Efficacy and safety of bortezomib in patients with renal impairment ...

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ORIGINAL ARTICLE Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study JF San-Miguel1, PG Richardson2, P Sonneveld3, MW Schuster4, D Irwin5, EA Stadtmauer6, T Facon7, J-L Harousseau8, D Ben-Yehuda9, S Lonial10, H Goldschmidt11, D Reece12, J Blade´13, M Boccadoro14, JD Cavenagh15, R Neuwirth16, AL Boral16, D-L Esseltine16 and KC Anderson2 1 Department of Hematology, Hospital Universitario. CIC Universidad de Salamanca-CSIC, Salamanca, Spain; 2Department of Medical Oncology/Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA; 3Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; 4Center for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, NY, USA; 5Bone and Marrow Transplantation Program, Alta Bates Cancer Center, Berkeley, CA, USA; 6Bone Marrow and Stem Cell Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 7Services des Maladies du Sang, Hospital Claude Huriez, Lille, France; 8Department of Hematology, Hotel Dieu Hospital, Nantes, France; 9Department of Hematology, Hadassah University Hospital, Jerusalem, Israel; 10The Winship Cancer Institute, Emory University, Atlanta, GA, USA; 11Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 12Division of Hematology–Oncology, Princess Margaret Hospital, Toronto, Canada; 13Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; 14Division of Hematology, University of Torino, Torino, Italy; 15Department of Haematology, St Bartholomew’s Hospital, London, UK and 16Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) o30, 30–50, 51–80 and 480 ml min1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl p50 ml min1 (severe-to-moderate) and 450 ml min1 (no/mild impairment). Response rates with bortezomib were similar (36–47%) and time to response rapid (0.7–1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severeto-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl p50 vs 450 ml min1 (P ¼ 0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl p50 vs 450 ml min1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-tomoderate vs no/mild impairment. Leukemia (2008) 22, 842–849; doi:10.1038/sj.leu.2405087; published online 17 January 2008 Keywords: multiple myeloma; bortezomib; creatinine clearance; renal impairment; clinical trial

Introduction Renal impairment is a common complication in multiple myeloma (MM) patients during diagnosis.1 Approximately 30% of patients have a serum creatinine X1.5 mg per 100 ml,2–4 and approximately 1–13% require dialysis depending on the Correspondence: Professor JF San-Miguel, Servicio de Hematologı´a, Hospital Universitario de Salamanca, Paseo San Vicente 58-182; Salamanca 37007, Spain. E-mail: [email protected] Received 2 October 2007; revised 27 November 2007; accepted 28 November 2007; published online 17 January 2008

population and the type of treatment center.3,5–10 Renal impairment in MM is primarily due to light-chain tubular cast nephropathy,1,7,11 so-called ‘myeloma kidney,’12 while other precipitating/aggravating factors include dehydration, hypercalcemia and tumor lysis syndrome.6,11,13,14 Renal impairment, as evidenced by elevated serum creatinine or reduced creatinine clearance (CrCl), is associated with a decreased response to therapy7 and an overall poor prognosis in terms of survival.2,3,7,9,13–18 This is likely due to the association of renal impairment with more advanced disease2 and higher tumor burden,14 the use of lower-dose therapy due to toxicity concerns and a high rate of early mortality3,7,9 among these patients. Renal impairment is partially or fully reversible with therapy in 26–58% of patients,3,5,7,14,19 and reversibility is more common in patients with only mild or moderate impairment.3,5,7 Reversal of renal impairment is in turn associated with improved survival.3,7,14 Nevertheless, renal impairment remains common throughout the course of disease. Given the proportion of MM patients who experience renal impairment, the development of new treatment approaches for this subset of patients with poor prognosis is highly important. Moreover, prompt treatment and rapid disease control is key in this patient population,20 along with early recovery of normal renal function; therefore, new therapeutic agents should have a rapid mechanism of action. In addition, to achieve optimal efficacy, it is important that these agents have a good safety profile and that the rate of dose reductions due to toxicity is not elevated in patients with renal impairment. The proteasome inhibitor bortezomib (VELCADE, Millennium Pharmaceuticals Inc. Cambridge, MA, USA, and Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA) is approved in the United States21 and European Union for the treatment of MM patients who have received at least one prior therapy, and in the United States for the treatment of mantle cell lymphoma patients who have received at least one prior therapy.22 Bortezomib primarily undergoes hepatic oxidative metabolism,22 and clearance has been shown to be independent of renal function.23 Bortezomib alone and in combination has been shown to be active and well tolerated in both relapsed and newly diagnosed MM with varying degrees of renal impairment, including those requiring dialysis.12,23–28

Bortezomib in renally impaired MM patients JF San-Miguel et al

The international, phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study enrolled 669 patients with relapsed MM who had received 1–3 prior therapies and who had varying degrees of renal impairment. Patients were randomized to receive either single-agent bortezomib or highdose dexamethasone.29 During the initial analysis of the study, bortezomib was shown to be significantly superior to dexamethasone in terms of time to progression (TTP), response rate (including complete response (CR) rate) and overall survival (OS).29 The dexamethasone arm was consequently halted as per the recommendations of the independent data-monitoring committee, and a companion crossover study that had initially offered single-agent bortezomib only to dexamethasone patients with progressive disease, was opened to all dexamethasone patients.29 In an updated analysis, with longer median followup, bortezomib was shown to provide a 6–month OS benefit compared with dexamethasone (median OS: 29.8 vs 23.7 months), despite 462% of dexamethasone patients having crossed over to receive single-agent bortezomib.30 The aim of this exploratory subgroup analysis of the APEX study was to assess the efficacy and safety profiles of bortezomib in patients with different degrees of renal impairment and to compare these data with corresponding subgroups of patients in the dexamethasone arm. This study represents the first analysis of the efficacy of bortezomib in the setting of renal impairment in a large, unselected series of patients included in a randomized trial. Indeed, this is the first analysis of the impact of renal function on outcomes, including the impact on OS, conducted within a randomized trial.

Materials and methods Full details of the APEX study have been published previously.29 Briefly, patients were randomized (1:1) to receive bortezomib Table 1

1.3 mg m2 on days 1, 4, 8 and 11 for eight 3-week cycles and then on days 1, 8, 15 and 22 for three 5-week cycles (N ¼ 333) or dexamethasone 40 mg on days 1–4, 9–12 and 17–20 for four 5-week cycles and then on days 1–4 for five 4-week cycles (N ¼ 336). Randomization was stratified according to the number of prior therapies (1 vs 41), b2-microglobulin level (42.5 vs p2.5 mg l1) and TTP after the last prior therapy (p6 vs 46 months), but not by renal function. Patients were required to have calculated CrCl of X20 ml min1. Response (CR, partial response (PR), minimal response, stable disease and progressive disease) was evaluated according to the European Group for Blood and Marrow Transplantation criteria31 every 3 weeks for 39 weeks and then every 6 weeks until disease progression. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0. Serious AEs (SAEs) were defined as any events that resulted in death, were life threatening, required hospitalization, resulted in persistent or substantial disability or had important medical consequences.29 On-study deaths were defined as deaths occurring within 30 days after the last dose of study drug or deaths occurring after this time considered to be study-drug related. Review boards at all participating institutions approved the study, and all patients provided written informed consent. The study was conducted according to the Declaration of Helsinki, the International Conference on Harmonisation and the Guidelines for Good Clinical Practice.

843

Analysis by degree of renal impairment Patients in each arm were divided into four subgroups defined by their degree of renal impairment at baseline in terms of calculated CrCl, using the Cockcroft–Gault formula:32 CrCl (ml min1) ¼ ((140age at baseline in years)  weight at baseline in kg)/(72  serum creatinine at baseline in mg per 100 ml) (for female patients, values are multiplied by 0.85). The

Baseline demographics and disease characteristics in patients treated with bortezomib or dexamethasone, by renal subgroups Bortezomib Total population

Dexamethasone Total population

Creatinine clearance (ml min1) o30 30–50

p50

51–80

480

Creatinine clearance (ml min1) o30 30–50 p50

450

51–80

480

450

N (%) 330 (100) 17 (5) 45 (14) 62 (19) 141 (43) 127 (39) 268 (81) 323 (100) 11 (3) 57 (18) 68 (21) 122 (38) 133 (41) 255 (79) Median age, 62 69 71 70.5 64 57 60 61 61 67 66 64 56 60 years Male, % 57 35 47 44 50 71 60 60 45 53 51 64 61 62 White, % 90 94 91 92 93 87 90 87 70 93 90 89 84 87 KPS X80%, % 87 53 84 75 88 92 90 83 82 75 76 85 85 85 3.7 11.7 5.9 6.8 3.7 2.9 3.3 3.5 11.6 6.7 7.0 4.0 2.9 3.3 Median b2-microglobulin, mg l1 X5.5 mg/l, 25 100 53 68 21 9 15 30 100 64 72 31 9 19 % of patients Creatinine X1.5 mg 16 100 51 65 9 0 4 17 100 58 65 10 0 5 per 100 ml, % of patients 108.0 99.0 103.5 102.0 106.0 114.0 109.0 109.0 99.0 103.0 102.0 110.5 111.0 111.0 Median hemoglobin, g l1 Median serum 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.4 2.3 2.3 2.3 2.3 calcium, mmol l1 ISS stage,17 % I II III

42 31 25

0 0 100

16 29 56

11 21 68

41 36 21

58 30 9

49 33 15

42 26 30

0 0 100

16 18 65

13 15 71

37 31 30

62 28 9

50 29 19

Leukemia

Leukemia

Abbreviations: CI, confidence interval; CR, complete response; NE, not estimable; PR, partial response. *P ¼ 0.62 for the comparison with bortezomib patients with CrCl 450 ml min1; P ¼ 0.02 for the comparison with dexamethasone patients with CrCl p50 ml min1; wPo0.0001 for the comparison with dexamethasone patients with CrCl 450 ml min1; zP ¼ 0.07 for the comparison with bortezomib patients with CrCI 450 ml min1; P ¼ 0.09 for the comparison with dexamethasone patients with CrCl p50 ml min1; #P ¼ 0.09 for the comparison with dexamethasone patients with CrCl 450 ml min1; zP ¼ 0.003 for the comparison with dexamethasone patients with CrCI 450 ml min1.

255 25.3 21.7, NE 133 29.1 19.5, NE 122 24.3 20.1, NE 68 12.6z 9.8, 27.0 57 12.6 8.3, 27.0 11 17.4 5.5, NE 323 23.7 19.1, 31.4 268 30.0# 24.9, NE 127 NE 23.2, NE 141 30.0 22.5, NE 62 22.8z 18.2, NE 45 22.8 14.0, NE 330 29.8 23.2, NE Overall survival N Median, months 95% CI

17 22.0 18.2, NE

255 3.5 2.9, 4.8 133 2.8 2.1, 3.5 122 4.9 3.9, 6.3 68 2.8 2.4, 4.1 57 2.9 2.4, 4.3 11 2.1 1.9, 6.7 323 3.5 2.9, 4.2 268 6.2w 4.9, 6.9 127 6.3 4.1, 7.6 141 6.2 4.8, 6.9 62 4.9* 4.2, 7.7 45 5.6 4.2, 9.4 330 6.2 4.9, 6.9 Time to progression N Median, months 95% CI

17 4.2 1.4, 7.7

123 13 (11) 1 (1) 12 (10) 1.4 118 30 (25) 0 30 (25) 1.4 62 10 (16) 1 (2) 9 (15) 0.8 52 9 (17) 1 (2) 8 (15) 0.8 255 97 (38) 16 (6) 81 (32) 1.4 118 42 (36) 5 (4) 37 (31) 1.4 137 55 (40) 11 (8) 44 (32) 1.2 58 23 (40) 4 (7) 19 (33) 1.4

p50

51–80

480

450

303 53 (17) 2 (1) 51 (17) 1.4

10 1 (10) 0 1 (10) 1.4

480 51–80 p50 30–50 o30

Creatinine clearance (ml min1)

Dexamethasone

Total population 30–50

43 16 (37) 4 (9) 12 (28) 0.7 15 7 (47) 0 7 (47) 1.6 313 120 (38) 20 (6) 100 (32) 1.4 Response-evaluable patients, N Response rate (CR+PR), n (%) CR, n (%) PR, n (%) Median time to first response, months

The response rate (CR þ PR) with bortezomib was similar across renal subgroups (Table 2). In patients with CrCl of p50 ml min1, the response rate was 40%, compared with 38% in patients with CrCl of 450 ml min1. The median time to first response in patients was similarly rapid across renal subgroups and was the same in patients with severe-to-moderate and no/mild renal impairment (1.4 months). TTP and OS with bortezomib appeared similar across renal subgroups, with overlapping CIs (Table 2). Between bortezomib patients with CrCl of p50 and 450 ml min1, TTP and OS were not statistically different, although the data indicated a trend toward shorter OS in patients with severe-to-moderate renal impairment compared with patients with no/mild renal impairment (median TTP: 4.9 vs 6.2 months, P ¼ 0.62; median OS: 22.8 vs 30.0 months, P ¼ 0.07). Kaplan–Meier plots of TTP and OS in bortezomib patients with CrCl of p50 or 450 ml min1 are shown in Figures 1 and 2, respectively. Bortezomib demonstrated greater efficacy compared with dexamethasone in all renal subgroups (Table 2), reflecting the overall results of the APEX study.29,30 Response rate was

o30

Efficacy

Creatinine clearance (ml min1)

Of the 333 patients randomized to bortezomib in the APEX study, baseline CrCl data were available for 330 patients. CrCl of o30, 30–50, 51–80 and 480 ml min1 was seen in 17 (5.2%), 45 (13.6%), 141 (42.7%) and 127 (38.5%) patients, respectively. In the bortezomib arm, median b2-microglobulin level at baseline was markedly higher in patients with CrCl of p50 vs 450 ml min1, as would be expected, as was the proportion of patients with International Staging System17 stage III disease. In addition, a lower proportion of bortezomib patients with CrCl of p50 ml min1 had Karnofsky Performance Status X80%, compared with patients with CrCl of 450 ml min1. Similar observations were noted in the dexamethasone arm (Table 1).

Total population

Results

Bortezomib

TTP and OS were assessed using Kaplan–Meier methods, and medians and 95% confidence intervals (CI) were calculated. A log-rank test was used for statistical comparisons of TTP and OS between the subgroups with severe-to-moderate and no/mild impairment within each treatment arm and between treatment arms for both subgroups.

Response rate, time to progression and overall survival in patients treated with bortezomib and dexamethasone, by renal subgroups

Statistical analysis

450

subgroups comprised patients with CrCl of o30, 30–50, 51–80 and 480 ml min1, corresponding to severe, moderate, mild and no renal impairment, respectively. Response rate (CR þ PR, European Group for Blood and Marrow Transplantation criteria)31 was determined in response-evaluable patients, TTP and OS were evaluated on an intent-to-treat basis and incidences of AEs and SAEs were assessed in patients who received any amount of study drug (safety population). Analyses of response rate, TTP and safety were conducted using the initial APEX data set.29 OS analysis was conducted using the updated APEX data set with extended follow-up (median 22 months).30 As the number of patients with severe renal impairment in each treatment arm is small, statistical comparisons of TTP and OS were conducted and safety profile assessed, for subgroups of patients with CrCl of p50 ml min1 (severe-to-moderate renal impairment) or 450 ml min1 (no/mild renal impairment).

Table 2

844

241 43 (18) 1 (o1) 42 (17) 1.4

Bortezomib in renally impaired MM patients JF San-Miguel et al

Bortezomib in renally impaired MM patients JF San-Miguel et al

845

Figure 1 Time to progression in patients receiving bortezomib or dexamethasone with creatinine clearance of p50 ml min1 (severe-to-moderate renal impairment) or 450 ml min1 (no/mild renal impairment). P ¼ 0.62 for the comparison between bortezomib patients with CrCl p50 ml min1 and bortezomib patients with CrCl 450 ml min1; P ¼ 0.02 for the comparison between bortezomib patients with CrCl p50 ml min1 and dexamethasone patients with CrCl p50 ml min1; Po0.0001 for the comparison between bortezomib patients with CrCl 450 ml min1 and dexamethasone patients with CrCl 450 ml min1.

Figure 2 Overall survival in patients receiving bortezomib or dexamethasone with creatinine clearance of p50 ml min1 (severe-to-moderate renal impairment) or 450 ml min1 (no/mild renal impairment). P ¼ 0.07 for the comparison between bortezomib patients with CrCl p50 ml min1 and bortezomib patients with CrCl 450 ml min1; P ¼ 0.09 for the comparison between bortezomib patients with CrCl p50 ml min1 and dexamethasone patients with CrCl p50 ml min1; P ¼ 0.09 for the comparison between bortezomib patients with CrCl 450 ml min1 and dexamethasone patients with CrCl 450 ml min1; P ¼ 0.003 for the comparison between dexamethasone patients with CrCl p50 ml min1 and dexamethasone patients with CrCl 450 ml min1.

higher with bortezomib in patients with severe-to-moderate renal impairment (40 vs 16%) and in patients with no/mild renal impairment (38 vs 18%). Similarly, TTP was significantly longer with bortezomib compared with dexamethasone in patients with CrCl of p50 ml min1 (median 4.9 vs 2.8 months; P ¼ 0.02) and in patients with CrCl of 450 ml min1 (median 6.2 vs 3.5 months; Po0.0001; Figure 1). For OS, the data indicated a trend toward longer OS with bortezomib compared with dexamethasone in patients with both CrCl of p50 ml min1 (median 22.8 vs 12.6 months; P ¼ 0.09) and CrCl of 450 ml min1 (median 30.0 vs 25.3 months; P ¼ 0.09; Figure 2). Notably, there was a significant difference in OS

between these renal subgroups for dexamethasone patients, with longer OS in patients with no/mild renal impairment (P ¼ 0.003).

Safety Duration of bortezomib treatment was comparable across all renal subgroups. Patients with both severe-to-moderate and no/ mild renal impairment received a median of six cycles of bortezomib. The safety profile of bortezomib in the overall population was reflected in the renal subgroups with similar incidences of AEs, grade X3 AEs and SAEs between patients Leukemia

Bortezomib in renally impaired MM patients JF San-Miguel et al

846 Table 3 Most commonly reported adverse events of any grade (in X20% of total population) and of grade X3 (in X5% of total population), plus incidences of serious adverse events and discontinuations and dose reductions/interruptions due to adverse events, in patients treated with bortezomib, by renal subgroup Adverse event, n (%)

Total population (N ¼ 329)

Creatinine clearance (ml min1) o30 (N ¼ 17)

30–50 (N ¼ 44)

p50 (N ¼ 61)

51–80 (N ¼ 141)

480 (N ¼ 127)

450 (N ¼ 268)

44 24 24 23 18 17 17 15 12 7 5 13 6 10

(100) (55) (55) (52) (41) (39) (39) (34) (27) (16) (11) (30) (14) (23)

61 36 35 31 27 25 21 24 17 8 12 18 13 11

(100) (59) (57) (51) (44) (41) (34) (39) (28) (13) (20) (30) (21) (18)

141 84 83 61 61 44 51 46 41 42 39 34 31 35

(100) (60) (59) (43) (43) (31) (36) (33) (29) (30) (28) (24) (22) (25)

127 69 71 48 51 48 43 44 28 35 33 22 26 21

(100) (54) (56) (38) (40) (38) (34) (35) (22) (28) (26) (17) (20) (17)

268 153 154 109 112 92 94 90 69 77 72 56 57 56

(100) (57) (57) (41) (42) (34) (35) (34) (26) (29)* (27) (21) (21) (21)

30 15 4 6 4

(68) (34) (9) (14) (9)

44 19 4 8 4

(72) (31) (7) (13) (7)

102 38 20 17 11

(72) (27) (14) (12) (8)

100 40 24 7 11

(79) (31) (19) (6) (9)

202 78 44 24 22

(75) (29) (16) (9) (8)

At least one AE of any grade Diarrhea NOS Nausea Constipation Fatigue Vomiting NOS Thrombocytopenia Pyrexia Anemia NOS Peripheral neuropathy NOS Headache NOS Anorexia Cough Paraesthesia

329 189 189 140 139 117 115 114 86 85 84 74 70 67

(100) (57) (57) (43) (42) (36) (35) (35) (26) (26) (26) (22) (21) (20)

17 12 11 8 9 8 4 9 5 1 7 5 7 1

(100) (71) (65) (47) (53) (47) (24) (53) (29) (6) (41) (29) (41) (6)

At least one grade X3 AE Thrombocytopenia Neutropenia Anemia NOS Peripheral neuropathy (high-level term) Diarrhea NOS Dyspnea NOS Fatigue

246 97 48 32 26

(75) (29) (15) (10) (8)

14 (82) 4 (24) 0 2 (12) 0

24 (7) 17 (5) 18 (5)

1 (6) 1 (6) 2 (12)

3 (7) 0 3 (7)

4 (7) 1 (2) 5 (8)

9 (6) 8 (6) 6 (4)

11 (9) 8 (6) 7 (6)

20 (7) 16 (6) 13 (5)

At least one SAE Patients discontinuing treatment due to AEs Patients with dose reductions/ interruptions due to AEs

144 (44) 120 (36)

12 (71) 7 (41)

18 (41) 16 (36)

30 (49) 23 (38)

55 (39) 50 (35)

59 (46) 47 (37)

114 (43) 97 (36)

231 (70)

12 (71)

32 (73)

44 (72)

99 (70)

88 (69)

187 (70)

Abbreviations: AE, Adverse event; NOS, not otherwise specified; SAE, seriously adverse event. *Po0.05 for the comparison between the incidence in patients with creatinine clearance p50 ml min1 and in patients with creatinine clearance 450 ml min1, w2 test.

with CrCl of p50 and 450 ml min1 (Table 3). The overall incidence of peripheral neuropathy was significantly lower (Po0.05) in patients with CrCl of p50 vs 450 ml min1 (13 vs 29%), but the incidence of grade X3 events was similar (7 vs 8%). A similar proportion of patients in each renal subgroup discontinued treatment due to an AE or had a dose reduction or interruption due to an AE (Table 3). By contrast, in the dexamethasone arm, the rates of grade X3 AEs, SAEs and discontinuations due to AEs were significantly elevated (Po0.05) in patients with CrCl of p50 ml min1 compared with those with CrCl of 450 ml min1 (Table 4), and the rate of dose reductions/interruptions also appeared higher. None of the on-study deaths that occurred in either treatment arm were related to renal causes.

Discussion The results of this subgroup analysis of the phase 3 APEX study show that bortezomib is active and well tolerated in patients with relapsed MM with impaired renal function, including 17 patients with severe renal impairment (CrCl o30 ml min1). The efficacy and safety of bortezomib do not appear to be substantially affected in patients with severe-to-moderate renal impairment in comparison to patients with no/mild renal impairment or the overall APEX population. Response rates Leukemia

and time to response were similar across the renal subgroups studied. Notably, time to first response to bortezomib was short in all subgroups; this is important as rapid disease control is the goal of treatment for patients with renal impairment.20 TTP with bortezomib was similar between patients with severe-to-moderate and no/mild renal impairment. Likewise, OS curves were similar between these renal subgroups, although the data indicated a trend toward longer OS in patients with CrCl of 450 ml min1. This apparent difference in OS may reflect a more advanced disease in patients with CrCl of p50 ml min1, as evidenced in the differences seen in a number of disease characteristics at baseline (Table 1). Previously reported results from the APEX study demonstrated superior efficacy, in terms of higher overall response rate and CR rate, and longer median TTP and median OS, with bortezomib compared with dexamethasone.29,30 The results of the current subgroup analysis indicate that this advantage of efficacy is maintained regardless of renal impairment. Bortezomib treatment resulted in higher response rates than dexamethasone in all four renal subgroups. TTP was significantly longer with bortezomib compared with dexamethasone in the two broader subgroups of patients with severe-to-moderate or no/mild renal impairment. Furthermore, the data indicated a trend toward longer OS with bortezomib vs dexamethasone in patients with CrCl of p50 or 450 ml min1. It is important to note that the negative impact of severe-to-moderate renal impairment on OS appeared

Bortezomib in renally impaired MM patients JF San-Miguel et al

847 Table 4 Most commonly reported adverse events of any grade (in X15%* of total population) and of grade X3 (in X5% of total population), plus incidences of serious adverse events and discontinuations and dose reductions/interruptions due to adverse events, in patients treated with dexamethasone, by renal subgroup Adverse event, n (%)

Total population (N ¼ 321)

Creatinine clearance (ml min1) o30 (N ¼ 11)

30–50 (N ¼ 56)

p50 (N ¼ 67)

51–80 (N ¼ 122)

480 (N ¼ 132)

450 (N ¼ 254)

11 3 3 4 1 2 1

(100) (27) (27) (36) (9) (18) (9) 0 3 (27) 0 5 (45)

56 20 10 15 12 11 11 9 5 10 7

(100) (36) (18) (27) (21) (20) (20) (16) (9) (18) (13)

67 23 13 19 13 13 12 9 8 10 12

(100) (34) (19) (28) (19) (19) (18) (13) (12) (15) (18)

121 41 34 25 26 21 16 16 21 16 19

(99) (34) (28) (20) (21) (17) (13) (13) (17) (13) (16)

129 38 42 28 28 23 23 24 20 22 16

(98) (29) (32) (21) (21) (17) (17) (18) (15) (17) (12)

250 79 76 53 54 44 39 40 41 38 35

(98) (31) (30) (21) (21) (17) (15) (16) (16) (15) (14)

(79) (16) (9) (11) (7)

53 13 5 6 6

(79) (19) (7) (9) (9)

64 10 11 3 8

(52) (8) (9) (2) (7)

74 11 12 13 7

(56) (8) (9) (10) (5)

138 21 23 16 15

(54)w (8)w (9) (6) (6)

At least one AE of any grade Fatigue Insomnia Anemia NOS Diarrhea NOS Dyspnea NOS Pyrexia Hyperglycemia NOS Muscle cramps Bone pain Constipation

317 102 89 72 67 57 51 49 49 48 47

(99) (32) (28) (22) (21) (18) (16) (15) (15) (15) (15)

At least one grade X3 AE Anemia NOS Hyperglycemia NOS Thrombocytopenia Pneumonia NOS

191 34 28 22 21

(60) (11) (9) (7) (7)

9 (82) 4 (36) 0 0 2 (18)

44 9 5 6 4

At least one SAE Patients discontinuing treatment due to AEs Patients with dose reductions/ interruptions due to AEs

137 (43) 93 (29)

7 (64) 4 (36)

33 (59) 25 (45)

40 (60) 29 (43)

48 (39) 31 (25)

49 (37) 33 (25)

97 (38)w 64 (25)w

108 (34)

2 (18)

26 (46)

28 (42)

40 (33)

40 (30)

80 (31)

Abbreviations: AE, adverse event; NOS, not otherwise specified; SAE, seriously adverse event *Note: A lower cut-off incidence was used in this table compared with Table 3 to provide information on a similar number of the most common toxicities by creatinine clearance rate. wPo.05 for the comparison between the incidence in patients with creatinine clearance p50 ml min1 and in patients with creatinine clearance 450 ml min1, w2 test.

more marked in the dexamethasone arm than in the bortezomib arm (Figure 2), with the difference between dexamethasone patients with CrCl of p50 or 450 ml min1 reaching statistical significance, something that was not seen among bortezomib patients. In fact, the OS curves suggest that patients with CrCl of p50 ml min1 who received bortezomib had similar outcomes to patients with CrCl of 450 ml min1 who received dexamethasone. Taken together, the data from this subgroup analysis suggest that treatment with bortezomib partially overcomes the poor prognosis conferred by renal impairment. However, comparisons of OS between the subgroups should be made with caution given the confounding factors of crossover to bortezomib from the dexamethasone arm and the availability of a number of active salvage regimens for subsequent therapy. The results of this subgroup analysis also indicate that the presence of renal impairment does not result in marked changes in the safety profile of bortezomib in patients with MM and does not raise any new safety concerns. This is as expected, given the findings of a pharmacologic study of bortezomib in adult cancer patients with impaired renal function, which indicated that bortezomib clearance is independent of renal function.23 The proportions of patients discontinuing bortezomib treatment due to AEs, or requiring dose modifications or interruptions due to AEs were similar in the subgroups of patients with CrCl of p50 or 450 ml min1. Consequently, the median duration of bortezomib therapy was similar across subgroups. These data show that the efficacy of bortezomib is not compromised by a specific need for reduction of dose in patients with renal impairment. By contrast, the effect of severe-to-moderate renal impairment on clinically significant toxicities appeared to be more marked in the dexamethasone arm, with patients with

CrCl of p50 ml min1 experiencing significantly elevated incidences of grade 3/4 AEs, SAEs and discontinuations due to AEs compared with those with CrCl of 450 ml min1. The findings of this analysis of the randomized APEX study regarding the efficacy and safety of bortezomib in patients with renal impairment are supported by other studies of bortezomib alone or in combination, in these patients. Bortezomib has been shown to be well tolerated in adult cancer patients regardless of CrCl in an NCI-sponsored pharmacological study.23 On the basis of updated data from this study, the FDA recently approved revised labeling for bortezomib stating that dosage adjustments are not necessary for patients with renal insufficiency, including those requiring dialysis.22 Renal function did not appear to significantly affect response rate, toxicity or extent of therapy in an analysis of two phase-2 studies of bortezomib in relapsed and/or refractory MM.12 In other studies in renally impaired patients with relapsed MM, including patients requiring dialysis, bortezomib and bortezomib-based combinations have been shown to produce high response rates, with durable responses and CRs.24–26,28 Notably, Chanan-Khan et al.25 reported a response rate of 75%, including 30% CR/near CR, with bortezomib-based combinations in a retrospective multicenter analysis of 24 patients with advanced renal failure requiring dialysis; furthermore, three patients became dialysis independent and one patient was spared dialysis. Most of these studies involve small series of selected patients. However, the present analysis has been conducted using a very large series of unselected patients, enabling the evaluation of the efficacy of bortezomib in patients with varying degrees of renal impairment. Moreover, the design of the study enabled comparison of the efficacy of bortezomib with that of high-dose Leukemia

Bortezomib in renally impaired MM patients JF San-Miguel et al

848 dexamethasone, which has been considered as a gold standard for the treatment of MM patients with renal failure. In conclusion, the present analysis represents to the best of our knowledge the first study on the prognostic influence of renal function within the setting of a randomized trial and demonstrates that bortezomib is active and well tolerated in patients with relapsed MM following 1–3 prior therapies and with varying degrees of renal impairment. The efficacy and safety of bortezomib were not substantially affected in patients with severe-to-moderate renal impairment compared with those with no/mild renal impairment, allowing similar dosage strategies. Therefore, on the basis of these results and those from other studies, plus the recent FDA-approved labeling change, bortezomib at the standard dose of 1.3 mg m2 should be considered an appropriate treatment option for the sizeable proportion of patients with relapsed MM who have any degree of renal impairment.

Acknowledgements This research was supported by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development LLC. We thank Steve Hill and Rosemary Washbrook for their assistance in drafting the manuscript. Steve Hill is a medical writer and Rosemary Washbrook is a medical editor with GardinerCaldwell London. We also thank the APEX Management Team; Dalton W, Anderson K, Harousseau J and San-Miguel J and the APEX Investigators; Abubakr Y, Agura E, Alexanian R, Alsina M, Andre M, Attal M, Avigan D, Baccarani M, Bahlis N, Barbui T, Barton, K, Belch A, Bensinger W, Ben-Yehuda D, Berdeja J, Bjorkstrand B, Blade´ J, Boccadoro M, Boue F, Bourhis J, Bron D, Catlett J, Cavenagh J, Cavet J, Chanan-Khan A, Coiffier B, Comenzo R, Craddock C, Dearden C, Delforge M, Densmore J, Doyen C, Durk H, Ehninger G, Einsele H, Engelhardt M, Facon T, Fay J, Fehrenbacher L, Feremans W, Fermand JP, Fernandez H, Giguere J, Glasmacher A, Glass J, Goldschmidt H, Gordon P, Gramatzki M, Gruber A, Gyan E, Hamm J, Hegewisch-Becker S, Huber C, Hulin C, Hussein M, Ifthikharuddin J, Irwin D, Jackson G, Jagannath S, Jagasia M, Jakubowiak A, Klein A, Kobbe G, Kovacs M, Krishnan A, Kropff M, Kuter D, Lacy M, Lenhoff S, Limentani S, Lokhorst H, Lonial S, Ludwig H, Mandelli F, Marie JP, Marsden GJ, Martin T, Mason J, Mavromatis B, Morris C, Morrison V, Nowrousian M, Orlowski R, Pecora A, Phelan J, Posada, J, Rahemtulla A, Rai K, Reece D, Richardson P, Rowe JM, Schilder R, Schmidt W, Schuster M, Sezer O, Shadduck R, Shustik C, Siegel D, Singhal S, Sonneveld P, Sotto JJ, Stadtmauer E, Tarantolo S, Van Droogenbroeck J, Van Oers MH, Vellenga E, Vesole D, Vij R, Zachee P and Zangari M.

Statement of originality The authors confirm that this manuscript contains original material.

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