Pegylated Liposomal Doxorubicin plus Bortezomib in Relapsed or ...

Brief Communication Pegylated Liposomal Doxorubicin plus Bortezomib in Relapsed or Refractory Multiple Myeloma: Efficacy and Safety in Patients with Renal Function Impairment Joan Bladé,1 Pieter Sonneveld,2 Jesús F. San Miguel,3 Heather J. Sutherland,4 Roman Hajek,5 Arnon Nagler,6 Andrew Spencer,7 Tadeusz Robak,8 M. Teresa Cibeira,1 Sen H. Zhuang,9 Jean-Luc Harousseau,10 Robert Z. Orlowski,11 for the DOXIL-MMY-3001 Study Investigators

Abstract A retrospective analysis was undertaken of patients (n = 193) with renal insufficiency (creatinine clearance [CrCl] < 60 mL/min) from a phase III trial comparing bortezomib ± pegylated liposomal doxorubicin (PLD) in relapsed/refractory myeloma (n = 646). The response rate (49% vs. 42%) and median time to disease progression (331 days vs. 199 days) were comparable or slightly better for patients with renal insufficiency treated with PLD/bortezomib compared with patients treated with bortezomib alone. There was a steady, clinically meaningful improvement in renal function for patients with renal insufficiency in both treatment arms. However, patients with impaired renal function were at a slightly increased risk of a drug-related serious adverse event (28% vs. 19% for CrCl < 60 and ≥ 60 mL/min, respectively). Clinical Lymphoma & Myeloma, Vol. 8, No. 6, 352-355, 2008; DOI: 10.3816/CLM.2008.n.051 Keywords: Creatinine clearance, Paraprotein reduction, Thrombocytopenia

Introduction Bortezomib was approved as second-line monotherapy for patients with relapsed/refractory multiple myeloma (MM) on the basis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remission) trial, which showed a significant survival benefit with 1Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain 2Erasmus Medical Center, Rotterdam, The Netherlands 3Department of Hematology, University Hospital of Salamanca, Center for

Cancer Investigation - IBMCC (CSIC-USAL), Salamanca, Spain 4Leukemia Bone Marrow Transplant Program of British Columbia, Vancouver, Canada 5Department of Internal Medicine and Hemato-oncology, University Hospital and

Faculty of Medicine Masaryk University, Brno, Czech Republic 6Chaim Sheba Medical Center, Tel Hashomer, Israel 7Malignant Haematology and Stem Cell Transplantation

Service, Alfred Hospital, Melbourne, Australia 8Department of Hematology, Medical University of Lodz, Poland 9Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ 10Department of Hematology, University Hospital Hotel-Dieu, Nantes, France 11Departments of Lymphoma/Myeloma and Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Apr 16, 2008; Revised: Aug 15, 2008; Accepted: Sep 22, 2008

Address for correspondence: Joan Bladé, MD, Hematology Department, Universitat de Barcelona Hospital Clínic, IDIBAPS Villarroel 170, E-08036 Barcelona, Spain Fax: 34-93-227-5484; e-mail: [email protected]

bortezomib compared with high-dose dexamethasone in this patient population.1 Renal dysfunction is observed in 25%-30% of patients with MM, and its reversibility improves long-term survival.2,3 Excessive urinary protein overflow by light-chain excretion or glomerular proteinuria can induce proinflammatory cytokine production by renal tubular cells via nuclear factor (NF)-κB– dependent or –independent pathways.4,5 This might result in tubular cell apoptosis, further inflammation, and progressive fibrosis, leading to end-stage renal failure.6 However, NF-κB inhibition has significantly reduced inflammation and fibrosis in experimental glomerulonephritis.7,8 As bortezomib inhibits NFκB, it might be possible that this agent has a direct therapeutic effect through this pathophysiologic mechanism. In a recent phase III trial that led to the approval of pegylated liposomal doxorubicin (PLD) in combination with bortezomib for patients with relapsed/refractory MM, the addition of PLD significantly increased median time to progression (TTP: 9.3 months vs. 6.5 months; P = .00004) and overall survival (hazard ratio [HR], 1.4; P = .0476) compared with bortezomib alone.9 Herein, we evaluate the effect of renal insufficiency, defined as baseline creatinine clearance (CrCl) < 60 mL/min, on the efficacy and safety of the PLD with bortezomib regimen and the treatment effect on renal function in patients with MM with renal impairment.

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Patients and Methods Full details of the primary study design, protocol, and treatment have been previously described.9 Briefly, patients naive to bortezomib with measurable disease who had progressed after ≥1 line of therapy or were refractory to initial treatment were randomized after stratification by β2-microglobulin (β2Μ) level and response to initial therapy. The intent-to-treat (ITT) population received bolus intravenous (I.V.) bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n = 322) or the same bortezomib regimen plus I.V. PLD 30 mg/m2 on day 4 (n = 324) of each cycle. Patients with severe renal impairment (CrCl ≤ 30 mL/min) were excluded. Creatinine clearance was estimated from the serum creatinine concentration using the CockroftGault formula. The current analysis involves a subset of the ITT population with renal insufficiency (baseline CrCl < 60 mL/min: 98 and 95 patients treated with bortezomib and PLD/bortezomib, respectively) compared with patients with CrCl ≥ 60 mL/min (224 and 229, respectively). Median and 95% confidence intervals (CIs) for TTP were estimated using the Kaplan-Meier method. Time to progression was compared using a stratified log-rank test, and a stratified Cox proportional hazards model was used to estimate the HR and its 95% CI. Similar analyses were performed for progression-free survival (PFS) and duration of response (DOR). Time to progression and responses were determined according to European Blood and Marrow Transplant Group criteria.10 Overall response rate (ORR) included complete responses and partial responses (CRs + PRs). The rate of CR + very good PR (VGPR) was also calculated, with VGPR (a PR subset) defined by the new international uniform response criteria.11 Response rates (CR + PR and CR + VGPR) were compared with the Cochran-Mantel-Haenszel test controlling for β2Μ stratification. Creatinine clearance change versus baseline was compared using the Student t test.

Results Baseline Demographic, Clinical, and Laboratory Characteristics The baseline demographic, clinical, and laboratory characteristics of the populations with CrCl < 60 or ≥ 60 mL/min, respectively, were generally similar apart from some parameters related to renal function: mean (± standard deviation) age (66 ± 9.5 years vs. 59 ± 8.8 years), mean serum creatinine (124 ± 52 vs. 87 ± 20 μmol/L), mean hemoglobin (106 ± 16 vs. 114 ± 17 g/L), and percent of patients with β2M > 5.5 mg/L (55% vs. 20%). However, there were no clinically meaningful differences in baseline demographic or disease characteristics among patients treated with bortezomib or PLD/bortezomib within each renal function subset (data not shown).

Patients with Creatinine Clearance < 60 mL/min In patients with CrCl < 60 mL/min, the combination of PLD/bortezomib resulted in significantly longer median TTP compared with bortezomib alone (331 days vs. 199 days; HR, 2.26; 95% CI, 1.32-3.84; P = .002; Table 1). Median PFS was longer for the combination versus bortezomib alone in patients with renal insufficiency (415 days vs. 212 days; HR 1.88; 95%

Table 1 Time to Progression and Response Rates Response Evaluation Criteria

Renal Insufficiency (CrCl < 60 mL/min) PLD + B (n = 95)

B (n = 98)

Adequate Renal Function (CrCl 60 mL/min) PLD + B (n = 229)

B (n = 224)

Median Time to Progression, 331 (276-NA) 199 (161-218) 270 (221-331) 190 (169-230) Days (95% CI)* P Value†

.002

Hazard Ratio (95% CI)‡

2.26 (1.32-3.84)

.0007 1.65

(1.22-2.24)

Response Rate, n

88

94

215

216

Objective CR + PR, n (%)

43 (49)

39 (42)

101 (47)

94 (44)

CR, n (%)

1 (1)

3 (3)

13 (6)

5 (2)

PR, n (%)

42 (48)

36 (38)

88 (41)

89 (41)

Near CR, n (%)

6 (7)

9 (10)

22 (10)

16 (7)

24 (27)

21 (22)

62 (29)

39 (18)

CR + VGPR, n (%) *Based

on Kaplan-Meier product-limit estimates. on stratified log-rank test. ‡B versus PLD + B. A hazard ratio 1 indicates an advantage for PLD + B. Abbreviations: B = bortezomib; CR = complete response; CrCl = creatinine clearance; NA = not available (not yet reached); PLD = pegylated liposomal doxorubicin; PR = partial response; VGPR = very good partial response †Based

CI, 1.17-3.04; P = .0087). Median DOR for patients with CR + PR was longer with PLD/bortezomib versus bortezomib in these patients (394 days [95% CI, 310-394 days]) versus 176 days [95% CI, 174-213 days]). Response rates (Table 1) were not significantly different for evaluable patients with CrCl < 60 mL/min between treatment groups.

Patients with Creatinine Clearance ≥ 60 mL/min Results in patients with CrCl ≥ 60 mL/min were similar to results in patients with renal insufficiency. PLD/bortezomib treatment resulted in significantly longer median TTP compared with bortezomib alone (270 days vs. 190 days; HR, 1.65; 95% CI, 1.22-2.24; P = .0007; Table 1). The combination demonstrated more benefit versus bortezomib alone for PFS in patients adequate renal function (338 days vs. 232 days; HR 1.60; 95% CI, 1.202.15 days; P = .0015). Median DOR for patients with CR + PR was longer with PLD/bortezomib versus bortezomib in these patients as well (311 days [95% CI, 297 days-NA]) versus 237 days [95% CI, 206-296 days]). Response rates (Table 1) were not significantly different for evaluable patients with CrCl ≥ 60 mL/min between treatment groups, except for CR + VGPR, which favored the combination (P = .0108).

Renal Function as Measured by Creatinine Clearance There was a steady and clinically meaningful improvement in mean CrCl compared with baseline in the renal insufficiency subset with either PLD/bortezomib or bortezomib alone. The improvement


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PLD/Botezomib in Relapsed/Refractory Multiple Myeloma

Mean Creatinine Clearance (mL/min)

Figure 1 Mean Creatinine Clearance During Treatment 100

‡

†

90

*

†

‡

Table 2 Treatment-Emergent Adverse Events in the Safety Population (Excludes Patients Not Receiving at Least One Dose of the Allocated Medication)

†

†

*

Patients with Baseline CrCl 60 mL/min

80 70 60 50

‡

‡

‡

†

‡

‡

‡

‡ ‡

*

‡

†

‡

‡

Patients with Baseline CrCl < 60 mL/min

40 30

PLD + Bortezomib

20

Bortezomib

1

2

3

4

5

6

7

8

Study Cycle Represented is the intent-to-treat population for patient subsets with baseline CrCl < 60 and 60 mL/min. Bars indicate 95% confidence interval. Statistical significance versus baseline. *P < .05. †P < .01. ‡P < .001. Abbreviations: CrCl = creatinine clearance; PLD = pegylated liposomal doxorubicin

was statistically significant for each arm across all cycles for patients patients with CrCl < 60 mL/min at baseline (Figure 1).

Safety Safety data are summarized in Table 2. The overall incidence of drug-related grade 3/4 adverse events (AEs) was comparable between the renal function subsets (< 60 and ≥ 60 mL/min, respectively) for patients treated with PLD/bortezomib (71% vs. 67%). There were higher incidences of all-cause grade 3/4 anemia (13% vs. 7.5%) and grade 3/4 diarrhea (18% vs. 7.1%) but a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.1% vs. 6.2%). Higher incidences of drug-related serious AEs (28% vs. 19%) and drug-related AEs causing death (4.3% vs. 0.4%) with PLD/ bortezomib were also observed in the renal insufficiency subset. The causes of the drug-related deaths with PLD/bortezomib in the renal insufficiency subset were tumor lysis syndrome, pulmonary hypertension, neutropenic sepsis, and cardiac arrest in 1 patient each.

Discussion Bortezomib has been studied alone or in combination therapy in small numbers of patients with severe renal impairment (CrCl < 30 mL/min)12 or advanced renal failure requiring dialysis13 with promising responses and renal function improvement. Reversal of acute paraprotein-induced renal failure with bortezomib-based therapy has been reported in 5 of 8 patients with MM, with a significant paraprotein reduction preceding renal function improvement.14 These authors suggested that bortezomib might accelerate the kidney response not only through the rapid decrease in monoclonal protein concentration but also via its NF-κB inhibitory effect, directly reducing inflammation in myeloma kidney.4-6 Our retrospective analysis in a large cohort of patients with MM with renal insufficiency (n = 193) demonstrates that renal impairment (CrCl < 60 mL/min) does not compromise the efficacy (TTP and ORR) of PLD/bortezomib in relapsed/refractory MM. Similar results were observed, albeit in a smaller cohort of patients, when a CrCl cutoff

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Adverse Event Characteristic, n (%)

B (n = 95)

PLD + B (n = 93)

B (n = 223)

PLD + B (n = 225)

Any Drug-Related AEs

84 (88)

87 (94)

189 (85)

212 (94)

Drug-Related Serious AEs

15 (16)

26 (28)

32 (14)

43 (19)

Drug-Related Grade 3/4 AEs

44 (46)

66 (71)

121 (54)

151 (67)

Drug-Related AE Causing Death

2 (2.1)

4 (4.3)

3 (1.3)

1 (0.4)

Anemia

14 (15)

12 (13)

14 (6.3)

17 (7.5)

CrCl < 60 mL/min

CrCl 60 mL/min

Most Common All-Cause Grade 3/4 AEs*

Neutropenia

17 (18)

31 (33)

29 (13)

61 (27)

Thrombocytopenia

17 (18)

23 (25)

32 (14)

48 (21)

Leukopenia

3 (3.2)

8 (8.6)

6 (2.7)

8 (3.6)

Diarrhea

3 (3.2)

17 (18)

11 (4.9)

16 (7.1)

Fatigue

3 (3.2)

7 (7.5)

4 (1.8)

10 (4.4)

0

1 (1.1)

0

14 (6.2)

Palmar-plantar erythrodysesthesia

Adverse events graded according to the National Cancer Institute Common Toxicity Criteria (version 3) and coded according to the MedRA dictionary (version 9.1) preferred term. *Occurring in 6% of patients in any subset, regardless of relationship to treatment. Abbreviations: AE = adverse event; B = bortezomib; CrCl = creatinine clearance; PLD = pegylated liposomal doxorubicin

value of 40 mL/min was used to define renal function impairment (n = 54) in this study. Furthermore, there was a steady, clinically significant improvement in renal function in each treatment arm for patients with baseline CrCl < 60 mL/min. The toxicity profile of PLD/ bortezomib was less favorable than with bortezomib alone, and a trend toward higher death in the PLD/bortezomib group was observed.

Conclusion Results suggest that in patients with relapsed refractory MM, PLD/ bortezomib could provide greater efficacy over bortezomib alone, with a trade-off in toxicity levels. However, both regimens appear to improve renal function in patients with MM with renal insufficiency.

Disclosures This work was supported by Johnson & Johnson Research and Development LLC. Joan Bladé has provided consulting services and received honoraria for lectures from Johnson & Johnson and Jansen Cilag Spain and grant support from Jansen Cilag Spain; Pieter Sonneveld has served on the Advisory Board of Jansson Cilag; Jesús F. San Miguel has received honoraria and served on advisory boards for Johnson & Johnson and Millennium Pharmaceuticals; Heather J. Sutherland has received honoraria and served on advisory boards for Ortho Biotech; Roman Hajek has received lecture honoraria; Tadeusz Robak has received a research grant from Johnson & Johnson; M. Teresa Cibiera has served on the Advisory Board of Jansson Cilag;

Joan Bladé et al Sen H. Zhuang is employed by Ortho Biotech Oncology Research & Development; Jean-Luc Harousseau has acted as a member of the Speakers’ Bureau for Ortho Biotech and the advisory boards of Millennium Pharmaceuticals and Ortho Biotech; and Robert Z. Orlowski has acted as a member of the advisory boards for Millennium Pharmaceuticals and Ortho Biotech. The authors acknowledge the editorial support of Tajut Ltd., Kaiapoi, New Zealand.

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