Thalidomide in Multiple Myeloma: current status and future prospects
Venous thromboembolism with thalidomide
The use of thalidomide in a variety of non-malignant conditions has generally been associated with a low but definite risk of venous thromboembolism (VTE) although neuropathy continued to be considered as the most serious potential adverse event. However, as experience has been gained with its use in myeloma, VTE has emerged as the single most important complication of thalidomide therapy in this setting.
Although VTE has been observed with the use of thalidomide as a single agent in the treatment of patients with advanced myeloma, VTE frequency has generally been less than 5%. Similarly, an excessive rate of VTE has not been reported with the use of thalidomide in combination with a variety of chemotherapies in patients with relapsed myeloma. However, an unexpectedly high risk of VTE has been observed when thalidomide is combined with chemotherapy for newly diagnosed patients with myeloma. Rajkumar and colleagues (2001c) have reported a 10% incidence of VTE when using the combination of thalidomide with dexamethasone as initial therapy which is higher than that observed when the same regimen is used in relapsed or refractory patients. This is roughly equivalent to the VTE rate seen with conventional VAD-like regimens.
Of more concern is a report by Comenzo and colleagues of a VTE incidence of 4/15 when the 'TAD' regimen was used as induction therapy for newly diagnosed patients (Osman et al, 2001). This comprised thalidomide (100 mg rising to 200 mg per day), peripheral bolus adriamycin and pulsed dexamethasone. Of the four VTE events, all were proximal lower limb DVTs; two were bilateral and all occurred early in the treatment schedule (Comenzo, personal communication). These findings led the investigators to terminate this Phase II study early.
Important corroborative evidence has come from investigators at The University of Arkansas for Medical Sciences. They compared the incidence of VTE amongst patients randomised to the addition of thalidomide (400 mg) to chemotherapy in their 'Total Therapy II' study (Zangari et al, 2001b). Amongst 100 patients so randomised, the incidence of VTE was 4% in the no thalidomide arm and 28% in the thalidomide arm (p 0.002). All episodes of VTE occurred within the first three cycles of chemotherapy. All 100 patients had central venous catheters (CVC) in place. In the 50 patients not receiving thalidomide, VTE was CVC-related in one case and distant in another case.
In contrast, for the 50 patients receiving thalidomide, VTE was CVC-related in three cases and distant in eleven. Therefore, it is clear that the major increase in risk is for distant, non CVC-related VTE. This suggests that the combination of thalidomide with chemotherapy in newly diagnosed patients with myeloma results in a systemic prothrombotic state.
Thus far, no identifiable prothrombotic laboratory abnormality has been found to be predictive of VTE in this group of patients (Zangari et al, 2000). In particular, neither the levels of Protein C, Protein S and Antithrombin III nor the incidence of antiphospholipid antibodies, resistance to activated Protein C (RAPC), Factor V Leiden and Prothrombin gene promoter mutation have been found to correlate with increased risk of VTE in patients receiving thalidomide (Zangari et al, 2001c), although only small numbers of patients have been studied thus far.
Amongst similar groups of patients being treated with thalidomide plus chemotherapy, the addition of adriamycin to the regimen resulted in an increased VTE rate (Zangari et al, 2001c). In an analysis of the FDA's passive reporting system, varying rates of VTE were found when thalidomide was used in different combinations in patients with a variety of cancers. VTE rates were 4.6%, 15% and 30.9% respectively when thalidomide was used alone, in combination with dexamethasone and with chemotherapy (Bennett et al, 2001) (See Table IV).
| Regimen | Incidence VTED | Comments | Reference |
| Thal alone | <5% | Barlogie et al 2001a | |
| Thal alone | 4.6% | Bennett et al 2001 | |
| Thal/Dexamethasone | 10% | Newly diagnosed | Rajkumar et al 2001a |
| Thal/Dexamethasone | 15% | Bennett et al 2001 | |
| Thal/Chemotherapy | 30.9% | Bennett et al 2001 | |
| TVAD | 33% | ¾ line related | Oakervee et al 2002a |
| MPT | 23% | Newly diagnosed All early in treatment |
Oakervee et al 2002b |
| MPT | 11% | Advanced | Oakervee et al 2002b |
| TAD | 26% | Newly diagnosed Early in treatment |
Osman et al 2001 |
| Total therapy II | 28% | Newly diagnosed Early in treatment |
Zangari et al 2001b |
TVAD: thalidomide,
vincristine, adriamycin and dexamethasone
MPT: melphalan, prednisolone and thalidomide
TAD: thalidomide, bolus adriamycin and dexamethasone
Total Therapy II: sequential chemotherapy and tandem melphalan
autografts
It can be concluded that the use of thalidomide concurrently with chemotherapy in patients with newly diagnosed myeloma carries a significant risk of VTE. This risk appears to be considerably greater than that associated with the use of thalidomide as a single agent or when combined with chemotherapy in patients with relapsed disease. In addition, the major risk of VTE occurs early on in treatment when the tumour load is maximal. It seems that it is the combination of thalidomide, chemotherapy and large disease bulk that is particularly prothrombotic in myeloma. In this regard, it is of potential interest that only 1/12 patients treated thus far on the UKMF T-VAD protocol has developed 'distal' VTE (Oakervee et al, 2002a). On this protocol, patients are treated with an initial cycle of VAD with a subsequent cyclophosphamide-primed stem cell harvest prior to commencing T-VAD. It is possible that the level of tumour reduction resulting from this initial chemotherapy reduces the risk of VTE when thalidomide is subsequently initiated. Clearly, a larger number of patients need to be treated with T-VAD in order to draw any firm conclusions.
Patients with myeloma frequently have multiple conventional risk factors for VTE such as immobility, dehydration, increased plasma viscosity, intercurrent infection and acquired activated protein C (APC) resistance (Zangari et al, 2001c). Indeed, in an analysis of 69 patients, acquired APC resistance was seen in 23% of patients and VTE was more common in this group of patients than in those without resistance (36% versus 15%, p=0.04). Acquired APC resistance is influenced by a large number of factors including the acute phase response (Clark et al, 2001) which are commonly found in myeloma patients. All such patients should be considered for appropriate VTE prophylaxis and preliminary observations from Barlogie's group suggest that prophylactic low-dose warfarin is effective in reducing the VTE rate to baseline in patients receiving thalidomide simultaneously with chemotherapy.
Furthermore, such combination treatment can be safely continued in patients with VTE once therapeutic anticoagulation has been established. Prospective studies will be needed to clarify what is the most effective method of, and the groups of patients who will benefit most from, VTE prophylaxis.