Aspirin Decreases the Thrombotic Complications (DVT) of Liposomal Doxorubicin, Vincristine, Decreased Frequency Dexamethasone and Thalidomide (DVd-T) Treatment of Multiple Myeloma (MM).

Abstract

Patients with plasma cell dyscrasia are at risk to develop DVT (prevalence in MGUS was 8%, in MM 10%) (Cancer101(3):558–566, 2004). The risk has been reported to be higher in newly diagnosed (ND) patients treated with Thalidomide and anthracyclines (Clinical Lymphoma. 4(1):32–5, 2003). DVd-T is effective in the treatment of MM patients but carries an increased risk of DVT. Our incidence of DVT with Thalidomide and Thalidomide/Dexamethasone with slow dose escalation and less frequent Dexamethasone was not different from non-Thalidomide containing regimens. We treated 105 patients with DVd-T from 8/2001to 4/2004. We included an algorithm to evaluate patients with symptoms of DVT aggressively and assayed different coagulation parameters (including Platelet Aggregation studies (PA) with Collagen, Epinephrine, ADP, Arachidonic Acid and different concentration of Ristocetin, factor V Leiden (FVL), Activated protein C resistance (APCR), and Von Willebrand factor (vWF)) at baseline and before each cycle of DVd-T. Because the first 35 patients had a high rate of DVT, the protocol was amended to add Aspirin (ASA) 81 mg daily based on preliminary laboratory data preformed on the first group of patients. Two patients on Warfarin for other indications were excluded from the analysis. Of the 103 patients remaining 54 were ND MM and 49 had (Relapsed/Refractory RR) MM. Mean age was 58.9 years, 56% were males and 26%, 42%, 19% and 13% had SWOG stage I, II, III and IV respectively. Four patients were heterozygous for FVL and did not develop DVT. Fifty-eight patients received ASA at the start of treatment while 26 received ASA after the start of treatment and 19 did not receive ASA. Twenty six post treatment (pRx) DVT occurred at a mean 109 days pRx with 15/84 (17.8%) occurring after the start of ASA and 11/19 (57.8%) occurring off ASA (p=0.0002). No significant bleeding complications were noted in patients on ASA. Two patients receiving ASA discontinued therapy; another patient during his travel was immobile for 5–6 hours at a time and inconsistent with ASA therapy, all three developed DVT. One patient on ASA developed below the knee DVT not requiring anticoagulation. Thus, pRx DVT on ASA that required anticoagulation was 11/82 (13%) versus 13/21 (61.9% p<0.001). When compared to pretreatment levels, PA 30 days after initiation of therapy to Arachidonic acid (P<0.001), ADP (P=0.025), Collagen (P<0.001), Epinephrine (P<0.001), Ristocetin 1500 mcg/ml (p=0.06) and 1200 mcg/ml (p=0.05) and vWF (p=0.01) were exaggerated. Following ASA therapy, 30 days pRx PA to ristocetin and vWF levels were not statistically different to pretreatment level suggesting that ASA has blunted the increase in PA. Baseline PA to Epinephrine was higher in patients who did not develop DVT and pRx PA to epinephrine was higher in patients who developed DVT (p<0.001 and p=0.08 respectively). ASA decreases the incidence of DVT following the DVd-T regimen without increasing the risk of bleeding. The mechanism of thrombosis prevention of ASA may involve attenuating the increase of vWF and PA that occurs after DVd-T.

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma

“…It is uncertain which of these measures accounts for the low incidence of DVT observed. It is worth noting however that the use of aspirin given at the same dose (81 mg/d) was also found in preliminary data to decrease the incidence of DVT during initial therapy with DVd-T (Baz et al, 2004).…”

Guidelines on the diagnosis and management of multiple myeloma 2005

“…Treatment should be continued to maximum response plus 3 months. Randomised trials have shown no advantage of continuing chemotherapy beyond this time (Medical Research Council's Working Party on Leukaemia in Adults, 1980;Belch et al, 1988). This applies to patients with stable disease (see Table VIII) as well as those meeting the criteria for response.…”

“…With the exception of data relating to a-IFN, there remains a lack of data relating to maintenance therapy. Continuing conventional chemotherapy therapy is not beneficial following the achievement of plateau phase (Medical Research Council's Working Party on Leukaemia in Adults, 1980;Belch et al, 1988). Several agents have been studied in maintenance including a-IFN, steroids and newer agents, such as thalidomide, thalidomide analogues and bortezomib.…”

“…Available evidence suggests that if the patient was initially treated with MP and achieved stable plateau, MP is appropriate treatment as a further response can be achieved in 50% patients (Belch et al, 1988). Patients who have been treated previously with alkylating agents may respond to VAD or related regimens (Barlogie et al, 1984) or an idarubicin-based regimen (Cook et al, 1996;Parameswaran et al, 2000).…”

Mieloma Múltiplo e distúrbios da hemostasia

“…Hassoun et al 27 relataram que, em 31 pacientes fazendo tratamento seqüencial com doxorrubicina e dexametasona, por três meses, e dexametasona e talidomida, por dois meses, e ácido acetil salicílico (81 mg/dia), a incidência de trombose venosa profunda foi de 9,6%. Por sua vez, Baz et al 28 trataram 103 pacientes com mieloma recém-diagnosticado ou em recaída/refratariedade, com o protocolo DVd-T (doxorrubicina peguilada, vincristina, dexametasona com freqüência reduzida e talidomida). Desse total de pacientes, 84 fizeram uso do ácido acetil salicílico, 81 mg por dia.…”