Received: 1 November 2019 | Revised: 20 December 2019 | Accepted: 23 December 2019 DOI: 10.1111/ejh.13377 ORIGINAL ARTICLE A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma Roman Hajek1,2 | Ludek Pour3 | Muhit Ozcan4 | Jesus Martin Sánchez5 | 6 Ramon García Sanz | Achilles Anagnostopoulos7 | Albert Oriol8 | Nicola Cascavilla9 | Andreas Terjung10 | Yihua Lee11 | Eva M. Briso10 | Edyta Dobkowska10 | Bernhard Hauns10 | Ivan Špička12 1 University Hospital of Ostrava, Ostrava- Poruba-Poruba, Czech Republic Abstract 2 Faculty of Medicine, University of Ostrava, Objective: We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, Ostrava, Czech Republic combined with bortezomib and dexamethasone in patients with relapsed or relapsed/ 3 University Hospital Brno, Brno, Czech Republic refractory multiple myeloma who had received 1-3 prior therapies. 4 Ankara University School of Medicine, Methods: This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). Ankara, Turkey The primary endpoint was progression-free survival (PFS). 5 Hospital Universitario Virgen del Rocio, Results: Seventy-six patients were enrolled; 74 received ≥1 dose of study treat- Sevilla, Spain 6 University Hospital of Salamanca, ment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: Salamanca, Spain 6.2-10.8); median overall survival was not reached. Overall response rate was 57% 7 General Hospital of Thessaloniki (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). “G. Papanikolaou,” Thessaloniki, Greece 8 Institut Català d’Oncologia and Institut Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Josep Carreras, Hospital Germans Trias i Incidence of major haemorrhage was 5%; one patient died from cerebral haemor- Pujol, Barcelona, Spain 9 rhage. After an observed increased incidence of serious (42%) and fatal (11%) in- IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy fections, enrolment was suspended to implement risk-minimisation measures. The 10 Pharmacyclics Switzerland GmbH, an safety profile was otherwise consistent with known safety profiles of the individual AbbVie Company, Schaffhausen, Switzerland 11 drugs. Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA Conclusion: Ibrutinib combined with bortezomib and dexamethasone elicited clinical 12 1st Department of Medicine - Department responses. However, efficacy assessments conducted at potential restart of enrol- of Hematology, First Faculty of Medicine, ment indicated that the targeted PFS could not be reached with additional patient Charles University and General Hospital in Prague, Prague, Czech Republic enrolment, and the study was terminated. Correspondence KEYWORDS Roman Hajek, University Hospital of Ostrava, 17. listopadu 1790, 708 52 bortezomib, dexamethasone, ibrutinib, multiple myeloma Ostrava-Poruba-Poruba, Czech Republic. Email: roman.hajek@fno.cz Funding information This study was supported by Pharmacyclics Switzerland GmbH, an AbbVie Company. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd Eur J Haematol. 2020;104:435–442. wileyonlinelibrary.com/journal/ejh | 435 436 | HAJEK et al. 1 | I NTRO D U C TI O N Novelty statements Multiple myeloma (MM) is a malignancy of terminally differenti- ated plasma cells and is the second most common haematological • What is the new aspect of your work? malignancy after non-Hodgkin's lymphoma.1,2 Although novel drug • This study evaluated the novel combination of ibruti- combinations have improved outcomes for patients with MM, most nib, a once-daily oral inhibitor of Bruton's tyrosine ki- patients will eventually relapse after initial treatment and the effi- nase, with bortezomib plus dexamethasone in patients cacy of salvage regimens declines with each subsequent relapse. 1 with relapsed/refractory multiple myeloma. Bruton's Treatment choices in the relapsed setting are influenced by various tyrosine kinase is overexpressed on multiple myeloma factors, such as age, performance status, comorbidities, and/or ef- cells and may contribute to development of drug re- ficacy and toxicity of previous treatments; the optimal treatment sistance. Ibrutinib has demonstrated in vitro synergy 3 remains uncertain and an area of unmet clinical need. Current treat- with bortezomib and encouraging activity in combina- ment strategies involve the use of multiple agents that target specific tion with dexamethasone and carfilzomib plus dexa- signalling pathways involved in tumour cell growth and survival. methasone in phase 1 and 2 studies in patients with Bruton's tyrosine kinase (BTK) is overexpressed on MM tumour relapsed/refractory multiple myeloma. cells relative to normal plasma cells and has been implicated in the • What is the central finding of your work? growth and survival of MM tumour cells.4,5 Overexpression of BTK • Ibrutinib in combination with bortezomib and dexa- in side population cells may contribute to the development of drug methasone elicited clinical responses. However, the 5 resistance in MM tumour cells. In particular, BTK-overexpressing study was closed early after efficacy assessments cells demonstrated increased activity of the ATP-binding cassette indicated that the targeted median progression-free (ABC) transporter efflux pump and increased expression of the survival of >12 months could not be reached with the ABCB1 transporter protein, thereby promoting resistance to bor- enrolment of additional patients. 5 tezomib, doxorubicin, and etoposide. Inhibition of the drug efflux • What is (or could be) the specific clinical relevance of pump was able to restore sensitivity to bortezomib.5 your work? Ibrutinib, a first-in-class, once-daily oral inhibitor of BTK, is ap- • The optimal treatment for multiple myeloma in the proved in the United States and European Union for the treatment of relapsed/refractory setting remains uncertain and an various B-cell malignancies. 6,7 Ibrutinib has been shown to suppress area of unmet clinical need. Despite strong ration- tumour growth and improve MM-induced bone lysis in a murine ale based on preclinical and early clinical studies, the model4 and has demonstrated in vitro cytotoxicity and synergy with combination of ibrutinib with bortezomib and dexa- bortezomib and lenalidomide in malignant plasma cells from patients methasone did not demonstrate sufficient activity to 8 with MM. In patients with relapsed/refractory (R/R) MM, ibrutinib warrant further study in patients with relapsed/refrac- demonstrated encouraging activity in combination with dexameth- tory multiple myeloma. Clinical studies evaluating the asone9 and in combination with carfilzomib plus dexamethasone,10 safety and efficacy of novel combinations are critical warranting further investigation of ibrutinib with steroids and prote- to identifying more effective salvage treatment op- asome inhibitors. Bortezomib, in combination with dexamethasone, tions for patients with multiple myeloma. The informa- is currently approved for the treatment of R/RMM. 11,12 tion gained from these studies of novel combinations, This study was designed to assess the efficacy, safety, and toler- regardless of the outcome, can help to inform future ability of the addition of ibrutinib to the established treatment reg- studies seeking to address this unmet clinical need. imen of bortezomib and dexamethasone in patients with relapsed or R/R MM. recent treatment regimen. Patients could have received prior bortezomib treatment but must not have been refractory or non- 2 | M E TH O DS responsive to bortezomib treatment. All patients were required to have measurable disease, defined as at least one of the following: 2.1 | Study design and patients serum monoclonal protein (SPEP) ≥1 g/dL (for patients with im- munoglobulin [Ig] A, IgD, IgE, or IgM MM SPEP ≥0.5 g/dL) or urine PCYC-1139 (ClinicalTrials.gov identifier, NCT02902965) was a monoclonal protein ≥200 mg by 24-hour urine electrophoresis. non-randomised, open-label, international, multicentre, sponsor- Additional inclusion criteria were Eastern Cooperative Oncology initiated, phase 2 study conducted at multiple sites in Europe. Group performance status ≤2 and adequate haematological (ab- Eligible patients were aged ≥18 years with a diagnosis of active solute neutrophil count ≥1.5 × 10 9/L; platelet count ≥75 × 10 9/L), 13 MM per International Myeloma Working Group (IMWG) criteria, hepatic, and renal function. Patients were excluded if they had had received one to three prior lines of therapy, and had demon- primary refractory disease (defined as failure to achieve a mini- strated progressive disease (PD) since completion of their most mal response or better with any therapy); had disease refractory HAJEK et al. | 437 (defined as progression on treatment or within 60 days of com- 13 onward, patients received ibrutinib 840 mg once daily in com- pletion) or non-responsive (defined as failure to achieve minimal bination with dexamethasone 40 mg once weekly in each 28-day response or better) to prior proteasome inhibitor therapy; had a cycle. For patients aged >75 years, adjustment of the dexametha- history of plasma cell leukaemia, primary amyloidosis, or POEMS sone dose to 10 mg was recommended for cycles 1 to 12, and (polyneuropathy, organomegaly, endocrinopathy, monoclonal adjustment to 20 mg was recommended for cycle 13 onward, at gammopathy, skin abnormalities) syndrome within 12 months the discretion of the investigator. Treatment with ibrutinib plus prior to first administration of study treatment; peripheral neu- dexamethasone was continued until PD, unacceptable toxicity, or ropathy grade ≥2 or grade 1 with pain at screening; had currently other protocol-specified reason for discontinuation. active or clinically significant cardiovascular disease (uncontrolled arrhythmia or class III or IV congestive heart failure as defined by the New York Heart Association Functional Classification), or 2.3 | Outcomes and assessments a history of myocardial infarction, unstable angina, or acute coro- nary syndrome within 6 months prior to enrolment; had currently Efficacy endpoints were assessed by investigators according to active, clinically significant hepatic impairment (mild impairment IMWG criteria.13 The primary efficacy endpoint was progression- or worse by Child-Pugh classification); or required treatment with free survival (PFS), defined as the time from the first dose of study strong CYP3A inhibitors. treatment to confirmed PD or death from any cause. Secondary After 74 patients had initiated study treatment, study enrol- endpoints were overall response rate (ORR), defined as partial re- ment was suspended because of an initially observed increase of sponse or better; PFS rate at landmark time points; duration of serious and fatal infections. During the enrolment halt, enrolled response, defined as the time from initial documentation of re- patients continued to receive treatment with the immediate imple- sponse to the first documented evidence of PD; overall survival mentation of risk-minimisation measures, which included modifica- (OS), defined as the time from the first dose of study treatment tions to the dexamethasone dosing regimen that effectively halved to death from any cause; time to progression, defined as the time the dose of dexamethasone in the triple combination (described in from the first dose of study treatment until PD; and the safety “Treatments” section below), and strengthened guidance for infec- and tolerability of ibrutinib in combination with bortezomib and tion prophylaxis. A Safety Review Committee was also established dexamethasone. Pharmacokinetic characteristics of ibrutinib and to evaluate the rate of new infections every 6 weeks following im- bortezomib when given in combination with dexamethasone were plementation of the risk-minimisation measures and enrolment was assessed as an exploratory endpoint. approved to restart approximately 6 months after the enrolment Response and progression were assessed per IMWG criteria13 halt as a result of these risk-minimisation measures. However, an every 3 weeks during cycles 2 to 12 and every 4 weeks thereaf- evaluation of the efficacy data performed at this time indicated that ter. In case of suspected complete response, pertinent assessments the primary endpoint was unlikely to be achieved. As a result, the were performed per the IMWG response assessment guidelines. study was terminated and enrolment was not restarted. Following confirmed PD, patients were contacted approximately The study was conducted in accordance with International every 12 weeks for long-term survival follow-up. Plasma samples Conference on Harmonization guidelines for Good Clinical Practice for analysis of ibrutinib and bortezomib pharmacokinetics were col- and principles of the Declaration of Helsinki. The protocol and its lected predose and at 30 minutes; 1, 2, 4, and 6 hours postdose on amendments were approved by independent ethics committees of day 1 of cycle 2; and predose on day 2 of cycle 2. all participating institutions and all patients provided written in- Safety assessments included adverse events (AEs), laboratory formed consent. evaluations, physical examinations, and vital signs. Adverse events were monitored throughout treatment until 30 days after the last dose of study treatment. Adverse events were coded by preferred term 2.2 | Treatments using the Medical Dictionary for Regulatory Activities (MedDRA), version 21.1, and were graded according to National Cancer Institute During cycles 1 to 8, patients received oral ibrutinib 840 mg once Common Terminology Criteria for Adverse Events, version 4.03. daily in combination with subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle. With the implemen- 2.4 | Statistical analysis tation of risk-minimisation measures, dosing of dexamethasone was limited to days 1, 4, 8, and 11. During cycles 9 to 12, patients Efficacy and safety were evaluated in all patients who received at received ibrutinib 840 mg once daily in combination with bort- least one dose of study treatment. Time-to-event endpoints were 2 ezomib 1.3 mg/m on days 1, 8, 22, and 29, and dexamethasone estimated using the Kaplan-Meier method. For PFS, two-sided 95% 20 mg on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. confidence intervals (CIs) were calculated using the Brookmeyer- With the implementation of risk-minimisation measures, dosing of Crowley method with the log-log transformed Greenwood variance dexamethasone was limited to days 1, 8, 22, and 29. From cycle estimate to test the null hypothesis. For ORR, two-sided 95% CIs were 438 | HAJEK et al. calculated using the exact binomial method. Pharmacokinetics were 3.2 | Safety analysed by non-compartmental methods using Phoenix WinNonlin (Certara USA Inc), and AEs were summarised descriptively. The median duration of treatment was 5.7 months (range, 0.1- A sample size of approximately 125 patients was required to 23.7) for ibrutinib, 4.5 months (range, 0.0-12.6) for bortezomib, achieve 80% power at a one-sided 0.025 significance level to test the null hypothesis of median PFS ≤8 months versus ≥12 months under TA B L E 2 Baseline demographic and disease characteristics the alternative hypothesis, with the assumption that the PFS follows Patients an exponential distribution. However, a review of the available ef- Characteristics N = 74 ficacy data at the time of potential restart of enrolment indicated Age that the primary endpoint was unlikely to be achieved; therefore, Median, years (range) 67.5 (37-86) hypothesis testing for PFS was not performed. ≥65 y, n (%) 45 (61) Male sex, n (%) 35 (47) 2.5 | Data sharing statement White race, n (%) 71 (96) ECOG PS, n (%) Requests for access to individual participant data from clinical stud- 0 43 (58) ies conducted by Pharmacyclics LLC, an AbbVie Company, can be 1 27 (36) submitted through Yale Open Data Access (YODA) Project site at 2 4 (5) http://yoda.yale.edu. Median time since diagnosis, years (range) 4.2 (0.4-13.7) ISS stage at baseline, n (%) I 25 (34) 3 | R E S U LT S II 29 (39) III 20 (27) 3.1 | Patients Measurable disease, n (%) A total of 76 patients were enrolled, and 74 patients received UPEP only 6 (8) at least one dose of study treatment (Table 1). Median age was SFLC only 0 67.5 years and 61% were aged ≥65 years (Table 2). All patients had SPEP only 42 (57) received prior systemic therapy for MM; 61% of patients had re- SPEP and UPEP 26 (35) ceived one line of therapy and 39% had received two or three lines Immunoglobulin (Ig) heavy chain class, n (%) of therapy. The most common prior systemic therapies (reported in IgA 21 (28) ≥30% of patients) were dexamethasone (88%), bortezomib (81%), IgE 0 cyclophosphamide (65%), lenalidomide (39%), and melphalan IgG 49 (66) (31%). Overall, 39% of all patients were refractory to the last line of IgM 1 (1) therapy. At the time of final analysis, all patients had discontinued None 5 (7) study treatment; the most common reasons for discontinuation Median bone marrow plasma cell percentage 23 (2-99) were PD (50%), AEs (18%), and patient withdrawal (14%) (Table 1). (range) The median follow-up duration was 19.6 months (range, 0.2-24.6). Number of prior lines of therapy, n (%) 1 45 (61) TA B L E 1 Patient disposition 2-3 29 (39) Patients Previous transplantation, n (%) 43 (58) Enrolled, n 76 Prior systemic therapies, n (%) Did not receive treatment, n 2 Dexamethasone 65 (88) Started treatment, n 74 Bortezomib 60 (81) Discontinued treatment, n (%) 74 (100) Cyclophosphamide 48 (65) Progressive disease 37 (50) Lenalidomide 29 (39) Adverse event 13 (18) Melphalan 23 (31) Withdrawal by patient 10 (14) Refractory to last line of therapy, n (%) 29 (39) Death 7 (9) Note: Abbreviations: ANC, absolute neutrophil count; ECOG PS, Eastern Physician decision 4 (5) Cooperative Oncology Group performance status; ISS, International Staging System; SFLC, serum-free light-chain assay; SPEP, serum Study termination by sponsor 3 (4) monoclonal protein; UPEP, urine monoclonal protein. HAJEK et al. | 439 and 5.6 months (range, 0.1-20.1) for dexamethasone. The most partial response or better, the median duration of response was common AEs of any grade were thrombocytopenia (61% of pa- 9.5 months (95% CI: 6.9-10.6) and the median time to progression tients), diarrhoea (55%), anaemia (38%), asthenia (30%), fatigue was 10.6 months (95% CI: 7.8-12.0). At the time of analysis, 27 pa- (28%), peripheral oedema (28%), upper respiratory tract infection tients (36%) had died and median OS was not reached (Figure 1B). (26%), nausea (24%), peripheral sensory neuropathy (24%), cough Estimated OS at 24 months was 54%. (20%), and back pain (20%) (Table 3). Grade 3/4 AEs were reported in 73% of patients, and fatal AEs were reported in 15% of patients. The most common grade 3 or higher AEs (occurring in ≥10% of pa- 3.4 | Pharmacokinetics tients) were thrombocytopenia (34%), pneumonia (16%), anaemia (15%), and asthenia (14%). Serious AEs of any grade occurred in 47 Steady-state plasma exposures of ibrutinib at the 840 mg dose level patients (64%). The only serious AE occurring in ≥5% of patients in this study were similar to those observed in patients with R/R was pneumonia, which occurred in 11 patients (15%); serious AEs MM receiving ibrutinib in combination with carfilzomib in the PCYC- of pneumonia were grade 3/4 in nine patients (12%), and grade 5 1119-CA study.10 Steady-state plasma exposures of bortezomib in two patients (3%). were consistent with those reported in the US prescribing informa- Infections were reported in 59 patients (80%) and were grade 3 or tion for bortezomib.14 higher in 32 patients (43%); the most common infections of any grade (occurring in ≥10% of patients) were upper respiratory tract infection (26%), pneumonia (18%), bronchitis (15%), conjunctivitis (14%), naso- 4 | D I S CU S S I O N pharyngitis (14%), and urinary tract infection (11%). Serious infections were reported in 31 patients (42%), with pneumonia being the most This phase 2 study evaluated the efficacy and safety of ibrutinib in common serious infection (15%). Fatal infections were reported as AEs combination with bortezomib plus dexamethasone in patients with in eight patients (11%), coded as MedDRA-preferred terms of sepsis R/R MM who had received one to three previous lines of therapy. (n = 3) and pseudomonal sepsis (n = 1) for a total of four fatal infections After 74 patients had received at least one dose of study treatment, due to sepsis; and pneumonia (n = 2), pneumonia Escherichia (n = 1), study enrolment was suspended as a risk-minimisation measure to ad- and pneumonia bacterial (n = 1) for a total of four fatal infections due dress concerns over an increased incidence of serious and fatal infec- to pneumonia. Additional fatal AEs were cerebral haemorrhage, death tions compared with other studies of ibrutinib in R/R MM.9,10 While (unknown cause), and sudden death (n = 1 each). the incidence of infection of any grade in this study (80%) was similar Bleeding events of any grade were reported in 23 patients (31%). Major haemorrhage was reported in four patients (5%); one event (ce- TA B L E 3 Adverse events of any grade occurring in ≥15% of rebral haemorrhage) resulted in treatment discontinuation and was patients subsequently fatal. Atrial fibrillation occurred in seven patients (9%) Patients (N = 74) and was grade 3/4 in three patients (4%). Adverse events leading to dose reduction of ibrutinib, bortezomib, and dexamethasone occurred Adverse event, n (%) Any Grade Grade 3/4 Grade 5 in 38 (51%), 30 (41%), and 19 (26%) patients, respectively, and AEs lead- Any adverse event 74 (100) 54 (73) 11 (15) ing to discontinuation of ibrutinib, bortezomib, and dexamethasone oc- Thrombocytopenia 45 (61) 25 (34) 0 curred in 18 (24%), 22 (30%), and 20 (27%) patients, respectively. The Diarrhoea 41 (55) 7 (9) 0 most common AEs leading to ibrutinib discontinuation were pneumo- Anaemia 28 (38) 11 (15) 0 nia (n = 3; 4%), atrial fibrillation, diarrhoea, and sepsis (n = 2 each; 3%). Asthenia 22 (30) 10 (14) 0 The most common AEs leading to bortezomib discontinuation were Fatigue 21 (28) 6 (8) 0 polyneuropathy (n = 3; 4%), atrial fibrillation, diarrhoea, peripheral Oedema peripheral 21 (28) 0 0 sensorimotor neuropathy, pneumonia, and sepsis (n = 2 each; 3%). The most common AEs leading to discontinuation of dexamethasone were Upper respiratory 19 (26) 2 (3) 0 tract infection atrial fibrillation, diarrhoea, pneumonia, and sepsis (n = 2 each; 3%). Nausea 18 (24) 1 (1) 0 Peripheral sensory 18 (24) 1 (1) 0 neuropathy 3.3 | Efficacy Back pain 15 (20) 2 (3) 0 Cough 15 (20) 0 0 After a median follow-up of 19.6 months, PFS events had occurred in 55 patients (74%). The median PFS was 8.5 months (95% CI: 6.2- Hypokalaemia 13 (18) 3 (4) 0 10.8) and estimated PFS at 20 months was 7% (Figure 1A). Pneumonia 13 (18) 10 (14) 2 (3) a The ORR was 57% (95% CI: 45-68), including complete response Pyrexia 13 (18) 0 0 in one patient, very good partial response in 13 patients, and partial a Does not include two additional grade 5 AEs of pneumonia reported as response in 28 patients (Table 4). Among 42 patients who achieved pneumonia escherichia and pneumonia bacterial (n = 1 each). 440 | HAJEK et al. (A) F I G U R E 1 Kaplan-Meier estimates of (A) PFS per investigator assessment and (B) OS. NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival r (B) r to rates reported with ibrutinib in other haematological malignancies not possible as no new patients were enrolled. Apart from infections, (68%-78%) over median follow-up durations of 9.4 to 33.4 months, the safety profile was consistent with the known safety profiles of the incidence of grade ≥3 infections (43%) was higher than rates pre- the individual study drugs.6,7,11,12 While safety profiles in general viously reported with ibrutinib (7%-29%).15-20 However, it should be may vary depending on dosage, combination with other drugs, and noted that a higher dose of ibrutinib (840 mg once daily) was used in by disease histology, incidences of AEs of interest with ibrutinib the current study compared with other haematological malignancies were largely consistent with previous reports across a range of hae- (420 mg or 560 mg once daily). The ibrutinib dose used in the current matological malignancies, including chronic lymphocytic leukaemia, study was chosen based on clinical activity and a favourable safety Waldenström’s macroglobulinemia, and mantle cell lymphoma.15-20 profile observed at the 840 mg dose level of ibrutinib in combination The median PFS of 8.5 months with ibrutinib plus bortezomib and with carfilzomib with or without dexamethasone and in combination dexamethasone was slightly longer than that observed in patients with dexamethasone in two early phase studies in MM.9,10 Plasma ex- with R/R MM treated with placebo plus bortezomib and dexameth- posures to ibrutinib and bortezomib were consistent with those pre- asone in the PANORAMA-1 study (median 8.1 months). 21 Such indi- 10,14 viously reported, suggesting that drug-drug interactions may not rect comparisons should, however, be interpreted with caution given be contributing factors to the safety observations. Relative to other differences in study design. Clinical response was observed in 57% studies conducted in patients with MM, the incidence of grade ≥3 of patients and was generally durable, with a median response dura- AEs observed with ibrutinib plus bortezomib and dexamethasone in tion of 9.5 months. Overall survival data were not yet mature, with the current study (88%) was similar to the incidence observed with 64% of patients remaining alive after a median follow-up duration of ibrutinib plus carfilzomib with or without dexamethasone (86%),10 but 19.6 months. Assessment of efficacy at the time of potential restart higher than that observed with ibrutinib alone or in combination with of enrolment indicated that the target median PFS for the alternative dexamethasone without a proteasome inhibitor (57%).9 hypothesis (≥12 months) could not be reached by enrolling additional A review of the data after the implementation of risk-minimisa- patients, and therefore, enrolment was not restarted. Because en- tion measures showed a lower rate of serious infections and no fatal rolment was suspended due to safety concerns before the target infections among patients already enrolled in the study. However, sample size had been reached, the hypothesis testing for the median validation of the effectiveness of the risk-minimisation measures was PFS was not performed. HAJEK et al. | 441 TA B L E 4 Best response per investigator assessment Ibrahim. JMS reports travel, accommodations, or other expenses from Amgen Iberia. RGS reports honoraria from Amgen, Janssen, Patients N = 74 and Takeda; consultancy/advisory role for Bristol-Myers Squibb and Takeda; research funding from Gilead, Incyte, Amgen, and Janssen; ORR, % (95% CI)a 57 (45-68) patents, royalties, or other intellectual property with Invivoscribe Best response, n (%) (EuroClonality/BIOMED-2); and travel, accommodations, or other sCR 0 expenses from Janssen and Takeda. AA reports nothing to dis- CR 1 (1) close. AO reports consultancy/advisory role for Celgene, Janssen, VGPR 13 (18) Amgen, and Takeda; and speakers bureau for Celgene and Amgen. PR 28 (38) NC reports nothing to disclose. AT, ED, and BH report employment MR 11 (15) with Pharmacyclics Switzerland GmbH, an AbbVie Company, and SD 13 (18) stock or other ownership in AbbVie. YL reports employment with PD 2 (3) Pharmacyclics LLC, an AbbVie Company, and stock or other own- Unconfirmed PD 0 ership in AbbVie. EMB reports employment with Pharmacyclics Not evaluable 1 (1) Switzerland GmbH, an AbbVie Company. IS reports honoraria from Not done 5 (7) and consultancy/advisory role with Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, and Sanofi; speakers bureau Note: Abbreviations: CI, confidence interval; CR, complete response; for Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent CR; SD, stable disease; and Novartis; and travel, accommodations, or other expenses from VGPR, very good partial response. Celgene, Amgen, Janssen-Cilag, and Bristol-Myers Squibb. a Confirmed sCR + CR + VGPR + PR. AU T H O R C O N T R I B U T I O N S In summary, an initially increased incidence of serious infections RH designed the study in collaboration with the study sponsor. RH, was observed with ibrutinib in combination with bortezomib and LP, MO, JMS, RGS, AA, AO, NC, and IS collected data. YL, EMB, and dexamethasone, and in response, risk-minimisation measures were ED confirmed the accuracy of the data, interpreted the data, and introduced. Following the implementation of risk-minimisation mea- compiled it for analysis. YL performed statistical analyses. All au- sures, very few serious and no fatal infections occurred, and reg- thors had full access to the data, contributed to data interpretation, ulatory authorities and ethics committees approved the restart of and vouch for accuracy of the data. All authors contributed to the enrolment. Ibrutinib in combination with bortezomib and dexameth- manuscript preparation and approved the final version of the manu- asone elicited clinical responses in patients with R/R MM. However, script for submission. an efficacy assessment at the time of the potential restart of enrol- ment indicated that even with the pending enrolment of additional ORCID patients, the targeted endpoint of median PFS could not be reached Roman Hajek https://orcid.org/0000-0001-6955-6267 and the study was terminated. REFERENCES AC K N OW L E D G E M E N T S 1. Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev We thank all the patients who participated in this study and their Dis Primers. 2017;3:17046. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J supportive families, as well as the investigators and clinical research Clin. 2018;68(1):7-30. staff from the study centres. We also thank Yvonne Pak, PhD, of 3. Nijhof IS, van de Donk N, Zweegman S, Lokhorst HM. 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