SEARCH

SEARCH BY CITATION

Keywords:

  • multiple myeloma;
  • thromboprophylaxis;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Summary. Introduction: The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) treated with thalidomide- and lenalidomide-based regimens is high. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. Purpose: To determine the absolute rates of VTE with and without different thromboprophylactic agents in patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens. Results: Patients with newly diagnosed MM treated with thalidomide in combination with dexamethasone have a VTE risk of 4.1 (95% CI, 2.8–5.9) per 100 patient-cycles. Therapeutic doses of anticoagulants seem to provide the largest absolute risk reduction of VTE. The rate of VTE in patients with previously treated MM receiving thalidomide in combination with dexamethasone is 0.8 (95% CI, 0.1–2.1) per 100 patient-months. A combination of lenalidomide and dexamethasone is associated with of risk of VTE of 0.8 (95% CI, 0.07–2.0) per 100 patient-cycles and 0.7 (95% CI, 0.4–0.9) per 100 patient-cycles in patients with newly diagnosed and previously treated MM, respectively. Similarly, the rates of VTE in patients also receiving thromboprophylaxis with aspirin were 0.9 (95% CI, 0.5–1.5) and 0.6 (95% CI, 0.01–2.1), respectively. Conclusion: Patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens in combination with dexamethasone are at high risk of VTE. The benefit of various types of thromboprophylaxis is difficult to quantify in patients with MM receiving immunomodulatory therapy, especially in those receiving lenalidomide-based therapy or who have previously treated MM. Randomized controlled trials are needed to address this important clinical need.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

The incidence of venous thromboembolism (VTE) in patients with multiple myeloma has been reported to be between 3% and 10% [1,2]. This increased risk of VTE might be attributable to disease- and treatment-specific risk factors. Patients with multiple myeloma (MM) have been shown to have higher production of factor VIII, von Willebrand factor (VWF) and inflammatory cytokines (IL-6, TNF and C-reactive protein) [3,4]. The production of procoagulant auto-antibodies with prothrombotic properties (anti-protein S40 and C41; lupus anticoagulant) has also been reported in patients with MM [5]. Finally, an acquired activated protein C resistance has been described in these patients [6].

Thalidomide and lenalidomide are immunomodulatory agents with potent anti-angiogenic and anti-inflammatory properties [7]. Thalidomide-based therapy has led to high response rates and increased survival in patients with MM [8]. Similarly, lenalidomide-based therapy has been shown to improve outcomes in patients with newly diagnosed or previously treated MM [9,10]. However, these treatment regimens have been shown to further increase the risk of VTE in MM patients, especially when combined with glucocorticoids and/or cytotoxic chemotherapy [11,12]. Thalidomide- and lenalidomide-based therapies seem to induce a transient elevation of factor VIII and VWF, decrease soluble thrombomodulin and restore PAR-1 expression on endothelial cells following damage from cytotoxic chemotherapy [13–15]. Recent observational studies of thalidomide- and lenalidomide-based regimens in patients with multiple myeloma have suggested the efficacy of thromboprophylaxis with aspirin (ASA), warfarin and low-molecular-weight heparin (LMWH) [11,12].

Prior to the adoption of thromboprophylaxis strategies in patients with MM undergoing immunomodulatory treatments, clinicians need to consider the absolute rates of VTE with and without different thromboprophylactic agents (ASA, warfarin and LMWH). These rates have not been estimated accurately and appear to vary depending on disease state and treatment. To address this knowledge gap, we performed a systematic review of the literature to quantify and summarize the rate of VTE in patients with MM undergoing immunomodulatory therapies using different thalidomide- or lenalidomide-based regimens and different thromboprophylaxis strategies.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Data sources and searches

We conducted a systematic literature search strategy to identify potential studies in MEDLINE (1950 to January week 2 2010), EMBASE (1980 to 2010 week 03) and OVID Health Star (1999 to January 2010) using the OVID interface. We also sought publications through a hand-search of potentially relevant journals and American Society of Hematology conference proceedings for the past 5 years (2005–2009). We reviewed the references of included studies and narrative reviews for additional potential studies. There were no restrictions on language, publication year or type of publication; our systematic search strategy is documented in Fig. S1.

Study selection

Using a structured question format to aid our literature search strategy, we reviewed all abstracts. We reviewed potentially relevant articles in full length to ensure that they satisfied three criteria: (i) prospective enrollment of consecutive patients with newly diagnosed or previously treated MM; (ii) patients with MM initiating a new immunomodulatory therapy regimen including thalidomide or lenalidomide; and (iii) one or more of the primary or secondary outcomes for this study were reported. Studies were excluded if the study design was retrospective, patients were not recruited consecutively or if duplicated data was reported.

Outcome measures

Our primary outcome measure was the diagnosis of symptomatic VTE. Venous thromboembolism was defined and graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0), the Common Terminology Criteria for adverse events (version 3.0) or the classification system of the World Health Organization (WHO) [16], or graded by the investigators of each individual study. Outcomes were allocated according to the intention-to-treat principle.

Rates of VTE have previously been reported to be lower in patients with previously treated MM [12]. Therefore, in our systematic review, the rates of VTE were reported according to the disease status (newly diagnosed MM or previously treated MM). The rates of VTE in patients with newly diagnosed MM were reported per 100 patient-cycles of chemotherapy to standardize for the different number of cycles used across studies prior to autologous stem cell transplantation or maintenance therapy. Rates per patient-cycle were established by dividing the total number of VTEs by the number of patients multiplied by the median number of cycles given within individual studies. Similarly, rates of VTE in patients with previously treated MM were reported in 100 patient-months. Rates per patient-month were established by dividing the total number of VTE by the number of patients multiplied by the median time of therapy.

Because the rates of VTE are likely to be different between thalidomide and lenalidomide and when these agents are combined with glucocorticoid and/or cytotoxic chemotherapy including anthracyclines (e.g. doxorubicin), the rates were reported separately for thalidomide- or lenalidomide-based regimens alone and in combination with glucocorticoid (dexamethasone or prednisone) or other chemotherapeutic agents, specifically doxorubicin. The rates of VTE were also stratified according to the type of thromboprophylactic strategy used (none, any, ASA, low-dose warfarin, prophylactic dose of LMWH or therapeutic anticoagulation). Doses of ASA ranged from 75 to 325 mg daily. Low-dose warfarin was defined as a fixed dose of 1–1.25 mg per day without any International Normalized Ratio (INR) monitoring. Therapeutic anticoagulation was defined as: (i) warfarin therapy with target INR between 2 and 3; or (ii) therapeutic doses of LMWH.

Our secondary outcome measure was major bleeding, defined as clinically overt bleeding associated with one or more of the following requirements for hospitalization: transfusion of at least 2 units of packed red blood cells; intracranial or retroperitoneal bleeding, or bleeding involving a body cavity; or death [17].

Data extraction and quality assessment

Two reviewers independently assessed eligibility of articles identified in the initial search strategy for inclusion in the review, discussed those deemed potentially eligible, independently extracted data (baseline characteristics, definition of outcomes, numbers of events) using a standardized data abstraction form, and assessed the studies’ methodological quality (using the Risk of Bias Assessment Tool from the Cochrane Handbook for randomized trials, and the Newcastle – Ottawa Quality Assessment scale for observational studies [18], G. Wells, unpublished data). The corresponding authors of the studies were contacted if outcome measures were not reported in the original article. Discrepancies were adjudicated by a third party.

Data synthesis and analysis

To estimate the weighted rates and 95% confidence intervals for the review’s primary outcomes, after extraction, individual study rates (patient-cycle or patient-month) were transformed into a quantity using the Freeman–Tukey variant of the arcsine square root transformed proportion [19]. We then calculated a pooled proportion as the back-transform of the weighted mean of the transformed proportions, using a random effects model. The weighing of outcomes accounts for differences in sample size and length of follow-up periods between the individual studies. Analyses were performed using StatsDirect software version 2.7.3 (StatsDirect Ltd, Altrincham, UK) [20].

The I2 statistic was used to estimate total variation among the pooled estimates across studies. An I2 of < 25% was considered as low-level heterogeneity, 25–50% was moderate level and higher than 50% was considered as high level [21].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

We identified 1870 citations in our literature search, and 71 articles were deemed eligible (Fig. S2). Sixty-one articles assessed thalidomide-based regimens, including 24 with newly diagnosed MM [2,22–44] and 37 with previously treated MM [6,45–81]. Of these, 11 were randomized controlled trials and 50 were prospective cohort studies. Ten articles assessed lenalidomide-based regimens, including four randomized controlled trials [9,10,82–89]. None of the studies screened patients for the presence of VTE. The baseline characteristics of the included studies are depicted in Tables 1–4.

Table 1.   Baseline characteristics of the included studies assessing thalidomide-based regimens in patients with newly diagnosed multiple myeloma
AuthorsYearDesignRegimenVTE prophylaxisNo. of patientsTotal VTE
  1. Dex, dexamethasone; Doxo, doxorubicin; LMWH, low-molecular-weight heparin; RCT, randomized controlled trial; Thal, thalidomide; TT2, total therapy 2 regimen; VTE, venous thromboembolism.

Osman [22]2001Prospective cohortThal, dex, doxoNone154
Rajkumar [23]2002Prospective cohortThal, dexNone506
Cavo [24]2002Prospective cohortThal, dexNone195
Weber [25]2003Prospective cohortThalNone281
Thal, dexWarfarin 1 mg246
Thal, dexWarfarin 2.0–3.0 or LMWH160
Cavo [26]2004Prospective cohortThal, dexNone192
Thal, dexWarfarin 1.25 mg per day524
Zervas [27]2004Prospective cohortThal, dex, doxo, vincristineNone394
Hassoun [28]2005Prospective cohortThal, dexASA 81 mg455
Palumbo [29]2005Prospective cohortThal, prednisone, melphalanNone499
Schutt [30]2005Prospective cohortThal, dex, epirubicin, vincristineNone318
Cavo [31]2005Prospective cohortThal, dexNone195
Thal, dexWarfarin 1.25 mg per day8110
Dimopoulos [32]2006Prospective cohortThal, dex, melphalanNone507
Offidani [33]2006Prospective cohortThal, dex, doxoWarfarin 1.25 mg per day507
Palumbo [34]2006RCTThal, prednisone, melphalanNone6513
Thal, prednisone, melphalanEnoxaparin 40 mg daily642
Rajkumar [2]2006RCTThal, dexNone10220
Barlogie [35]2006RCTThal, TT2None12745
Thal, TT2Warfarin 1 mg per day3511
Thal, TT2Enoxaparin 40 mg daily15236
Miller [36]2006Prospective cohortThal, dex, doxo, vincristineWarfarin 1–2 mg242
Facon [37]2007RCTThal, prednisone, melphalanNone1258
Zervas [38]2007RCTThal, dex, doxo, vincristineASA 100 mg355
Thal, dex, doxo, vincristineLMWH (no dose)824
Wang [39]2007Prospective cohortThal, dex, bortezomibWarfarin 2.0–3.0 or LMWH382
Rajkumar [40]2008RCTThal, dexNone23543
Hulin [41]2009RCTThal, prednisone, melphalanNone1137
Ludwig [42]2009RCTThal, dexNone498
Thal, dexLMWH (no dose)969
Cini [43]2010Prospective cohortThal, dexWarfarin 1.25 mg16616
Lokhorst [44]2010RCTThal, dex, doxoNadroparin 285026827
Table 2.   Baseline characteristics of the included studies assessing thalidomide-based regimens in patients with previously treated multiple myeloma
AuthorsYearDesignRegimenVTE prophylaxisNo. of patientsTotal VTE
  1. Cyclo, cyclophosphamide; Dex, dexamethasone; Doxo, doxorubicin; LMWH, low-molecular-weight heparin; RCT, randomized controlled trial; Thal, thalidomide; VTE, venous thromboembolism.

Hus [45]2001Prospective cohortThalNone532
Dimopoulos [46]2001Prospective cohortThal, dexNone443
Camba [47]2001Prospective cohortThal, dex, cisplatin, doxo, cyclo, etoposideNone185
Palumbo [48]2001Prospective cohortThal, dexNone770
Barlogie [49]2001Prospective cohortThalNone1693
Urbauer [50]2002Prospective cohortThal, dex, cisplatin, cyclo, etoposideNone143
Zangari [51]2002Prospective cohortThal, dex, cisplatin, doxo, cyclo, etoposideNone19231
Thal, dex, cisplatin, cyclo, etoposideNone401
Kropff [52]2003Prospective cohortThal, dex, cycloNone605
Anagnostopoulos [53]2003Prospective cohortThal, dexNone474
Lee [54]2003Prospective cohortThal, dex, cisplatin, doxo, cyclo, etoposideNone12137
Mileshkin [55]2003Prospective cohortThal, interferonNone753
Offidani [56]2004Prospective cohortThal, melphalanNone273
Schey [57]2003Prospective cohortThalNone693
Dimopoulos [58]2004Prospective cohortThal, dex, cycloNone981
Garcia-Sanz [59]2004Prospective cohortThal, dex, cycloNone715
Waage [60]2004Prospective cohortThalNone652
Offidani [61]2003Prospective cohortThal, melphalanNone273
ThalNone231
Richardson [62]2004Prospective cohortThalNone301
Tosi [63]2004Prospective cohortThal, dexNone200
Palumbo [64]2004Prospective cohortThal, dexNone1202
Kyriakou [65]2005Prospective cohortThal, dex, cycloWarfarin 1 mg per day526
Hovenga [66]2005Prospective cohortThal, cycloNone381
Baz [67]2005Prospective cohortThal, dex, doxo, vincristineNone1911
Thal, dex, doxo, vincristineASA 81 mg from start584
Thal, dex, doxo, vincristineASA 81 mg during protocol2611
Badros [68]2005Prospective cohortThal, dex, G3130Warfarin 1 mg per day333
Ochiai [69]2005Prospective cohortThal, dexNone120
Prince [70]2005Prospective cohortThalNone663
Schutt [71]2005Prospective cohortThal, dexNone291
Ciolli [72]2006Prospective cohortThal, dex, bortezomibWarfarin INR 2-3180
Palumbo [73]2006Prospective cohortThal, prednisone, melphalanNone241
Martino [74]2007Prospective cohortThalProphylactic LMWH170
Palumbo [75]2007Prospective cohortThal, prednisone, melphalan, bortezomibNone303
Sharma [76]2007Prospective cohortThalNone121
Suvannasankha [77]2007Prospective cohortThal, prednisone, cycloLow dose ASA373
Offidani [79]2009RCTThal, dexNone520
Spencer [80]2009RCTThal, prednisoneNone1146
Palumbo [81]2010Prospective cohortThal, prednisoneDefibrotide231
Table 3.   Baseline characteristics of the included studies assessing lenalidomide-based regimens in patients with newly diagnosed multiple myeloma
AuthorsYearDesignRegimenVTE prophylaxisNo. of patientsTotal VTE
  1. *Dexamethasone 40 mg on days 1–4, 9–12 and 17–20 of each 28-day cycle. Dexamethasone 40 mg on days 1, 8, 15 and 22 of each 28-day cycle. Cyclo, cyclophosphamide; Dex, dexamethasone; Doxo, doxorubicin; LMWH, low-molecular-weight heparin; RCT, randomized controlled trial; Thal, thalidomide; VTE, venous thromboembolism.

Rajkumar [82]2005Prospective cohortLenalidomide, dexASA 80 or 325 mg341
Zonder [83]2007RCTLenalidomide, dexNone126
Lenalidomide, dexASA 325 mg8814
Niesvizky [84]2008Prospective cohortLenalidomide, dex,ASA 81 mg729
Richardson [85]2010Prospective cohortLenalidomide, dex, bortezomibASA 81 or 325 mg664
Rajkumar [10]2010RCTLenalidomide, dex (high dose)*None required13224
Lenalidomide, dex (high dose)*Thromboprophylaxis9133
Lenalidomide, dex (low dose)None required1345
Lenalidomide, dex (low dose)Thromboprophylaxis8622
Table 4.   Baseline characteristics of the included studies assessing lenalidomide-based regimens in patients with previously treated multiple myeloma
AuthorsYearDesignRegimenVTE prophylaxisNo. of patientsTotal VTE
  1. Dex, dexamethasone; Doxo, doxorubicin; IU, International Units; LMWH, low-molecular-weight heparin; RCT, randomized controlled trial; VTE, venous thromboembolism.

Baz [86]2006Prospective cohortLenalidomide, dex, doxo, vincristineASA 81 mg626
Weber [87]2007RCTLenalidomide, dexNone required17726
Dimopoulos [9]2007RCTLenalidomide, dexNone17615
Minnema [88]2009Prospective cohortLenalidomide, dex,None81
Knop [89]2009Prospective cohortLenalidomide, dex, doxoASA 100 mg or enoxaparin 40 mg or dalteparin 5000 IU693

Thirty-six studies (51%) graded VTE according to the National Cancer Institute’s Common Toxicity Criteria (version 2.0), 12 studies (17%) used the WHO criteria and 7 (10%) studies used the National Cancer Institute Common Terminology Criteria for adverse events (version 3.0). Four studies (5%) defined VTE using diagnostic imaging reports (ultrasonography, venography and computed tomographic pulmonary angiography). Finally, 12 (17%) studies did not report definitions of adverse events or VTE.

The study quality of the randomized controlled trials and prospective cohort studies is summarized in Tables S1 and S2. Eight (53%) and seven (47%) of the 15 randomized controlled trials reported adequate sequence generation and allocation concealment, respectively (Table S1). Only a third of the trials were blinded to patients and physicians. A study protocol was available or all expected outcomes were reported for all the included trials. The quality of the prospective cohort studies was homogeneous among studies (Table S2). All studies had adequate representativeness and follow-up. Twelve studies (17%) did not report on the assessment of VTE.

Thalidomide-based regimens

The rates of VTE in patients with newly diagnosed MM and treated with a thalidomide-based regimen are reported in Table 5. Patients with newly diagnosed MM treated with thalidomide alone or in combination with dexamethasone have a risk of VTE of 1.3 (95% CI, 0.4–7.2; I2, 89%) and 4.1 (95% CI, 2.8–5.9; I2, 75%) per 100 patient-cycles, respectively. The rate of VTE is 2.6 (95% CI, 2.1–3.2; I2, 34%) per 100 patient-cycles in patients treated with a combination of thalidomide with dexamethasone and also receiving thromboprophylaxis. Among the different types of thromboprophylaxis assessed, the use of therapeutic doses of anticoagulants (warfarin with target INR between 2.0 and 3.0 or therapeutic doses of LMWH) seems to provide the largest absolute reduction of risk of VTE.

Table 5.   Rate of venous thromboembolism (per 100 patient cycles) in patients with newly diagnosed multiple myeloma treated with thalidomide-based regimens
 No prophylaxisAny prophylaxisASAWarfarin 1–1.25 mg per dayProphylactic LMWHTherapeutic doses of anticoagulation*
  1. *Therapeutic doses of anticoagulation: (i) warfarin with target INR between 2.0 and 3.0 or (ii) therapeutic doses of low-molecular-weight heparin. CI, confidence intervals; LMWH, low-molecular-weight heparin; n, total number of patients.

Thalidomide without dexamethasone (95% CI)1.3 (0.4–2.7) (n = 380)   0.5 (0.4–0.6) (n = 64) 
Thalidomide + dexamethasone (95% CI)4.1 (2.8–5.9) (n = 628)2.6 (2.1–3.2) (n = 993)2.3 (0.9–7.9) (n = 80)2.8 (2.0–3.9) (n = 387)2.1 (1.1–3.6) (n = 446)1.6 (0.2–4.1) (n = 80)

The rates of VTE in patients with previously treated MM receiving thalidomide-based regimens are shown in Table 6. The rate of VTE in patients with previously treated MM receiving thalidomide in combination with dexamethasone is 0.8 (95% CI, 0.1–2.1; I2, 86%) per 100 patient-months (Table 6). A total of 6.7 (95% CI, 0.5–18.9; I2, 96%) per 100 patient-months will have a VTE when treated with a combination of thalidomide, dexamethasone and doxorubicin (Table 6). Few studies reported on the use of the different thromboprophylactic agents (Table 6). None of the studies reported major bleeding events.

Table 6.   Rate of venous thromboembolism (per 100 patient-months) in patients with previously treated multiple myeloma managed with thalidomide-based regimens
 No prophylaxisASAWarfarin 1–1.25 mg per dayProphylactic LMWHTherapeutic doses of anticoagulation*
  1. *Therapeutic doses of anticoagulation: (i) warfarin with target INR between 2.0 and 3.0 or (ii) therapeutic doses of low-molecular-weight heparin. Only one study reported subgroups of patients with ASA thromboprophylaxis started at the initiation of (n = 58) or during (n = 26) the study protocol. CI, confidence intervals; LMWH, low-molecular-weight heparin; n, total number of patients.

Thalidomide alone (95% CI)0.4 (0.2–0.8) (n = 706)  0 (0–1.72) (n = 17) 
Thalidomide + prednisone (95% CI)0.6 (0.2–1.1) (n = 258)    
Thalidomide + other chemotherapy agents (95% CI)0.4 (0.01–1.2) (n = 38)0.4 (0.01–0.9) (n = 37)   
Thalidomide + dexamethasone (95% CI)0.8 (0.1–2.1) (n = 321)   
Thalidomide + dexamethasone + other chemotherapy agents (95% CI)0.9 (0.3–1.8) (n = 321) 2.4 (1.3–4.0) (n = 102) 0 (0–2.2) (n = 18)
Thalidomide + dexamethasone + multi-agent chemotherapy including doxorubicin (95% CI)6.7 (0.5–18.9) (n = 331) 3.5 (1.2–6.5) (n = 50)  

Lenalidomide-based regimens

The rates of VTE in patients with newly diagnosed and previously treated MM treated with a lenalidomide-based regimen are reported in Tables 7 and 8. No studies reported the rate of VTE in patients treated with lenalidomide alone. A combination of lenalidomide and dexamethasone is associated with a risk of VTE of 0.8 (95% CI, 0.07–2.0; I2, 95%) per 100 patient-cycles and 0.7 per 100 patient-cycles (95% CI, 0.4–0.9; I2, 25%) in patients with newly diagnosed and previously treated MM, respectively. Similarly, the rates of VTE in patients also receiving thromboprophylaxis with ASA were 0.9 (95% CI, 0.5–1.5; I2, 55%) and 0.6 (95% CI, 0.01–2.1; I2, 70%) in patients with newly diagnosed and previously treated MM, respectively. None of the studies reported major bleeding events.

Table 7.   Rate of venous thromboembolism (per 100 patient-cycles) in patients with newly diagnosed multiple myeloma treated with lenalidomide-based regimens in combination with dexamethasone
 No prophylaxisAny prophylaxisASA
  1. CI, confidence intervals; n, total number of patients.

Lenalidomide + dexamethasone (95% CI)0.8 (0.07–2.0) (n = 278)0.7 (0.5–1.1) (n = 349)0.9 (0.5–1.5) (n = 172)
Table 8.   Rate of venous thromboembolism (per 100 patient-months) in patients with previously treated multiple myeloma managed with lenalidomide-based regimens in combination with dexamethasone
 No prophylaxisASA
  1. CI, confidence intervals; n, total number of patients.

Lenalidomide + dexamethasone (95% CI)0.7 (0.4–0.9) (n = 361) 
Lenalidomide + dexamethasone + other chemotherapy agents including doxorubicin (95% CI) 0.6 (0.01–2.1) (n = 131)

Sensitivity and subgroup analyses according to study quality and VTE grading system were planned a priori. However, the small number of studies within each category precluded the analyses.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Our systematic review demonstrates that patients with MM treated with immunomodulatory regimens (thalidomide- or lenalidomide-based regimens) are at a high risk of VTE. Patients with newly diagnosed MM seem to be at higher risk than patients with previously treated disease. This risk is increased further when thalidomide or lenalidomide is combined with dexamethasone and reached 6.7 (95% CI, 0.5–18.9) per 100 patient-cycles in combination with doxorubicin. The use of thromboprophylaxis seems to be associated with lower risk of VTE in this patient population. Formal comparisons could not be performed between the different types of thromboprophylactic strategies, and the potential benefit from each individual strategy has not been established. Furthermore, rates of major bleeding complications are unknown and hence the risk:benefit ratio of thromboprophylaxis is unclear.

Patients with newly diagnosed MM receiving thalidomide- or lenalidomide-based regimens have an increased risk of VTE that is comparable to other high-risk populations. For example, high-risk medically ill patients (e.g. congestive heart failure, respiratory illness, etc.) admitted to hospital that are not receiving thromboprophylaxis during their hospitalization have a 3% risk of symptomatic DVT or PE during the 3-month follow-up period [90]. Based on these results, thromboprophylaxis is recommended in these high-risk medically ill patients [91]. Our systematic review shows that patients with newly diagnosed MM receiving thalidomide alone or in combination with dexamethasone without thromboprophylaxis have a 3-month VTE risk of approximately 4% and 12%, respectively. Similarly, patients with newly diagnosed MM receiving lenalidomide in combination with dexamethasone have a 3-month risk of VTE of approximately 3%. Although the risk of VTE is lower in patients with previously treated MM receiving thalidomide alone, the 3-month VTE risk in those receiving thalidomide or lenalidomide in combination with dexamethasone or other chemotherapeutic agents is approximately 3%. Therefore, the risk of VTE in patients with MM receiving immunomodulatory therapies is as high as in other higher risk populations for which there is consensus that thromboprophylaxis is effective and is recommended [91].

Based on our review, the type of thromboprophylaxis strategy to recommend is still unclear. All the trials included in our systematic review reported observational data regarding thromboprophylaxis regimens. Furthermore, the inconsistent reporting of VTE in therapeutic trials undermines our confidence in the true event rates in these studies. The lack of a randomized control trial comparing any one of the thromboprophylaxis agents with a controlled group also raises real concerns about the true efficacy and safety of these agents in this population. The rate of major bleeding events in patients with MM on thromboprophylaxis is unknown, as a large majority of the studies did not report this as an outcome. Currently, the ESMO, ACCP and NCCN guidelines do not have specific recommendations for MM patients receiving thalidomide- or lenalidomide-based regimens [91,92]. The ASCO guidelines recommend that MM patients receiving thalidomide or lenalidomide in combination with dexamethasone or other chemotherapeutic agents receive LMWH or adjusted-dose warfarin (INR of 1.5) for thromboprophylaxis [93]. It is important to note that the absence of ASA from these recommendations is based on extrapolation from studies of postoperative thromboprophylaxis in orthopedic surgery, which is an entirely different patient population. Our results show that ASA did not seem to reduce the risk of VTE in patients with newly diagnosed or previously treated MM receiving lenalidomide in combination with dexamethasone. The International Myeloma Working Group proposes using different types of thromboprophylaxis strategies based on stratification of the patient’s underlying risk of VTE using individual, myeloma and therapy-related risk factors [11]. This risk assessment model has not been formally tested. Randomized controlled trials evaluating different thromboprophylaxis strategies are desperately needed in patients with MM receiving thalidomide or lenalidomide in combination with dexamethasone and/or other chemotherapeutic agents. Finally, the role of novel oral anticoagulants, including direct thrombin inhibitors (dabigatran etexilate), Xa inhibitors (rivaroxaban and apixaban) and defibrotide, is unknown and prospective clinical trials would be beneficial to assess their potential benefit in patients with MM undergoing immunomodulatory therapy.

It is important to note the limitations of our study. First, most of our data are extracted from studies that were not designed to study VTE as an outcome. This is highlighted by the fact that 17% of the studies did not even mention VTE in the publication (Fig. S2). Important articles, particularly assessing lenalidomide in patients with previously treated MM, had to be excluded due to incomplete reporting of VTE outcomes [94–96]. These studies are suggesting that the rate of VTE is low in patients with previously treated MM managed with single agent lenalidomide. Two of these studies included patients receiving thromboprophylaxis, which may have contributed to the reduction in the risk of VTE [94,96]. The GIMEMA group also performed a study in which patients with newly diagnosed MM randomized to different thalidomide-based regimens in combination with dexamethasone underwent a second randomization to receive ASA, LMWH or VKA [97]. The trial was reported at the American Society of Hematology Annual Meeting in 2009 but has not yet been published [97]. The abstract could not be included in the analyses as the table did not report the results separately for the different immunomodulatory therapies and only preliminary data were published in the abstract (final analysis presented at meeting only) [97]. Second, the definition of VTE varied across studies. A majority of studies used pre-established definitions from toxicity classification systems (National Cancer Institute’s Common Toxicity Criteria [version 2.0], WHO Criteria or National Cancer Institute Common Terminology Criteria for adverse events [version 3.0]). Although these classification systems are standardized and widely used in MM studies, they do not outline the diagnostic criteria for DVT or PE, and are used primarily to grade the severity of the event, with the assumption that the diagnosis is accurately made. None of the classification systems discriminate between: (i) superficial vein thrombosis vs. DVT; (ii) distal vs. proximal DVT; or (iii) upper vs. lower extremity DVT. Only one classification system (National Cancer Institute Common Terminology Criteria for adverse events) includes specific reporting for catheter-related DVT. All these factors are important to consider as they are associated with different rates of embolization and risk of recurrent VTE and hence, might alter management (e.g. systemic anticoagulation or not). To accurately determine the need for thromboprophylaxis and the optimal anticoagulant regimen, future trials should include DVT and PE as standard safety outcomes using recognized definitions.

Third, we were unable to report rates of major bleeding due to lack of reporting from individual studies. We recommend that a standard definition of major bleeding [17] be used instead of the usual toxicity classification systems in order to establish the risk:benefit ratio of thromboprophylaxis in MM patients receiving immunomodulatory regimens. Fourth, all pooled estimates had moderate-to-high heterogeneity (Data not shown). Sensitivity analysis by stratifying studies according to quality did not significantly alter heterogeneity. The most likely explanation for the heterogeneity is the difference between VTE definitions and outcome ascertainment. Fifth, rates of VTE could not be formally compared between the different treatment groups (thalidomide- and lenalidomide-based regimens), patient populations (newly diagnosed and previously treated) and thromboprophylaxis strategies due to the uncertainty of the true event rates. Finally, our study does not address other factors, including costs, lifestyle modifications, burden of laboratory monitoring, and patient values and preferences, which, in addition to estimated VTE and major bleeding rate differences, should be taken into account when individual decisions about thromboprophylaxis are being made.

In conclusion, patients with newly diagnosed or previously treated MM receiving immunomodulatory regimens (thalidomide or lenalidomide) are at high risk of VTE. Thromboprophylaxis seems to reduce the risk of VTE in this patient population; however, none of the thromboprophylaxis strategies assessed in our systematic review has demonstrated a clear benefit. Further prospective trials using standardized definitions of VTE and major bleeding and directly comparing different thromboprophylaxis strategies are required to assess the competing risk and benefit of thromboprophylaxis in this patient population.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

M. Carrier, G. Le Gal: designed research, performed research, analyzed data and wrote the paper. J. Tay: performed research. C. Wu: designed research. A. Y. Lee: designed research and wrote the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information
  • 1
    Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein MA. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer 2004; 101: 55866.
  • 2
    Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 4316.
  • 3
    Zangari M, Saghafifar F, Mehta P, Barlogie B, Fink L, Tricot G. The blood coagulation mechanism in multiple myeloma. Semin Thromb Hemost 2003; 29: 75282.
  • 4
    Rajkumar SV, Leong T, Roche PC, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, Greipp PR. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000; 6: 31116.
  • 5
    Yasin Z, Quick D, Thiagarajan P, Spoor D, Caraveo J, Palascak J. Light-chain paraproteins with lupus anticoagulant activity. Am J Hematol 1999; 62: 99102.
  • 6
    Elice F, Fink L, Tricot G, Barlogie B, Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Br J Haematol 2006; 134: 399405.
  • 7
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 40825.
  • 8
    Palumbo A, Facon T, Sonneveld P, Blade J, Offidani M, Gay F, Moreau P, Waage A, Spencer A, Ludwig H, Boccadoro M, Harousseau JL. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008; 111: 396877.
  • 9
    Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD, Multiple M. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. [Erratum appears in N Engl J Med 2009 Jul 30; 361: 544]. N Engl J Med 2007; 357: 212332.
  • 10
    Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. [Erratum appears in Lancet Oncol 2010 Jan; 11: 14]. Lancet Oncol 2010; 11: 2937.
  • 11
    Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A, Knop S, Joshua D, Sezer O, Ludwig H, Vesole D, Blade J, Kyle R, Westin J, et al. ; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22: 41423.
  • 12
    Musallam KM, Dahdaleh FS, Shamseddine AI, Taher AT. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb Res 2009; 123: 67986.
  • 13
    Corso A, Lorenzi A, Terulla V, Airo F, Varettoni M, Mangiacavalli S, Zappasodi P, Rusconi C, Lazzarino M. Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone. Ann Hematol 2004; 83: 58891.
  • 14
    Kaushal V, Kaushal GP, Melkaveri SN, Mehta P. Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology. J Thromb Haemost 2004; 2: 32734.
  • 15
    Ward CM, Yen T, Harvie R, Pavlakis N. Elevated levels of factor VIII and von Willebrand factor after thalidomide treatment for malignancy: relationship to thromboembolic events. Hematol J 2003; S1: Abstract 265.
  • 16
    Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 20714.
  • 17
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 6924.
  • 18
    Higgins JPT. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2. Cochrane Database Syst Rev 2009.
  • 19
    Miller J. The inverse of the Freeman-Tukey double arcsine transformation. Am Stat 1978; 32: 138.
  • 20
    Laird NM, Mosteller F. Some statistical methods for combining experimental results. Int J Technol Assess Health Care 1990; 6: 530.
  • 21
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 153958.
  • 22
    Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 2001; 344: 19512.
  • 23
    Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 431923.
  • 24
    Cavo M, Zamagni E, Cellini C, Tosi P, Cangini D, Cini M, Valdre L, Palareti G, Masini L, Tura S, Baccarani M. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood 2002; 100: 22723.
  • 25
    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21: 169.
  • 26
    Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89: 82631.
  • 27
    Zervas K, Dimopoulos MA, Hatzicharissi E, Anagnostopoulos A, Papaioannou M, Mitsouli C, Panagiotidis P, Korantzis J, Tzilianos M, Maniatis A; Greek Myeloma Study Group. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol 2004; 15: 1348.
  • 28
    Hassoun H, Reich L, Klimek VM, Dhodapkar M, Cohen A, Kewalramani T, Zimman R, Drake L, Riedel ER, Hedvat CV, Teruya-Feldstein J, Filippa DA, Fleisher M, Nimer SD, Comenzo RL. Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma. Br J Haematol 2006; 132: 15561.
  • 29
    Palumbo A, Bertola A, Musto P, Caravita T, Callea V, Nunzi M, Grasso M, Falco P, Cangialosi C, Boccadoro M. Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma. Cancer 2005; 104: 142833.
  • 30
    Schutt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Hoiczyk M, Flasshove M, Hense J, Bojko P, Metz K, Moritz T, Seeber S, Nowrousian MR. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. Eur J Haematol 2005; 74: 406.
  • 31
    Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 359.
  • 32
    Dimopoulos MA, Anagnostopoulos A, Terpos E, Repoussis P, Zomas A, Katodritou E, Kyrtsonis MC, Delibasi S, Vassou A, Pouli A, Zervas K, Anagnostopoulos N, Maniatis A; Greek Myeloma Study Group. Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma. Haematologica 2006; 91: 2524.
  • 33
    Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, Galieni P, Catarini M, Burattini M, Centurioni R, Ferranti M, Rupoli S, Scortechini AR, Giuliodori L, Candela M, Capelli D, Montanari M, Olivieri A, Poloni A, Polloni C, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood 2006; 108: 215964.
  • 34
    Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stephano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G et al. ; Italian Multiple Myeloma Network G. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 82531.
  • 35
    Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 102130.
  • 36
    Miller KC, Padmanabhan S, Dimicelli L, Depaolo D, Landrigan B, Yu J, Doran V, Marshal P, Chanan-Khan A. Prospective evaluation of low-dose warfarin for prevention of thalidomide associated venous thromboembolism. Leuk Lymphoma 2006; 47: 233943.
  • 37
    Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, et al. ; Intergroupe Francophone dM Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: 120918.
  • 38
    Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol 2007; 18: 136975.
  • 39
    Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 2007; 12: 2359.
  • 40
    Rajkumar SV, Rosinol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Blade J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 2008; 26: 21717.
  • 41
    Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azais I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009; 27: 366470.
  • 42
    Ludwig H, Hajek R, Tothova E, Drach J, Adam Z, Labar B, Egyed M, Spicka I, Gisslinger H, Greil R, Kuhn I, Zojer N, Hinke A. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009; 113: 343542.
  • 43
    Cini M, Zamagni E, Valdre L, Palareti G, Patriarca F, Tacchetti P, Legnani C, Catalano L, Masini L, Tosi P, Gozzetti A, Cavo M. Thalidomide-dexamethasone as up-front therapy for newly diagnosed multiple myeloma patients: thrombophilic alterations, thrombotic complications and thromboprophylaxis with low-dose warfarin. Eur J Haematol 2010; 84: 48492.
  • 44
    Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, et al. ; Dutch-Belgian Hemato-Oncology Group. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010; 115: 111320.
  • 45
    Hus M, Dmoszynska A, Soroka-Wojtaszko M, Jawniak D, Legiec W, Ciepnuch H, Hellmann A, Wolska-Smolen T, Skotnicki A, Manko J; Polish Multiple Myeloma Study Group. Thalidomide treatment of resistant or relapsed multiple myeloma patients. Haematologica 2001; 86: 4048.
  • 46
    Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, Vervessou E, Samantas E, Papadimitriou C, Economou O, Gika D, Panayiotidis P, Christakis I, Anagnostopoulos N. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 2001; 12: 9915.
  • 47
    Camba L, Peccatori J, Pescarollo A, Tresoldi M, Corradini P, Bregni M. Thalidomide and thrombosis in patients with multiple myeloma. Haematologica 2001; 86: 11089.
  • 48
    Palumbo A, Giaccone L, Bertola A, Pregno P, Bringhen S, Rus C, Triolo S, Gallo E, Pileri A, Boccadoro M. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001; 86: 399403.
  • 49
    Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, Shaughnessy J, Ayers D, Spoon D, Tricot G. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98: 4924.
  • 50
    Urbauer E, Kaufmann H, Nosslinger T, Raderer M, Drach J. Thromboembolic events during treatment with thalidomide. Blood 2002; 99: 42478.
  • 51
    Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, Morris C, Fink L, Tricot G. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002; 100: 116871.
  • 52
    Kropff MH, Lang N, Bisping G, Domine N, Innig G, Hentrich M, Mitterer M, Sudhoff T, Fenk R, Straka C, Heinecke A, Koch OM, Ostermann H, Berdel WE, Kienast J. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Br J Haematol 2003; 122: 60716.
  • 53
    Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 2003; 121: 76871.
  • 54
    Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. TPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. [Erratum appears in J Clin Oncol 2008 Apr 20; 26: 2066]. J Clin Oncol 2003; 21: 27329.
  • 55
    Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, McKendrick J, Briggs P, Seymour JF, Lillie K, Smith JG, Zeldis JB, Prince HM. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood 2003; 102: 6977.
  • 56
    Offidani M, Corvatta L, Marconi M, Olivieri A, Catarini M, Mele A, Brunori M, Candela M, Malerba L, Capelli D, Montanari M, Leoni P. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematol J 2004; 5: 3127.
  • 57
    Schey SA, Cavenagh J, Johnson R, Child JA, Oakervee H, Jones RW. An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment. Leuk Res 2003; 27: 90914.
  • 58
    Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J 2004; 5: 1127.
  • 59
    Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, Polo-Zarzuela M, Sureda A, Barrenetxea C, Palomera L, Lopez R, Grande-Garcia C, Alegre A, Vargas-Pabon M, Gutierrez ON, Rodriguez JA, San Miguel JF. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004; 18: 85663.
  • 60
    Waage A, Gimsing P, Juliusson G, Turesson I, Gulbrandsen N, Eriksson T, Hjorth M, Nielsen JL, Lenhoff S, Westin J, Wisloff F; Nordic Myeloma Study Group. Early response predicts thalidomide efficiency in patients with advanced multiple myeloma. Br J Haematol 2004; 125: 14955.
  • 61
    Offidani M, Marconi M, Corvatta L, Olivieri A, Catarini M, Leoni P. Thalidomide plus oral melphalan for advanced multiple myeloma: a phase II study. Haematologica 2003; 88: 14323.
  • 62
    Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, Weller E, Mitsiades C, Hideshima T, Davies F, Doss D, Freeman A, Bosch J, Patin J, Knight R, Zeldis J, Dalton W, Anderson K. Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 2004; 79: 87582.
  • 63
    Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S, Baccarani M, Cavo M. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004; 73: 98103.
  • 64
    Palumbo A, Bertola A, Falco P, Rosato R, Cavallo F, Giaccone L, Bringhen S, Musto P, Pregno P, Caravita T, Ciccone G, Boccadoro M. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004; 5: 31824.
  • 65
    Kyriakou C, Thomson K, D’Sa S, Flory A, Hanslip J, Goldstone AH, Yong KL. Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol 2005; 129: 76370.
  • 66
    Hovenga S, Daenen SM, de Wolf JT, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, Vellenga E, Hovenga S, Daenen SMGJ, de Wolf JTM, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, Vellenga E. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study. Ann Hematol 2005; 84: 3116.
  • 67
    Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E, Karam MA, Faiman B, Jawde RA, Andresen S, Zeldis J, Hussein MA. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80: 156874.
  • 68
    Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B, Takebe N, Heyman M, Zwiebel J, Streicher H, Gocke CD, Tomic D, Flaws JA, Zhang B, Fenton RG. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 2005; 23: 408999.
  • 69
    Ochiai N, Yamada N, Uchida R, Fuchida S, Okano A, Hatsuse M, Okamoto M, Ashihara E, Shimazaki C. Combination therapy with thalidomide, incadronate, and dexamethasone for relapsed or refractory multiple myeloma. Int J Hematol 2005; 82: 2437.
  • 70
    Prince HM, Mileshkin L, Roberts A, Ganju V, Underhill C, Catalano J, Bell R, Seymour JF, Westerman D, Simmons PJ, Lillie K, Milner AD, Iulio JD, Zeldis JB, Ramsay R. A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2005; 11: 550414.
  • 71
    Schutt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Poser M, Muller S, Flasshove M, Moritz T, Seeber S, Nowrousian MR. Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival. Ann Hematol 2005; 84: 594600.
  • 72
    Ciolli S, Leoni F, Gigli F, Rigacci L, Bosi A. Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients. Leuk Lymphoma 2006; 47: 1713.
  • 73
    Palumbo A, Avonto I, Bruno B, Ambrosini MT, Bringhen S, Cavallo F, Falco P, Boccadoro M. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol 2006; 76: 2737.
  • 74
    Martino M, Console G, Callea V, Stelitano C, Massara E, Irrera G, Messina G, Morabito F, Iacopino P. Low tolerance and high toxicity of thalidomide as maintenance therapy after double autologous stem cell transplant in multiple myeloma patients. Eur J Haematol 2007; 78: 3540.
  • 75
    Palumbo A, Boccadoro M. A new standard of care for elderly patients with myeloma. [Erratum appears in Lancet. 2008 Mar 22; 371: 986]. Lancet 2007; 370: 11912.
  • 76
    Sharma A, Raina V, Uppal G, Kumar R, Grover J. Long term use of thalidomide: safe and effective. Indian J Cancer 2007; 44: 10810.
  • 77
    Suvannasankha A, Fausel C, Juliar BE, Yiannoutsos CT, Fisher WB, Ansari RH, Wood LL, Smith GG, Cripe LD, Abonour R. Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21. Oncologist 2007; 12: 99106.
  • 78
    Zemanova M, Scudla V, Adam Z, Gregora E, Pour L, Minarik J, Pavlicek P, Pika T, Bacovsky J. Low-dose thalidomide regimens in therapy of relapsed or refractory multiple myeloma. Neoplasma 2008; 55: 3459.
  • 79
    Offidani M, Corvatta L, Polloni C, Piersantelli MN, Gentili S, Galieni P, Visani G, Alesiani F, Catarini M, Brunori M, Samori A, Burattini M, Centurioni R, Ferranti M, Giuliodori L, Candela M, Mele A, Marconi M, Leoni P. Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study. Br J Haematol 2009; 144: 6539.
  • 80
    Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 2009; 27: 178893.
  • 81
    Palumbo A, Larocca A, Genuardi M, Kotwica K, Gay F, Rossi D, Benevolo G, Magarotto V, Cavallo F, Bringhen S, Rus C, Masini L, Iacobelli M, Gaidano G, Mitsiades C, Anderson K, Boccadoro M, Richardson P; Italian Multiple Myeloma Network GIMEMA. Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of multicenter phase I/II trial. Haematologica 2010; 95: 11449.
  • 82
    Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106: 40503.
  • 83
    Zonder J, Crowley J, Hussein M, Bolejack V, Moore DL, Whittenberger BF, Abidi MH, Durie B, Barlogie B. Superiority of lenalidomide (Len) plus high-dose dexamathasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma: results of the randomized, double-blinded, placebo-controlled SWOG trial S0232. Blood 2007; 110: Abstract 77.
  • 84
    Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood 2008; 111: 11019.
  • 85
    Richardson P, Weller E, Lonial S, Jakubowiak A, Jagannath S, Raje N, Avigan D, Xie W, Ghobrial I, Schlossman R, Mazumdar M, Munshi N, Vesole D, Joyce R, Kaufman JL, Doss D, Warren D, Lunde LE, Kaster S, DeLaney C, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 5: 67986.
  • 86
    Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, Reed J, Faiman B, Ellis Y, Brand C, Srkalovic G, Andresen S, Knight R, Zeldis J, Hussein MA. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006; 17: 176671.
  • 87
    Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple M. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357: 213342.
  • 88
    Minnema MC, van der Veer MS, Aarts T, Emmelot M, Mutis T, Lokhorst HM. Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4+ Foxp3+ T cells. Leukemia 2009; 23: 6057.
  • 89
    Knop SG, Gerecke C, Liebisch P, Topp MS, Platzbecker U, Sezer O, Vollmuth C, Falk K, Glasmacher A, Maeder U, Einsele H, Bargou RC. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood 2009; 113: 413743.
  • 90
    Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793800.
  • 91
    Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice guidelines (8th Edition). Chest 2008; 133: 381S453S.
  • 92
    Wagman LD, Baird MF, Bennett CL, Bockenstedt PL, Cataland SR, Fanikos J, Fogarty PF, Goldhaber SZ, Grover TS, Haire W, Hassoun H, Jahanzeb M, Leung LL, Linenberger ML, Millenson MM, Ortel TL, Salem R, Smith JL, Streiff MB. Venous thromboembolic disease. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2006; 4: 83869.
  • 93
    Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, Kakkar A, Kuderer NM, Levine MN, Liebman H, Mendelson D, Raskob G, Somerfield MR, Thodiyil P, Trent D, Francis CW. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490505.
  • 94
    Richardson PGW. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 2009; 27: 57139.
  • 95
    Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108: 345864.
  • 96
    Richardson PJ. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009; 114: 7728.
  • 97
    Palumbo A, Cavo M, Bringhen S, Cavalli M, Patriarca F, Rossi D, Tacchetti P, Pescosta N, Crippa C, Galli M, Spadano T, Carella AM, Caravita T, Cellini C, Ledda A, Pisani F, Peccatori J, Elice F, Nozza A, De Stefano V, et al. A phase III study of enoxaparin vs aspirin vs low-dose warfarin as thromboprophylaxis for newly diagnosed myeloma patients treated with Thalidomide based-regimens. Blood (ASH Annual Meeting Abstracts) 2009; 114: Abstract 492.

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Figure S1. The systematic search strategy.

Figure S2. Flow diagram summarizing the identification process of relevant clinical trials.

Table S1. Quality of included studies using the ‘Risk of bias’ assessment tool from the Cochrane Handbook.

Table S2. Quality of included studies using the Newcastle – Ottawa quality scale for cohort studies.

FilenameFormatSizeDescription
JTH_4215_sm_FigS1-S2-TableS1-S2.doc218KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.