Life‐threatening bowel perforation while on thalidomide‐based triplet regimen for multiple myeloma: a retrospective case series

Multiple Myeloma (MM) is a malignancy characterized by the clonal proliferation of plasma cells in the bone marrow with associated end-organ damage. The annual incidence of myeloma in the UK is approximately 60–70 per million with a median age at presentation of approximately 70 years; only 15% of patients are aged less than 60 years (Bird et al, 2011). Over the last two decades, there has been a significant improvement in myeloma survival in both young and old patients. A key-contributing factor to this has been the introduction of novel agents, which include the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor (PI) bortezomib. The introduction of these novel therapies has been shown to improve patient outcome, with those patients diagnosed in the last decade showing a 50% improvement in overall survival against patients diagnosed prior to this (44 8 vs. 29 9 months respectively) (Kumar et al, 2008). Thalidomide is an oral agent that has shown significant anti-myeloma activity in both pre-clinical and clinical studies. As a result, it is currently recommended as first-line treatment in both transplant–eligible and –ineligible patients (Bird et al, 2011). The mechanisms by which thalidomide exerts its antimyeloma effects are thought to include a combination of immunomodulation, anti-angiogenesis and pro-apoptotic effects (Chang et al, 2014). Given this broad range of actions, other organ systems can also be targeted, resulting in adverse effects. These have been well documented and include peripheral neuropathy, venous thromboembolism, skin rashes and constipation. Subsequently, recommendations have been published on supportive measures that can be used to counteract these adverse effects (Ghobrial & Rajkumar, 2003). However, other adverse effects have been recorded and noted as uncommon, including diverticulitis with associated bowel perforation (Kumar & Rajkumar, 2006). Recent figures have suggested that this occurs in <1% of patients receiving thalidomide, as confirmed by a report from the Food and Drug Administration (FDA) conducted between 2004 and 2012 (http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2014/020785s055lbl.pdf). These findings were contradicted by McClay and Cervi (2007) who reported four cases of bowel perforation in patients receiving thalidomide within a 2 year period. At the time it was suggested that thalidomide should be used with caution, particularly in patients with a known background of diverticular disease. However, the sample size was too small to deem this a clinically significant association and further studies were suggested. We are the first group to corroborate these findings, as a number of our myeloma patients receiving thalidomidebased regimens developed diverticulitis-associated bowel perforation while on this treatment. We performed a retrospective case series examining the written and electronic medical records for all patients receiving thalidomide either as a single agent or in combination regimens for multiple myeloma between 1 January 2007 and 31 December 2014 at Epsom and St Helier Hospital NHS Trust. Overall a total 118 patients received thalidomide-based regimens for newly diagnosed multiple myeloma during this time period, of which six (5%) developed diverticular-associated bowel perforation. Notably, three of these cases presented in the last 12 months. All six patients were receiving thalidomide and dexamethasone (TD) with either cyclophosphamide or bortezomib (CTD or VTD respectively). The median age for this group was 69 years (range 56–86 years) with an equivalent number of males and females (Table I). At the time of diagnosis, two patients were International Staging System (ISS) I while four were ISS III. The median number of cycles received was four (range 2 5–6) with five patients receiving 100 mg thalidomide with 20 mg dexamethasone while one patient was taking 200 mg thalidomide with 40 mg dexamethasone. All patients received thromboprophylaxis and, notably, none of them had a prior history of diverticular disease. By their acute presentation, five of the six patients had achieved a disease response, with one complete response (CR), one very good partial response (VGPR) and three partial responses (PRs), as per the International Myeloma Working Group response criteria (Durie et al, 2006). All 6 patients presented with abdominal pain and distension, with a median time to presentation of 24 d (range 14–37 d) from day one of their cycle. Notably, none of the patients were neutropenic at presentation with a median nadir count of 5 1 9 10/l (range 1 1–14 4 9 10/l). Computerized tomography imaging confirmed diverticular perforation and all patients were managed surgically with subsequent bowel biopsies confirming diverticulitis with no underlying dysplastic features. Five patients made a good post-operative recovery and were subsequently discharged. Of these, three received further treatment with one patient being recommenced on thalidomide-based combination therapy while the correspondence