Characterization of haematological parameters with bortezomib–melphalan–prednisone versus melphalan–prednisone in newly diagnosed myeloma, with evaluation of long-term outcomes and risk of thromboembolic events with use of erythropoiesis-stimulating agents: analysis of the VISTA trial

Authors


Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA 02115, USA.
E-mail: paul_richardson@dfci.harvard.edu

Summary

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, = 344) versus MP (= 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76–1·39); = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (< 0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.

Haematotoxicity, such as anaemia, thrombocytopenia and neutropenia, and thromboembolic events are frequent complications of solid tumours and haematological malignancies, and the therapies used to treat them. For example, around 30–90% of patients with cancer have anaemia although the prevalence is affected by the definition of anaemia, cancer type, and disease stage (Knight et al, 2004). Anaemia is associated with a number of symptoms (e.g. fatigue, decreased exercise tolerance, and depression) that contribute to poorer patient quality of life (Gillespie, 2002; Cella et al, 2003; Cella, 2006; Palazzuoli et al, 2006) and has been linked to reduced survival (Caro et al, 2001; Knight et al, 2004). Current US guidelines grade anaemia based on haemoglobin levels as mild (100–lower limit of normal g/l), moderate (80–<100 g/l) and severe (<80 g/l), with anaemia defined as life-threatening when haemoglobin levels fall below 65 g/l (National Comprehensive Cancer Network [NCCN], 2010). Thrombocytopenia is chiefly associated with bleeding complications and is traditionally defined as a platelet count <150 × 109/l (Finnish Medical Society Duodecim, 2007). Neutropenia is linked to an increased frequency of infections and fever and is generally defined as an absolute neutrophil count (ANC) of <1·5 × 109 cells/l (Godwin & Braden, 2009).

The aetiology of anaemia in cancer patients is multi-factorial and includes both disease-related and chemotherapy-induced mechanisms (NCCN, 2010). Disease-related anaemia may be attributed to underlying co-morbidities (e.g. renal insufficiency), or direct (e.g. suppression of haematopoiesis) or indirect (e.g. nutritional deficiencies caused by loss of appetite; changes in coagulation leading to bleeding and/or haemolysis) effects of the malignancy (NCCN, 2010). Chemotherapy-induced anaemia is linked to myelosuppressive effects of cytotoxic treatment and, although it can occur in around 55% of patients without evidence of anaemia prior to chemotherapy (Birgegard et al, 2006), it is often under-recognized and under-treated (Groopman & Itri, 1999; Ludwig et al, 2004a; Cella, 2006). Similarly, the main cause of thrombocytopenia and neutropenia in cancer is chemotherapy-induced myelosuppression; cytotoxic effects on megakaryocytes can lead to thrombocytopenia (Zuckerman, 1998; Kaufman & Anderson, 2003; Lonial et al, 2008), and disruption of haemopoiesis either by cytotoxic agents or myeloma itself can result in neutropenia (Zuckerman, 1998; Lonial et al, 2008).

Haematological toxicities are common complications in multiple myeloma (MM), either as a direct result of the disease or the agents used to treat it, such as melphalan (Facon et al, 2007). Anaemia is present, to some degree, in approximately two-thirds of MM patients at presentation (Durie et al, 2003; Ludwig et al, 2004b). Once any reversible causes of anaemia have been excluded (e.g. iron deficiency), treatment options for symptomatic anaemia include repeat red-blood-cell (RBC) transfusions and/or erythropoiesis-stimulating agents (ESAs) (Durie et al, 2003; NCCN, 2009, 2010) RBC transfusion is recommended when an immediate improvement in circulatory oxygen-carrying capacity is required (Durie et al, 2003). ESA therapy can be considered for patients with persistent anaemia and can help avoid the need for RBC transfusions (Durie et al, 2003; NCCN, 2009, 2010). Evidence for the impact of ESA therapy on transfusion outcomes and quality of life is strongest in patients with baseline haemoglobin <100 g/l; therefore, recently updated guidelines for patients with chemotherapy-induced anaemia recommend that ESA use should not be initiated until haemoglobin levels approach or fall below 100 g/l (Rizzo et al, 2008).

The goal of ESA therapy is to optimize haemoglobin levels, which correlate with an improvement in health-related quality of life (Ludwig et al, 2004a; Witzig et al, 2005; Cella, 2006). However, in patients with cancer, there have been concerns that ESA use may reduce overall survival (OS) (Henke et al, 2003; Leyland-Jones, 2003; Bohlius et al, 2006, 2008; Arbuckle et al, 2008; Bennett et al, 2008; Juneja et al, 2008; NCCN, 2010). Several studies have also suggested that ESA use may increase the risk of venous thromboembolic events, such as deep-vein thrombosis (DVT) and pulmonary embolism (PE), especially in patients receiving immunomodulatory-drug-based regimens and/or anthracyclines with glucocorticoids (Niesvizky et al, 2006; Bennett et al, 2008). However, data on the impact of ESA use on long-term survival (Osterborg et al, 2005; Baz et al, 2007; Katodritou et al, 2008) or the risk of DVT/PE (Harousseau et al, 2006; Niesvizky et al, 2006) specifically in patients with MM are limited and the evidence is somewhat contradictory.

To date, there have been no large, prospective studies on the impact of ESA use in MM. The large, international, phase III Velcade® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone (VISTA) trial (San Miguel et al, 2008a) (ClinicalTrials.gov number: NCT00111319) compared the efficacy and safety of bortezomib plus melphalan/prednisone (VMP) and melphalan/prednisone (MP) alone in previously untreated patients with MM, who were ineligible for high-dose therapy. As melphalan is associated with myelosuppression (http://www.medicines.org.uk/EMC/medicine/703/SPC/Alkeran+Injection/., accessed February 2011) and bortezomib is associated with transient, cyclical thrombocytopenia and neutropenia (Lonial et al, 2005, 2008), we characterized the haematological toxicities and associated interventions, including ESA use and RBC transfusions for anaemia, with VMP and MP in VISTA. As evidence regarding the concomitant use of ESA in MM is presently unclear, we conducted a post-hoc sub-analysis assessing the impact of concomitant ESA use on rates of DVT/PE, and the impact of ESA support or RBC transfusions on time to progression (TTP), and OS in each arm.

Methods

Patients and study design

Full details of the VISTA trial have been published previously (San Miguel et al, 2008a). Briefly, patients with previously untreated, measurable MM who were ineligible for high-dose therapy plus stem cell transplantation were randomized to receive nine 6-week cycles of VMP or MP alone. Dose regimens were as follows: bortezomib 1·3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2, days 1–4, cycles 1–9; prednisone 60 mg/m2, days 1–4, cycles 1–9. No protocol-specified antithrombotic prophylaxis was required. The VISTA study was approved by institutional review boards at all centres, and was conducted according to the provisions of the Declaration of Helsinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice. All patients provided written informed consent.

To be eligible for inclusion, patients were required to have the following pre-treatment haematology values (within 14 d of randomization): platelet count ≥100 × 109/l, or ≥70 × 109/l if thrombocytopenia was considered by the investigator to be due to myeloma infiltration of bone marrow; ANC ≥1·0 × 109/l; and haemoglobin ≥80 g/l (≥4·96 mmol/L). Prior RBC transfusions or ESA use were allowed during the study. The protocol provided recommendations on RBC transfusion and ESA use according to international treatment guidelines and product prescribing information. In particular, the use of ESA was to be considered if the patient was receiving ESA at time of enrolment or if haemoglobin was <110 g/l.

Safety was assessed throughout the VISTA trial and until 30 d after the last dose of study drug was administered, or until the start of subsequent myeloma therapy (if earlier). All toxicities were graded using NCI CTCAE v3.0 (National Cancer Institute, 2006). Haematology laboratory analyses, including platelet count, ANC, haemoglobin, and absolute lymphocyte counts were performed prior to bortezomib dosing in the VMP arm, and on days 1, 8, 22, and 29 in the MP arm. The primary efficacy endpoint of VISTA was TTP; OS was assessed as a secondary endpoint. Response was assessed every 3 weeks during treatment and every 8 weeks post-treatment until disease progression according to European Group for Blood and Marrow Transplantation (EBMT) criteria (Blade et al, 1998) using a central laboratory for M-protein quantification. Patients were then followed at least every 12 weeks for subsequent therapy and survival.

For the present analysis, occurrence of haematological toxicities in each treatment arm was calculated from an analysis with a data cut-off of April 25, 2008, after a median follow-up of 25·9 months, when all patients had completed study treatment (San Miguel et al, 2008b). The incidence of thromboembolic events was assessed by ESA use. TTP by ESA use and RBC transfusions was calculated using data from the initial analysis of VISTA (data cut-off: June 15, 2007) (San Miguel et al, 2008a); formal centralized collection of M-protein data was stopped at this analysis, thus subsequent data on TTP were not updated, as they were not based on the stringent methodology used at the initial analysis. Assessment of OS by ESA use and RBC transfusions was based on an updated analysis of VISTA (data cut-off: March 16, 2009).

Statistical analysis

The present analysis considers on-treatment ESA use or RBC transfusion; therefore, patients with new-onset requirement for ESA and/or RBC transfusions at any time during treatment were included; as such, all analyses were conducted in the safety population (all patients who received at least one dose of study drug). The correlation between TTP (time from randomization to first evidence of progressive disease [PD]/relapse) or OS (time from randomization to death) and ESA use was assessed using a time-dependent Cox regression analysis with ESA exposure as a covariate, as well as treatment, age, sex, race, β2-microglobulin, albumin, region, myeoloma type, Karnofsky score, and number of baseline bone lesions; similarly, RBC transfusion was included as a covariate in a corresponding Cox regression analysis. Summary statistics were used to describe safety results. TTP and OS by ESA use or RBC transfusions required during the study were also analysed using the Kaplan–Meier method. Where relevant, a two-sided P-value of <0·05 was considered to be statistically significant.

Results

Patient baseline characteristics

In the overall VISTA population, patient demographics and baseline characteristics were similar between the VMP and MP arms (San Miguel et al, 2008a). Baseline haematology laboratory values in the overall VISTA population were also similar between the VMP and MP arms, including median haemoglobin levels (VMP: 104 g/l; MP: 106 g/l) (San Miguel et al, 2008a).

Patients received a median of nine cycles (50 weeks) of VMP and eight cycles (48 weeks) of MP; MP total doses and dose intensities were similar between treatment arms. In the VMP arm, patients received median total doses of 39 mg/m2 of bortezomib, 295·05 mg/m2 of melphalan, and 2108·6 mg/m2 of prednisone; in the MP arm, median total doses were 274 mg/m2 of melphalan and 1983·6 mg/m2 of prednisone.

On-treatment ESA use and RBC transfusions.  During the treatment period, 233 patients in VISTA received treatment with an ESA (VMP: = 102; MP: = 131) and 204 had a RBC transfusion (VMP: = 87; MP: = 117). Of these, 84 patients (VMP: = 29; MP: = 55) received both an ESA and a RBC transfusion. Patients who were treated with an ESA received either darbepoetin alfa (VMP: = 38; MP: = 61), or recombinant human erythropoietin (VMP: = 67; MP: = 81).

Haematological toxicities and interventions

Treatment-emergent haematological toxicities are summarized in Table I. The overall (53% vs. 47%) and grade ≥3 (38% vs. 31%) rates of thrombocytopenia were slightly higher in the VMP arm versus the MP arm, but rates of grade ≥3 bleeding events were low and identical across both treatment arms (3%). The rate of platelet transfusions was slightly higher in the VMP versus the MP arm (13% vs. 10%, respectively). Mean platelet counts showed transient cyclical decreases, with mean counts at cycle-start gradually decreasing during treatment in both arms.

Table I.   Summary of treatment-emergent haematological toxicities and associated interventions (safety population).
 VMP (= 340)MP (= 337)
  1. Interventions are highlighted in italics.

  2. *Dose reduction of bortezomib and melphalan for VMP arm, and melphalan for MP arm.

  3. ESA, erythropoiesis-stimulating agent; MP, melphalan and prednisone; RBC, red blood cell; VMP, bortezomib plus melphalan and prednisone. G-CSF, Granulocyte colony-stimulating factor

Thrombocytopenia, n (%)181 (53)160 (47)
 Grade ≥3130 (38)104 (31)
 Dose reduction*, n (%)8 (2) and 27 (8)22 (7)
 Discontinuation, n (%)12 (4)20 (6)
Platelet transfusions43 (13)33 (10)
Neutropenia, n (%)165 (49)156 (46)
 Grade ≥3137 (40)128 (38)
 Dose reduction*, n (%)6 (2) and 18 (5)24 (7)
 Discontinuation, n (%)07 (2)
G-CSF71 (21)78 (23)
Anaemia, n (%)149 (44)188 (56)
 Grade ≥363 (19)92 (27)
 Dose reduction*, n (%)2 (1) and 1(<1)3 (1)
 Discontinuation, n (%)2 (1)7 (2)
ESA use, n (%)102 (30)131 (39)
RBC transfusions, n (%)87 (26)117 (35)
Lymphopenia, n (%)84 (25)58 (17)
 Grade ≥368 (20)37 (11)
 Dose reduction*, n (%)0 and 1 (<1)1 (<1)
 Discontinuation, n (%)01 (<1)

The rates of neutropenia (overall, 49% vs. 46%; grade ≥3, 40% vs. 38%) and granulocyte colony-stimulating factor (G-CSF) use (21% vs. 23%) were similar in both the VMP and MP arms (Table I); febrile neutropenia rates were low and also similar between treatment arms (3% vs. 4%, respectively). Cyclical, transient, and reversible decreases in ANCs were reported in each arm, predominantly attributable to reversible melphalan myelosuppression.

Rates of anaemia by reported toxicities are shown in Table I. The incidence of grade ≥3 treatment-emergent anaemia, as determined via laboratory assessment of haemoglobin, was lower in the VMP than the MP arm (22% vs. 33%; = 0·0023). Median haemoglobin levels in all patients improved from baseline during treatment: from 104 to 110 g/l in the VMP arm and from 106 to 115 g/l in the MP arm. As shown in Table II, median haemoglobin levels when ESA therapy was initiated were 97·5 g/l in the VMP arm and 93·0 g/l in the MP arm.

Table II.   VISTA haematology laboratory values at baseline (ITT population) and haemoglobin values pre-anaemia treatment (safety population).
 VMP (= 340)MP (= 337)
ESA (= 102)Non-ESA (= 238)ESA (= 131)Non-ESA (= 206)
  1. *Safety population. ESA: VMP n = 102, MP n = 131; RBC transfusion: VMP n = 87, MP n = 117

  2. ESA, erythropoiesis-stimulating agent; MP, melphalan and prednisone; RBC, red blood cell; VMP, bortezomib plus melphalan and prednisone.

Median platelet count (range), ×109/l229·5 (68–441)218·5 (83–515)221 (33–587)224 (67–526)
 Platelets grade ≥3, n<1<11<1
Median neutrophil count (range), ×109/l2·9 (0·9–13·9)3 (1·0–15·1)3·1 (0·6–8·5)3·1 (0·9–13·5)
 Neutrophils grade ≥3, n1<12<1
Median white blood cell count (range), ×109/l5·2 (2·0–15·5)5·3 (1·8–17·7)5·6 (1·7–11·9)5·6 (1·8–14·3)
 White blood cells grade ≥3, n<1<14<1
Median haemoglobin (range), g/l102·0 (64–140)106·0 (77–159)101·0 (75–141)108·0 (73–165)
 Haemoglobin grade ≥3, n2<121
Pre-ESA median haemoglobin (range), g/l97·5 (67–121)*93 (66–120)*
 RBC transfusion (= 87)No RBC transfusion (= 253)RBC transfusion (= 117)No RBC transfusion (= 220)
Median platelet count (range), ×109/l215·5 (81–379)225·5 (68–515)203 (33–519)233·4 (74–587)
 Platelets grade ≥3, n<1<11<1
Median neutrophil count (range), ×109/l2·9 (1·0–7·7)3·0 (0·9–15·1)2·8 (0·6–8·6)3·2 (0·9–13·5)
 Neutrophils grade ≥3, n<1<121
Median white blood cell count (range), ×109/l4·9 (2·1–13·6)5·5 (1·8–17·7)5·1 (1·7–11·9)5·9 (1·8–14·3)
 White blood cells grade ≥3, n<1<14<1
Median haemoglobin (range), g/l94 (64–141)107 (79–159)97 (75–140)110 (73–165)
 Haemoglobin grade ≥3, n2<131
Pre-RBC transfusion median haemoglobin (range), g/l85 (47–133)*77 (49–120)*

Analyses by ESA use and RBC transfusions

Patient baseline characteristics.  Consistent with the overall VISTA population, patient demographics and baseline characteristics were similar between the ESA and non-ESA groups, although a slightly greater proportion of patients receiving ESA were aged ≥75 years (37% vs. 27% in the non-ESA group) and fewer had a Karnofsky performance status ≤70% (Table III). Baseline characteristics according to receipt of RBC transfusion were also similar between the two subgroups (Table SI), although patients receiving RBC transfusions appeared more likely to have advanced disease (by International Staging System stage) or Karnofsky performance status ≤70%, compared with those not receiving RBC transfusion. Baseline haematology laboratory values were consistent across subgroups with no differences observed between the ESA and non-ESA groups, or between the RBC-transfusion and non-RBC-transfusion groups (Table II).

Table III.   VISTA patient demographics and baseline disease characteristics by ESA subgroup (safety population).
 VMP (= 340)MP (= 337)Total (= 677)
ESA (= 102)Non-ESA (= 238)ESA (= 131)Non-ESA (= 206)ESA (= 233)Non-ESA (= 444)
  1. ß2M, ß2 microglobulin; CrCl, creatinine clearance; ESA, erythropoiesis-stimulating agent; ISS, International Staging System; KPS, Karnofsky Performance Status; MP, melphalan and prednisone; VMP, bortezomib plus melphalan and prednisone.

Male, %535049505150
White, %948695839484
Median age, years737172717271
 Aged ≥75 years, %382836263727
KPS ≤70%, %313827372937
ISS Stage I/II/III, %23/43/3417/49/3417/48/3520/47/3319/46/3519/48/34
Median ß2M, mg/l4·44·14·34·34·34·2
 ß2M <2·5/2·5–5·5/>5·5 mg/l, %12/56/3212/55/3311/56/3312/55/3312/56/3312/55/33
Median albumin, g/l3·43·33·33·33·33·2
 Albumin <35 g/l, %555965606160
Region: EU-Australia/N America/Other, %82/13/578/8/1480/15/577/5/1781/14/577/7/16
IgG/IgA/light chain, %64/22/1164/26/766/24/860/28/765/23/962/27/7
CrCl, median (ml/min)55·4160·1658·0557·9655·9159·59
 CrCl >20–30/>30–60/>60 ml/min, %11/52/372/46/515/50/453/50/467/51/422/48/49

Thromboembolic events by ESA use.  In the overall VISTA safety population, the frequency of thromboembolic complications was low in both treatment arms (both 2%). Furthermore, the frequency of thromboembolic events was not affected by ESA use; 3% of patients receiving ESA therapy reported a thromboembolic event compared with 2% of patients who did not receive an ESA. The frequency of DVT was similar between the VMP (1%) and MP (2%) arms and was not affected by ESA use (ESA: VMP = 2%, MP = 3%; non-ESA: VMP = 1%, MP = 1%). Likewise, the frequency of PE in the VMP (1%) and MP (1%) arms was similar and no differences were observed between the ESA groups (ESA: VMP = 1%, MP = 2%; non-ESA: VMP = 1%, MP = <1%).

Outcomes by ESA use and RBC transfusions.  ESA use had no negative impact on TTP [hazard ratio (HR) 1·030 (95% confidence interval (CI): 0·763–1·390); = 0·8478]. Median TTP was similar between the ESA and non-ESA patient subgroups in both treatment arms (Fig 1A); in patients receiving ESA, median TTP was 19·9 months in the VMP arm and 15·0 months in the MP arm (Table IV). Similarly, ESA use had no impact on OS [HR 0·945 (95% CI: 0·714–1·250); = 0·6907; Fig 1B]. The 1-, 2- and 3-year OS rates were also similar between ESA and non-ESA patient subgroups in each treatment arm (Table IV).

Figure 1.

 Time to progression by investigator assessment (A) and overall survival (B) according to on-treatment erythropoiesis-stimulating agent use and treatment (Trt). ESA, erythropoiesis; MP, melphalan and prednisone; VMP, bortezomib plus melphalan and prednisone.

Table IV.   Time to progression and overall survival rates by ESA use and treatment or RBC transfusions and treatment, per investigator, in VISTA (safety population).
 VMP (= 340)MP (= 337)
ESA (= 102)Non-ESA (= 238)ESA (= 131)Non-ESA (= 206)
  1. CI, confidence interval; ESA, erythropoiesis-stimulating agent; MP, melphalan and prednisone; NE, not estimable; RBC, red blood cell; TTP, time-to-progression; VMP, bortezomib plus melphalan and prednisone.

Median TTP, months (95% CI)19·9 (18·9, NE)NE (18·3, NE)15·0 (13·5, 21·8)17·5 (14·7, 19·0)
1-year survival rate, % (95% CI)92·0 (84·6, 95·9)87·1 (82·1, 90·8)82·9 (75·2, 88·4)80·9 (74·7, 85·7)
2-year survival rate, % (95% CI)83·9 (75·1, 89·8)74·9 (68·7, 80·1)71·8 (63·1, 78·8)66·7 (59·6, 72·9)
3-year survival rate, % (95% CI)69·5 (58·7, 78·0)68·1 (61·4, 73·9)59·3 (49·5, 67·9)50·4 (42·8, 57·5)
 RBC transfusion (= 87)No RBC transfusion (= 253)RBC transfusion (= 117)No RBC transfusion (= 220)
Median TTP, months (95% CI)NE (24·0, NE)21·7 (18·9, NE)14·1 (10·8, 16·6)18·0 (15·2, 20·0)
1-year survival rate, % (95% CI)79·9 (69·7, 87·0)91·5 (87·3, 94·4)69·6 (60·3, 77·2)88·2 (83·0, 91·9)
2-year survival rate, % (95% CI)68·9 (57·7, 77·6)80·6 (75·1, 85·1)56·2 (46·6, 64·8)75·6 (69·1, 80·8)
3-year survival rate, % (95% CI)57·0 (45·0, 67·3)72·3 (66·0, 77·7)42·1 (32·6, 51·2)60·7 (53·1, 67·4)

For patients who received RBC transfusions, a trend towards shorter TTP than those who did not receive a RBC transfusion was observed [HR 1·329 (95% CI: 0·979–1·803)], although this was not statistically significant (= 0·0678). In the MP arm, median TTP was slightly shorter in patients receiving RBC transfusion (14·1 months) compared with those who did not (18·0 months; Fig 2A; Table IV). In the VMP arm, median TTP was similar between patients who received RBC transfusions compared with those who did not (Fig 2A; Table IV). A significant impact was, however, observed on OS [HR 1·786 (95% CI: 1·368–2·333); < 0·0001; Fig 2B]. In both treatment arms, 1-, 2- and 3-year OS rates appeared lower for patients who received RBC transfusions, compared with those who did not; 3-year OS rates were 57·0% vs. 72·3% in the VMP arm, and 42·1% vs. 60·7% in the MP arm, respectively (Table IV).

Figure 2.

 Time to progression by investigator assessment (A) and overall survival (B) according to on-treatment red blood cell transfusion use and treatment (Trt). MP, melphalan and prednisone; RBC, red blood cell; VMP, bortezomib plus melphalan and prednisone.

Discussion

Given the nature of MM and the agents used in its treatment, haematological toxicities are common complications (Zuckerman, 1998; Armoiry et al, 2008; Lonial et al, 2008; Miceli et al, 2008; Chen et al, 2009); melphalan is associated with myelosuppression http://emc.medicines.org.uk/medicine/4429/SPC/Alkeran+Injection+50+mg., accessed December 2010), and bortezomib has been associated with transient, cyclical thrombocytopenia and neutropenia (Lonial et al, 2005, 2008). Therefore, haematological toxicities, including thrombocytopenia, neutropenia, anaemia, leucopenia and lymphopenia were frequent in the VISTA trial. However, despite the overlapping haematological toxicity profiles of bortezomib and melphalan, there was no substantial increase in haematological toxicities in the VMP arm compared with the MP arm. Moreover, the overall rates of DVT were low in this particularly at-risk population. Myelosuppression (mainly neutropenia and thrombocytopenia) was generally predictable and manageable. The pattern of platelet counts over time (within a cycle) fluctuated more with VMP than MP, although the total number of patients with grade 3/4 abnormal platelet counts closely mirrored the pattern in the MP arm. This suggests that melphalan dosing-related myelosuppression was the primary influence on platelet count. Treatment-associated neutropenia and thrombocytopenia were transient and cyclical, and without major differences in clinical consequences, such as febrile neutropenia or bleeding between the VMP and MP arms. Haemoglobin levels increased steadily over time in both treatment arms. The lower rates of treatment-emergent anaemia in the VMP arm perhaps reflect greater anti-myeloma activity. In accordance with this, the rates of ESA use and RBC transfusion were also lower in the VMP arm.

In one of the largest outcome analyses of anaemia in MM to date, the data from our post-hoc analysis indicate that ESA use in patients with newly diagnosed MM who were treated with either VMP or MP, was not associated with an adverse impact on long-term outcomes. ESA use in combination with VMP did not appear to be associated with poorer survival, as determined both by subgroup analysis and time-dependent assessment of OS. However, the need for RBC transfusions did appear to have an adverse effect on OS in both arms. One possible explanation is that the requirement for RBC transfusion may have been associated with more severe anaemia. Upregulation of pro-apoptotic factors, such as transforming growth factor (TGF)β1, tumour necrosis factor (TNF)α, interferon (IFN)-γ, and Fas ligand (Fas-L) in MM, which are involved in modulating the maturation of erythroid cells, may contribute to development of anaemia (Silvestris et al, 2002). Depending on the type of anaemia experienced by those patients requiring RBC transfusion, it may, therefore, have been indicative of more aggressive disease. Additionally, the finding that transfusions were associated with a poorer outcome while ESA use was not, suggests that physicians may have applied different criteria for the use of these two treatments, i.e. the decision to transfuse may have been based on additional factors such as disease or performance status rather than simply haemoglobin levels (as indicated by Table II). This may have resulted in two distinct groups of patients with differing disease severities and prognoses.

In patients with various types of solid tumours or haematological malignancies, a recent meta-analysis suggested that use of ESAs was associated with an increased mortality risk (Bennett et al, 2008). In other studies in MM specifically, there have been contradictory findings. A retrospective study of 257 MM patients indicated that ESA use was associated with improved survival (Baz et al, 2007), whereas another multivariate analysis of 323 patients suggested that ESA use had a detrimental effect on survival (Katodritou et al, 2008). A third, long-term follow-up study in patients with lymphoproliferative malignancies showed that epoetin-beta had no significant effect on OS compared with placebo (Osterborg et al, 2005). However, it should be noted that many of these studies were conducted before the change in recommendations regarding ESA use was made; current guidelines state that ESAs should only be initiated when haemoglobin is <100 g/l (Durie et al, 2003) and discontinued once haemoglobin reaches 120 g/l (Juneja et al, 2008). As such, in those studies where its use was associated with improved survival, ESA therapy may have been optimized (i.e. to achieve a haemoglobin target that was not beyond the correction of anaemia). Alternatively, the differences in findings between these studies and the present analysis may reflect distinct consequences of ESA treatment in different cancer settings, and indeed, MM was the first cancer in which a benefit of ESAs was demonstrated. A further hypothesis, proposed by Mittelman et al (2004) suggested that ESAs may have a direct anti-myeloma effect. Prospective randomized studies in patients with MM plus anaemia are needed to further investigate the relationship between ESA and long-term outcomes (Ludwig et al, 2008; Shehata et al, 2008).

The present analysis indicated that ESA use did not appear to increase the risk of thromboembolic complications when administered with VMP or MP in patients with newly diagnosed MM included in the VISTA trial. These data support previous findings from three studies in relapsed/refractory MM, which showed that bortezomib is not associated with an elevated thromboembolic risk, either alone or in combination with dexamethasone and/or ESA (Lonial et al, 2008). ESA use did not increase the risk of DVT in another large cohort of MM patients receiving a number of different first-line chemotherapeutic regimens, although the low incidence of DVT observed was not unexpected because these patients received DVT prophylaxis (Katodritou et al, 2008). In contrast, a recent meta-analysis showed an increased risk of venous thromboembolism with use of ESAs in patients with cancer (Bennett et al, 2008). In MM specifically, an increased thrombotic risk has been observed in patients who received concomitant ESA with lenalidomide plus dexamethasone (Knight et al, 2006; Niesvizky et al, 2006), although a third study showed no impact of ESA (Menon et al, 2008).

A limitation of this analysis of the VISTA study was the lack of stringent criteria guiding either RBC transfusion or ESA use. This lack of consistency makes it difficult to confidently compare the impact of RBC transfusion or ESA use on survival and TTP.

In conclusion, these analyses of the VISTA phase III, randomized trial demonstrate that bortezomib does not add to melphalan haematological toxicity; haematological toxicities observed in VISTA were manageable, with no cumulative effects. The finding that ESA use did not adversely impact on TTP or OS or increase the risk of thromboembolic events indicates that ESA can be administered concomitantly with VMP or MP for the treatment of anaemia in front-line MM patients. However, prospective, randomized studies are needed to further investigate the relationship between ESA use and RBC transfusions, other agents, and long-term outcomes in both newly diagnosed and relapsed and/or refractory MM patients.

Acknowledgements

The authors gratefully acknowledge the administrative support of Katherine Redman of the Dana-Farber Cancer Institute, and the writing assistance of Sarah Maloney and Catherine Crookes of FireKite (funded by Millennium Pharmaceuticals, Inc.), during the development of this publication. Research support for this study was provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Millennium Pharmaceuticals, Inc.

Conflict of interest disclosures

PGR has served as an advisory board member for Celgene, Johnson & Johnson and Millennium Pharmaceuticals Inc.; MD has acted as a consultant for, and received honoraria from, Millennium Pharmaceuticals Inc. and Ortho-Biotech; OS was a steering committee member for a study funded by Millennium Pharmaceuticals Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C; MK has received honoraria from Ortho-Biotech and Celgene; MTP has received honoraria from Celgene and Janssen Cilag; TR has received research funding from Johnson & Johnson and has served as a member of an advisory board for Celgene; MVM has received honoraria from Ortho-Biotech and Millennium Pharmaceuticals, Inc.; KCA has served as a consultant for Millennium Pharmaceuticals Inc., Johnson & Johnson, Celgene, and Novartis, has received research funding from Millennium Pharmaceuticals Inc. and Celgene, has received honoraria from Millennium Pharmaceuticals Inc., Novartis, Celgene, Johnson & Johnson, and Onyx, and has served on an advisory committee for Millennium Pharmaceuticals Inc., Onyx, and Novartis; D-LE, AC are employed full time by Millennium Pharmaceuticals and D-LE has an ownership interest in Johnson & Johnson; AC, WD, KL and HV are employed full time by Johnson & Johnson and have ownership interests in Johnson & Johnson; KL also has ownership interests in Merck; JSM has served as a member of an advisory board for Celgene, Janssen Cilag and Millennium Pharmaceuticals Inc.; JH, RS, MCV, VR, NK have no competing financial interests to declare.

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