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Bendamustine, Thalidomide and Dexamethasone is an effective salvage regimen for advanced stage multiple myeloma

2011; Wiley; Volume: 156; Issue: 4 Linguagem: Inglês

10.1111/j.1365-2141.2011.08887.x

1365-2141

Elisabeth Grey‐Davies, Jennifer L. Bosworth, Kevin Boyd, Caroline Ebdon, Radovan Sašo, Dipti Chitnavis, Jane Mercieca, Gareth J. Morgan, Faith E. Davies,

Cancer therapeutics and mechanisms

We read with interest the letter concerning bendamustine, thalidomide and dexamethasone (BTD) in renal impairment (Ramasamy et al, 2011). We have used a similar regimen with promising results in another high-risk patient group, those with relapsed-refractory disease. Preclinical and clinical data suggest bendamustine may have activity in the setting of resistance to other alkylators (Leoni et al, 2008), making this an attractive therapy in the relapsed-refractory setting, including post high-dose melphalan. This is because bendamustine is a novel alkylating agent with a benzimidazole ring and has a unique mechanism of action. Whilst the mechlorethamine group is similar to other alkylators, the benzimidazole ring has structural homogeny with some purine analogues, suggesting that bendamustine may have purine analogue in addition to alkylator activity (Kalaycio, 2009). Experience of bendamustine in combination with other anti-myeloma agents is limited, especially in advanced-stage myeloma. A Phase III randomized study that compared bendamustine and prednisolone to melphalan and prednisolone established bendamustine as a viable first-line treatment option, with a superior response rate (75% vs. 70%), time to treatment failure and quality of life in the bendamustine arm (Pönisch et al, 2006). In the relapse setting, response rates of 55–86% were reported at first relapse after high-dose therapy or conventional chemotherapy, with the latter rate achieved in combination with thalidomide and prednisolone (Knop et al, 2005; Pönisch et al, 2008). Data are scarce to support bendamustine use in advance-staged disease, particularly in patients exposed to novel agents. As the combination of bendamustine, corticosteroids and thalidomide shows promise in myeloma, this regimen was given to a small group of advanced stage multiple myeloma (MM) patients in a compassionate use programme in the UK between December 2008 and April 2010. Twenty-three relapsed/refractory MM patients were treated with bendamustine, thalidomide and dexamethasone. Patients received 60 mg/m2 bendamustine on days 1, 8 (and 15), 50–200 mg thalidomide daily and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 21 and 22 of each 28-day cycle. The day 15 dose was omitted in the latter 13 patients after review revealed haematological toxicity. Venous thromboembolism prophylaxis was administered according to published guidelines (Palumbo et al 2008). Response was assessed by The European Group of Bone Marrow Transplantation criteria (Bladéet al, 1998). Time-to-event analysis was performed using the Kaplan–Meier method with graphpad prism software. Patients were heavily pre-treated, with a median of five previous lines of therapy (range 3–7). All had received thalidomide and the majority had received bortezomib (n = 21), lenalidomide (n = 20) and high-dose therapy (n = 19). Patient characteristics are summarized in Table I. The median number of cycles administered was 3 (range 1–6) with a median cumulative bendamustine dose of 390 mg/m2. Thalidomide was escalated, depending on tolerance, to a maximal dose of 200 mg (n = 6), 150 mg (n = 2), 100 mg (n = 9) and 50 mg (n = 6). In addition to the nine patients with baseline grade 3/4 cytopenia (eight thrombocytopenia, five neutropenia) a further nine developed grade 3/4 haematological toxicity, consistent with alkylating agent therapy. Five developed thrombocytopenia with no clinically significant bleeds and seven developed neutropenia. Seven patients required hospitalization for infection, of whom five had progressive disease (PD). Transfusion and granulocyte colony-stimulating factor (GCSF) support was administered as required, with 15 patients requiring packed red cells (1–18 units), 15 platelet transfusion (1–18 units) and 15 GCSF support. Most non-haematological toxicity was related to dexamethasone, thalidomide, or to progressive myeloma. One patient experienced a pulmonary embolus despite aspirin prophylaxis. Three patients reported grade one or two neuropathy and one symptomatic bradycardia, all attributed to thalidomide. Dexamethasone side-effects included grade three hyperglycaemia in two patients and corticosteroid-induced myopathy. Dexamethasone and thalidomide were dose-reduced accordingly. Stable disease (SD) was considered a valid therapeutic goal in this relapsed-refractory group and clinical benefit (≥SD) was seen in 61% of patients [complete response (CR), 4% (n = 1) partial response (PR) 22% (n = 5) minimal response (MR) 17% (n = 4) SD 17% (n = 4) and PD 39% (n = 9)]. The median time to best response was 3 months (range 1–5). The median progression-free survival and overall survival (OS) for the overall group was 3 (range 1–12) and 13 (range 1–17) months, respectively. Compared to non-responders, those achieving at least SD had an improved OS of 15 vs. 3 months, P < 0·001 (Hazard Ratio 36·72; 95% confidence interval 7·65–176·6). The Kaplan Meier survival curve is illustrated (Fig 1). Comparison of responders (≥SD) with non-responders. Those achieving ≥SD had an OS of 15 months vs. 3 months in non-responders, P < 0·001. A Phase I study (n = 28) of a similar regimen (bendamustine 60 mg/m2 days 1, 8, and 15, thalidomide and prednisolone) at first relapse after conventional or high-dose chemotherapy reported superior response rates [CR 14% (n = 4) PR 71% (n = 20) MR 4% (n = 1) SD 7% (n = 2) and PD 4% (n = 1)] (Pönisch et al, 2008). This patient group was less heavily pre-treated (two versus five previous lines), few had received thalidomide or bortezomib (all had received alkylating agents) and those with baseline cytopenia (leucocyte count <3 × 109/l or platelet count <75 × 109/l) were excluded. Despite this exclusion, 18%, 43% and 7% of patients experienced grade 3/4 anaemia, neutropenia and thrombocytopenia, respectively. A number of other doses and schedules of bendamustine in combination with steroids have been reported. In a dose-escalating study, bendamustine 60–100 mg/m2 days 1, 2 was administered to 31 patients at first relapse after high-dose therapy with an overall response rate (MR, PR and CR) of 55% and mild haematological toxicity (Knop et al, 2005). In another study, 39 patients (median two previous lines of therapy) received bendamustine 80–150 mg days 1, 2 with or without corticosteroids with response rates of [CR 0% PR 36% MR 18% SD 26% and PD 20%] and grade 3/4 anaemia, neutropenia and thrombocytopenia of 10%, 41% and 26%, respectively (Michael et al, 2010). Given the rates of grade 3/4 toxicity in these studies, we used weekly dosing in our heavily pre-treated population with cytopenia at study entry to enable therapy modification mid cycle. This allowed for the day-15 bendamustine dose to be omitted avoiding excess haematological toxicity. No previous studies have explored bendamustine in combination in such a heavily pre-treated patient group. Expectations of response should be reduced in patients who have previously received novel agents and exhausted other treatment options. Our results demonstrate that, with careful management, BTD can be safely delivered to this patient group even with pre-existing pancytopenia. We recommend a 3-month trial of BTD for patients who have exhausted other treatment options. An alternative approach to improve response rate, currently employed in a Myeloma UK clinical trial, is to move the combination to an earlier treatment line. In conclusion, in addition to the recent data presented by Ramasamy et al (2011) showing activity of BTD in patients with renal failure, our data demonstrate that BTD is a useful salvage regimen for another high-risk patient group, those with advanced-stage myeloma with prior exposure to bortezomib and lenalidomide. Napp Pharmaceuticals – open access to bendamustine. Performed the research – G-DE, BJL, BKD, EC, SR, CD, MJE, MGJ, DFE. Designed the research – MGJ, DFE. Wrote the paper – G-DE, BKD, BJL, DFE.