomized treatment phase. Results from the open-label, safety run-in and the post-dex salvage phase are reported separately. Assessment of efficacy. The primary endpoint in the randomized treatment phase was progression-free survival (PFS) in all randomized patients (the intentionto-treat (ITT) population), according to European Group for Blood and Marrow Transplantation (EBMT) registry criteria [17] implemented by a validated computer algorithm and modified to include near complete response (nCR). Responses were evaluated for patients who had measurable disease at baseline, 1 study-agent administration, and 1 postbaseline disease assessment pre-dex (the responseevaluable population). In the randomized treatment phase, major secondary efficacy endpoints were overall response rate (ORR; complete response [CR] 1 partial response [PR] before dex/study withdrawal) confirmed at least 6 weeks apart, 1year overall survival (OS) rate, CR rate, and OS. Other efficacy endpoints were time to response, time to progression (TTP), and response duration. Response was assessed q6w using laboratory disease assessments evaluated by a central laboratory. Assessment of safety, pharmacokinetics, immunogenicity, pharmacodynamics, and patient-reported outcomes. AEs were recorded through 30 days after the last studyagent dose according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0. Safety assessments included routine lab-

doi:10.1002/ajh.23868

Bortezomib with or without Siltuximab in Multiple Myeloma oratory tests, physical examination, vital signs, electrocardiography, and recording of concomitant medications. All patients who received 1 dose of study drug were included in the safety analysis. Blood samples were collected from all patients in the safety run-in and a subset of patients in the randomized treatment phase during cycle 1 to evaluate plasma B concentrations using an assay based on a validated liquid chromatography-mass spectrometry/mass spectrometry method. The B pharmacokinetic analysis included all patients who received 1 full dose of B and had B pharmacokinetic samples obtained, at a minimum, on cycle 1 days 4, 8, and 11. Blood samples were collected immediately following S dosing and before B administration in cycles 1, 2, and 3 from all patients in the safety run-in, and a subset of patients in the randomized treatment phase to evaluate serum S concentrations using a validated assay based on an electrochemiluminescent immunoassay format on the Meso Scale Discovery (MSD) platform. The S pharmacokinetic analysis included all patients who received 1 full dose of S and had 1 post-dose S pharmacokinetic sample. Blood samples to evaluate immunogenicity were collected from all patients before the first S administration, at treatment discontinuation, and every 3 months (up to 3 times) after the last S dose, and when an infusion reaction occurred. Blood samples were also collected on day 1 of each cycle from all patients for serum biomarker analysis of baseline IL-6 and percent change from baseline in Creactive protein (CRP). Low- and high-molecular weight IL-6 complexes were measured using a newly developed, single-plex, panoptic IL-6 assay based on the MSD platform with a lower limit of quantification (LLOQ) of 9.77 pg/mL. Low-molecular weight IL-6 was also measured using the standard MSD Human IL-6 Ultra-Sensitive Kit. Interleukin-6 was measured only at baseline because accurate quantification of IL-6 in post-treatment samples is not currently possible, as siltuximab-neutralized antibody–Interleukin-6 complexes distort current immunological-based IL-6 quantification methods. C-reactive protein concentration was analyzed at a central laboratory (Covance) using a high-sensitivity CRP assay with a LLOQ of 0.20 mg/L. In the randomized treatment phase, patient-reported outcomes were assessed using the European Organization for Research on the Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [18], the Functional Assessment of Chronic Illness Therapy—Fatigue scale (FACIT-Fatigue) [19], and the pain intensity scale from the brief pain inventory (BPI) [20]. Statistical analyses. The sample size for the open-label, safety run-in was not based on hypothesis testing. An independent data monitoring committee (IDMC) reviewed safety results and decided that enrollment should begin for the randomized treatment phase. This phase enrolled approximately 270 patients (135/group) using dynamic randomization. The data cutoff for the primary analysis was to be after 193 PFS events had occurred and all ongoing patients had been treated for 6 months. Assuming 50% improvement in median PFS of the combination group over the control group, the study had at least 80% power to achieve statistical significance at a two-sided level of 0.05, under exponential distribution for PFS. Sensitivity analyses of PFS using Cox proportional hazards regression were performed according to prespecified subgroups (age, gender, race, ECOG-PS, b2-microglobulin level, ISS stage, prior SCT, number of prior therapies, BPI score, and FACIT-Fatigue category and score). An interim futility analysis was performed by the IDMC approximately 2 months after 104 patients (39% of sample size) were randomized. The IDMC also monitored unblinded safety data in the randomized phase. Descriptive statistics were used to summarize data. For time-to-event variables, Kaplan–Meier estimates and 95% confidence intervals (CIs) were calculated. Analysis of variance was used to compare all continuous variables. The Cochran–Mantel–Haenszel test was used to compare discrete variables. Log-rank testing stratified by b2-microglobulin (< or 3.5 mg/L) and number of prior lines of therapy (1 or >1) was used for time-toevent variables. All tests were at a two-sided a of 0.05.

䊏 Results From November 2006 to July 2009, a total of 307 patients with relapsed or refractory MM were enrolled at 88 sites in 18 countries (Belgium, Brazil, Bulgaria, Canada, Czech Republic, France, Germany, Greece, Hungary, Netherlands, Poland, Portugal, Romania, Russia, Slovakia, Spain, United Kingdom, and United States).

Safety run-in Twenty-one patients received S 1 B for a median of four cycles. The median durations of treatment with S and B were 142 and 144 days, respectively, and the majority of patients discontinued treatment due to AEs (29%) or PD (24%; Supporting Information Table I). Demographics and disease characteristics are summarized in Supporting Information Table 2. At the interim analysis, the safety of S 1 B was deemed acceptable by the IDMC, and enrollment was initiated for the randomized treatment phase. AEs are summarized in Supporting Information Tables III and IV. American Journal of Hematology, Vol. 90, No. 1, January 2015

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Figure 1. Patient disposition in the randomized treatment phase pre- and post-dexamethasone. ITT, intention-to-treat.

Pre-dexamethasone randomized treatment phase A total of 286 patients were randomized (ITT population: 142 S 1 B. 144 plc 1 B), and 281 were treated (safety population: 142 S 1 B, 139 plc 1 B; Fig. 1). Five patients were not treated due to unmet entry criteria (n 5 3), AE (n 5 1), or withdrawal of consent (n 5 1). Three patients randomized to plc 1 B incorrectly received treatment with S 1 B at some time point during treatment; these patients were included in the plc 1 B group for efficacy analysis, but in the S 1 B group for safety. Siltuximab/plc was discontinued in 106 (75%) S 1 B and 91 (66%) plc 1 B patients, mainly due to PD (20 versus 22%), AE (18 versus 16%), or CR (7 versus 3%). Bortezomib was discontinued in 134 (94%) S 1 B and 125 (90%) plc 1 B patients, mainly due to PD (32 versus 42%) or AE (28 versus 21%). The majority of S/B discontinuations occurred during the first four cycles. Baseline characteristics of patients in the randomized treatment phase are presented in Table I. The median age was 64 years in S 1 B and 61 years in plc 1 B. The median duration since diagnosis was 2.7 years (range 0.2, 24) in S 1 B and 2.4 years (range 0.2, 14) in plc 1 B. Similar proportions of patients in S 1 B and plc 1 B had ISS stage III (26 versus 25%) disease at randomization. The proportions of patients receiving 1 (49 versus 53%), 2 (33% each), or 3 (18 versus 14%) lines of prior therapy or prior SCT (36 versus 38%) were comparable between groups. Common prior antimyeloma therapies were corticosteroids (98%), alkylating agents (88%), anthracycline (46%), and thalidomide/lenalidomide (41%). In S 1 B and plc 1 B, 58 versus 51% had relapsed and refractory disease, defined as PD while on treatment (24 versus 19%), SD on treatment (15 versus 17%), or PD within 60 days (19 versus 15%) of the last therapy. Baseline characteristics were similar between S 1 B and plc 1 B except for immunoglobulin A subtype (27 versus 20%), ECOG-PS score of 2 (13 versus 19%), age 65 years (48 versus 40%), and FACIT-Fatigue score 30 (71 versus 61%). 44


Efficacy. The primary efficacy endpoint analysis in the ITT population was performed after 192 PFS events were observed in the predex randomized treatment phase. Median PFS was 8.0 months in S 1 B and 7.6 months in plc 1 B (HR 0.869 [95% CI: 0.650, 1.162], P 5 0.345; Fig. 2A). Forty-nine and 45 patients were censored, respectively, in S 1 B and plc 1 B groups due to initiation of dex (69% each), withdrawal of consent (14 versus 20%), or clinical cutoff (16 versus 11%). No significant differences in PFS were found between treatment groups according to prespecified subgroup sensitivity analyses. After 24.5 months of follow-up, the median OS in the S 1 B and plc 1 B groups was 30.8 versus 36.8 months (P 5 0.103; Fig. 2B). Sixty-seven versus 53 deaths were observed, the majority during the follow-up period. The 1-year OS rate with S 1 B and plc 1 B was 81 versus 85% (P 5 0.380), and the 2-year OS rate was 57 versus 68% (P 5 0.060). From an ad hoc analysis, an asymmetry in the use of rescue treatment was apparent between the S 1 B and plc 1 B groups with protocol-specified high-dose dex (32 versus 46 patients) and with SCT (7 versus 16 patients). An ad hoc analysis of OS in patients who did not receive subsequent per-protocol high-dose dex salvage or SCT found no decrease in OS with S and numerically longer median OS for S 1 B (n 5 106) versus plc 1 B (n 5 85) (34.4 versus 24.9 months, P 5 0.631). One hundred thirty-one patients in S 1 B and 137 patients in plc 1 B comprised the tumor response-evaluable population. Overall response rate was 55 versus 47% (P 5 0.213), CR was 11 versus 7% (P 5 0.351). Time to CR was shorter with S 1 B than plc 1 B (4.1 versus 5.1 months). Near CRs without bone marrow confirmation were 4 versus 2%, and nCRs with positive immunofixation were 7 versus 5%. Partial response was seen in 44 versus 39% of patients, and minimal response was seen in 6 versus 10%. There were no statistically significant differences between the S 1 B and plc 1 B groups in the other secondary efficacy endpoints. doi:10.1002/ajh.23868

RESEARCH ARTICLE

Bortezomib with or without Siltuximab in Multiple Myeloma

TABLE I. Baseline Characteristics in the Pre-dexamethasone Randomized Treatment Phase Siltuximab 1 bortezomib

Placebo 1 bortezomib

Patients treated Patients randomized 142 144 Age (years) 64 [36, 82] 61 [37, 81] Sex Male 72 (51) 85 (59) Female 70 (49) 59 (41) Race Caucasian 126 (89) 130 (90) Black 6 (4) 6 (4) Asian 2 (1) 2 (1) Other 8 (6) 6 (4) ECOG performance status score 0 36/141 (26) 44 (31) 1 86/141 (61) 72 (50) 2 18/141 (13) 28 (19) 3 1/141 (1) 0 Time from diagnosis (years) 2.7 [0.2, 24] 2.4 [0.2, 14] a Immunoglobulin isotype Immunoglobulin G 92/142 (65) 102/143 (71) Immunoglobulin A 38/142 (27) 29/143 (20) Light chain 10/142 (7) 10/143 (7) ISS stage at randomization I 48/141 (34) 44/143 (31) II 57/141 (40) 63/143 (44) III 36/141 (26) 36/143 (25) Relapsed and refractory disease PD on last prior therapy 34 (24) 27 (19) SD on last prior therapy 21 (15) 24 (17) PD within 60 days of last prior therapy 27 (19) 22 (15) Prior lines of therapy 1 70 (49) 76 (53) 2 47 (33) 48 (33) 3 25 (18) 20 (14) Prior treatment regimens Autologous stem cell transplantation 51 (36) 54 (38) Corticosteroids 138 (97) 143 (99) Alkylating agents 120 (85) 131 (91) Anthracycline 64 (45) 68 (47) Thalidomide/lenalidomide 57 (40) 60 (42) CRP serum concentration (mg/L) 2.88 [0.10, 161] 3.54 [0.10, 299] a

In siltuximab 1 bortezomib, 1 patient had immunoglobulin D, and 1 patient was not detected. In placebo 1 bortezomib, 2 patients had immunoglobulin D. Data presented as n (%) or median [range]. CRP; C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; PD, progressive disease; SD, stable disease.

Time to response (CR or PR) was 2.6 with S 1 B versus 4.0 months with plc 1 B (HR 1.298 [95% CI 0.923, 1.827], P 5 0.133). Time to progression (EBMT) was 9.2 versus 9.0 months (HR 0.849 [95% CI 0.632, 1.155], P 5 0.296) for the S 1 B and plc 1 B groups. Duration of response was 10.1 with S 1 B versus 8.7 months with plc 1 B (HR 0.784 [95% CI 0.511, 1.204], P 5 0.266). Serum M-protein response was evaluable for patients in the ITT population with measureable serum M-protein at baseline; in 131 and 133 patients in S 1 B and plc 1 B, respectively, 24 versus 19% achieved 100% reduction while 58 versus 56% achieved 50% reduction. Urine M-protein response was evaluated in 10 patients each in S 1 B and plc 1 B with nonmeasurable (5-fold concentrations of IL-6 using the panoptic IL-6 assay compared with the standard MSD IL-6 assay. However, baseline circulating serum IL-6 concentrations, as determined by both assays, were not predictive of clinical response per EBMT criteria. doi:10.1002/ajh.23868

RESEARCH ARTICLE


TABLE II. Key Safety Events in the Pre-dexamethasone Randomized Treatment Phase

Patients treated Patients with AEs AEs of grade 3 SAEs SAEs of grade 3 AEs leading to discontinuation of siltuximab AEs leading to discontinuation of bortezomib AEs causing temporary dose interruption of siltuximab AEs causing temporary dose interruption or modification of bortezomib AEs leading to death Patients with common adverse eventsa Neutropenia Thrombocytopenia Peripheral sensory neuropathy Diarrhea Anemia Fatigue Nausea Leukopenia Decreased appetite Neuralgia Constipation Vomiting Pain in extremity Arthralgia Asthenia Back pain Pyrexia

Siltuximab 1 bortezomib

Placebo 1 bortezomib

142

139

140 (99) 129 (91) 41 (29) 38 (27) 34 (24)

136 (98) 103 (74) 33 (24) 29 (21) 27 (19)

47 (33)

33 (24)

86 (61)

62 (45)

118 (83)

101 (73)

11 (8) 140 (99)

7 (5) 136 (98)

84 (59) 81 (57) 69 (49) 51 (36) 44 (31) 38 (27) 38 (27) 35 (25) 32 (23) 31 (22) 29 (20) 28 (20) 24 (17) 22 (15) 21 (15) 21 (15) 9 (6)

50 (36) 63 (45) 71 (51) 48 (35) 40 (29) 37 (27) 40 (29) 14 (10) 25 (18) 32 (23) 21 (15) 27 (19) 13 (9) 13 (9) 26 (19) 24 (17) 25 (18)

Data presented as n (%) unless otherwise noted. AEs, adverse events; SAEs, serious adverse events. a Reported by 15% of patients in either treatment group.

䊏 Discussion In this randomized, controlled study of patients with relapsed or refractory MM who had received 1–3 prior therapies not containing bortezomib, the median PFS by EBMT criteria before dexamethasone salvage was not significantly improved when siltuximab was added to bortezomib (8.0 months) compared with bortezomib alone (7.6 months). Although combination treatment led to faster time to response and numerically longer duration of response than bortezomib alone, the response with bortezomib alone improved with prolonged treatment. Notably, the median PFS with single-agent bortezomib in this study is longer than in the APEX [9] and DOXILMMY3001 [22] studies because patients in our study received bortezomib until PD, while those studies had a definite treatment cutoff, suggesting that longer bortezomib treatment had an enhanced effect. This effect was corroborated in our study by the regional differences in bortezomib exposure, showing that a higher cumulative bortezomib dose led to a greater PFS benefit without a remarkable increase in adverse effects or toxicities. Although most efficacy endpoints were numerically better with combination therapy, a trend toward worse OS was observed with combination therapy. After 24.5 months of follow-up, median OS was 30.8 months with S 1 B and 36.8 months with plc 1 B. Although the median OS in the combination group was comparable to the survival rate observed in historical studies conducted with bortezomib in doi:10.1002/ajh.23868

Figure 3. Mean (1standard deviation) serum C-reactive protein (CRP) concentrations in the overall study. C, cycle; D, day.

this population, the median OS of the bortezomib alone group was better than those observed in the APEX study (29.8 months) [9] and in the study of subcutaneous versus intravenous bortezomib administration (28.7 months) [23]. In our study, there was no OS difference between treatment groups in NA/WE. The OS disadvantage noted for the ROW for combination treatment may be explained in light of the asymmetric use of dexamethasone rescue and subsequent SCT. Patients in the ROW also received less lenalidomide as subsequent anticancer therapy compared with NA/WE. Despite preclinical studies suggesting a synergistic interaction between bortezomib and siltuximab in IL-6-dependent models, the combination of S 1 B was not superior to single-agent bortezomib in this relapsed or refractory population. Interleukin-6 has been shown to induce expression of CRP, a surrogate marker of IL-6 bioactivity [21], by activating transcription factors STAT3 and CCAAT-enhancerbinding protein (C/EBP) b. Activation of nuclear factor kappa B (NFjB) may also enhance the effect of STAT3 and C/EBPb, and blockade of NF-ŒB by bortezomib has been shown to down-regulate IL-6-triggered cascades [24]. Preliminary pharmacokinetic/pharmacodynamic modeling from an open-label study showed that siltuximab given at 11 mg/kg q3w would decrease CRP to below 1 mg/L in multicentric CD patients [25]. While S 1 B suppressed systemic CRP concentrations to below the level of detection, single-agent bortezomib also led to a less pronounced CRP decrease (Fig. 3), which suggests that siltuximab and bortezomib may have had overlapping mechanisms. Systemic CRP suppression was not associated with clinical response. This may explain to some degree why the combination of these two agents did not show a significant additive effect. It is also possible that IL-6 was insufficiently suppressed in the bone marrow microenvironment given the possibility of paracrine, autocrine, and intracrine IL-6 production by tumor cells [26–28]. Although IL-6 in the local environment is a well-known growth factor for tumor plasma cells [29], only 24% of our patients had detectable serum IL-6 concentrations before study entry, and no consistent association was observed between systemic IL-6 levels and the clinical American Journal of Hematology, Vol. 90, No. 1, January 2015

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stage or phase of disease. Treatment with S 1 B resulted in sustained suppression of CRP, a marker for indirect measurement of in vivo IL6 neutralization, but systemic IL-6 concentrations do not necessarily reflect IL-6 concentrations in the tumor niche, or the tumor cell utilization of IL-6, which are more likely to impact response to treatment. Additionally, while our study was in progress, pharmacokinetic/pharmacodynamic modeling showed that the 6 mg/kg q2w regimen may be suboptimal [21] and a clear dose–response with optimal efficacy was observed at 12 mg/kg q3w in a B-cell lymphoproliferative disorder population without dose-related toxicity [15]. Even if complete IL-6 neutralization was achieved in our study, simply blocking 1 cytokine in the bone marrow microenvironment may not have had a significant effect due to compensatory increases in other myeloma growth factors, such as insulin-like growth factor 1 [29], or other mechanisms activated in later disease. A concurrent study in relapsed or refractory MM patients who had received 2 therapies including bortezomib showed no clinical activity with single-agent siltuximab and only modest response with siltuximab and dexamethasone [30]. Despite providing earlier responses and higher CR/nCR rates, siltuximab plus bortezomib–melphalan–prednisone in newly diagnosed, transplant-ineligible MM did not translate into a PFS benefit compared with standard bortezomib–melphalan– prednisone in a randomized phase 2 study [31]. Although we believe that IL-6 remains a good target in MM based on a strong rationale from the literature [32], the role of IL-6 may be more prominent in earlier disease. A study of siltuximab monotherapy in high-risk smoldering MM is ongoing. Combination treatment did not appear to affect the pharmacokinetic profile of either agent. The AE profile before dexamethasone salvage was mainly driven by bortezomib and was consistent with the APEX study [9]. Adding siltuximab to bortezomib compared with bortezomib alone did not change the type of AEs but increased the frequency of neutropenia (59 versus 36%), thrombocytopenia (57 versus 45%), and gastrointestinal events (60 versus 53%). The higher incidence of AEs in the blood and lymphatic system, however, did not translate into an increased incidence of high-grade infections (16 versus 14%) or bleeding (2% each). The incidence of peripheral neuropathy was similar (49 versus 51%), suggesting that IL-6 is not involved in bortezomib-induced peripheral neuropathy or that block-

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ing IL-6 alone is insufficient to alleviate this type of neuropathy. The incidence of AEs leading to bortezomib discontinuation was higher in the combination therapy group (33 versus 24%), which prevented longer bortezomib dosing in the S 1 B group and explains in part the higher cumulative bortezomib dose in the single-agent bortezomib group. In conclusion, this randomized, phase 2 study does not provide evidence that the addition of siltuximab to bortezomib improved outcomes in patients with relapsed or refractory MM who have received 1–3 prior therapies not containing bortezomib. Baseline IL-6 levels and systemic suppression of CRP were not associated with IL-6blockade-induced clinical response. Neutropenia and thrombocytopenia were more frequent and severe when siltuximab was administered in combination with bortezomib. The results of this study do not support further investigation of siltuximab in the treatment of advanced MM. Disclosure: T.A. Puchalski, M. Reddy, R. Bandekar, H. van de Velde, and H. Xie are or were employees of Janssen Research & Development, own stock in Johnson & Johnson and/or are currently conducting research sponsored by Janssen. R. Z. Orlowski has served on advisory boards for Millennium Pharmaceuticals and Janssen Pharmaceuticals. C. Williams received honoraria for speaking and received travel grants from Janssen-Cilag. T. Robak received a research grant from Janssen Research & Development. T. Masszi has served on an advisory board for Janssen-Cilag. M. A. Dimopoulos has received personal fees from Ortho-Biotech, Celgene, and Onyx. I. Spicˇka served as a consultant for and received lecture fees from Celgene and Janssen-Cilag and received lecture fees from Novartis. J. Blade received grants and personal fees from Janssen. L. Gercheva, H. Sutherland, V. Goranova-Marinova, J. D. Cavenagh, A. Maiolino, A. Suvorov, O. Samoylova, and J-F. Rossi have no competing interests.

䊏 Acknowledgments This study was supported by Janssen Research & Development. The authors thank Jennifer Han, MS, formerly of Janssen Scientific Affairs for assistance in writing and preparing the manuscript for publication and Gianna Paone, MS, of Janssen Scientific Affairs for editorial and submission support.

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