Bendamustine for the fourth-line treatment of multiple myeloma

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1 LONDON CANCER NEW DRUGS GROUP RAPID REVIEW Bendamustine for the fourth-line treatment of multiple myeloma Contents Summary 1 Background 2 Epidemiology 3 Cost 6 References 7 Summary There is no standard approach for the treatment of relapse in multiple myeloma and there are a number of options available. Thalidomide, bortezomib and lenalidomide (generally in combination with steroids ±alkylating agent) are most often used in the UK, and NICE has issued positive guidance on bortezomib (monotherapy at first relapse) and lenalidomide (in combination with dexamethasone; in those who have received at least two previous lines of therapy). The published evidence for bendamustine plus thalidomide and corticosteroids (dexamethasone or prednisolone) in the treatment of relapsed/refractory MM (an offlicense use) is limited to three small retrospective studies (n=9, 23, 30) and one Phase I clinical trial. A retrospective study including patients treated as part of a compassionate use programme in the UK reported clinical benefit (stable disease [SD] or better) in 61%. An overall response (complete or partial) was seen in 26% and minimal response in 17%. The median progression-free survival (PFS) for the overall group was 3 months (range 1-12) and the median OS was 13 months (range 1-17). A further retrospective UK audit, including patients who had previously received treatment with both bortezomib and lenalidomide, reported an overall response rate (partial response or better) in 41.7%, a median PFS of 2.4 months (0-11 months) and OS of 7.6 months ( months). Haematological toxicity with these regimens is frequent. The smaller study was an audit of nine patients with MM and renal impairment (four with relapsed disease) who received a regimen incorporating a different dose of bendamustine (fixed at 120mg on day 1) this resulted in a complete response (CR) in three patients (33%) a partial response (PR) in two (22%) and two (22%) had stable disease. Anaemia was reported in 8 patients (1 grade 3/4), thrombocytopenia in 2 (both grade 3/4) and neutropenia in 5 (1 grade 3/4; nil febrile). Produced for the London New Drugs Group Contact: Nicola Pocock Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Tel: Fax: Nicola.pocock@gstt.nhs.uk The optimal dose of bendamustine when combined with thalidomide and dexamethasone in the treatment of relapsed/refractory MM is yet to be defined and is being investigated in an ongoing Phase II study. The Phase I clinical trial included prednisolone rather than dexamethasone and evaluated escalating doses of thalidomide. The study reported 14% CR, 21% very good PR, and 50% PR, with median PFS and OS of 11 and 19 months, respectively. Only a small number of the patients included in this study had previously received thalidomide or bortezomib. The published data for bendamustine in combination with steroids in the treatment of relapsed/refractory MM is limited to two retrospective audits; in one (n=39) it was given in combination with steroids in 69% of patients and in the other (n=110) it was routinely administered with prednisolone. These reported ORRs of 30-36%. Findings from two further European compassionate use programs have recently been presented at conference these summarise the results of patients with relapsed/ refractory MM who received a number of different bendamustine-containing regimens after a median of four previous lines of therapy, and report ORRs of 29-30%. Produced for use within the NHS. Not to be reproduced for commercial purposes

2 Background Disease background Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in the bone marrow, leading to bone destruction and marrow failure (1). There were 4,784 new cases of MM diagnosed in the UK in 2009 and the annual incidence is approximately per million (6-7 per 100,000) (2, 3). It remains an incurable disease with current approaches, with an average survival of 4 to 6 years (5-year overall survival was 37% in ) and the goals of therapy are to control disease and maximise quality of life (2, 3). Although the introduction of new drugs has led to improvements in survival of patients with MM, much work is needed to determine the best sequence and combinations of therapies (3). The choice of initial treatment depends on factors such as age and performance status (4). High-dose chemotherapy (HDT) with autologous stem-cell transplantation (ASCT) is the first-line standard of care in those deemed biologically fit (aged 65 years with adequate performance status and organ function) (3). Where this is not feasible, treatment options include single agent or combination therapies (e.g. thalidomide-containing regimens or bortezomib in combination with melphalan and prednisolone). Although patients usually experience a period of remission following initial treatment, almost all will eventually relapse, and others have disease which is refractory to treatment (4). Guidelines on the diagnosis and management of MM were issued by the British Committee for Standards in Haematology (BCSH) in 2010 (3). These note that there is no standard approach for treatment at relapse because of disease heterogeneity and variability in patient-specific factors including co-morbidities and the persistence of toxicities related to previous therapy. In the UK, thalidomide, bortezomib and lenalidomide are most often used in treating relapsed patients; these are generally used in combination with corticosteroids (pulsed or weekly dexamethasone) and sometimes an alkylating agent, most commonly cyclophosphamide. The guideline does not make any recommendations on the use of bendamustine as this was in development at the time it was produced (3). Guidelines on MM from the National Comprehensive Cancer Network (NCCN) in the US comment that there are a number of options for salvage therapy; those that they list are based on combinations including bortezomib, lenalidomide and/or thalidomide, and some single-agents are recommended. Bendamustine is listed as a category 2a* treatment option for relapsed/refractory myeloma, both as monotherapy and when used in combination with lenalidomide and dexamethasone (its use in combination with thalidomide and dexamethasone is not discussed) (1). [*Category 2a recommendations are based on lower-level evidence, with uniform NCCN consensus that the intervention is appropriate] License status Bendamustine (Levact ) is licensed in the UK for the front-line treatment of MM (Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years who are not eligible for ASCT and who have clinical neuropathy at time of diagnosis precluding the use of thalidomide or bortezomib containing treatment (5). Its use in the treatment of relapsed disease would be off-license. NICE guidance NICE has not issued any guidance concerning the use of bendamustine in the treatment of MM. Although an appraisal of its first-line use in MM (as per license) was considered at a scoping workshop, it was noted that the marketing authorisation (anticipated at the time) restricts the population to approximately patients or less per year. In addition, workshop attendees indicated that there is no clinician demand for this drug as a first-line treatment. Therefore following the consultation exercise and the scoping workshop, the Institute was of the opinion that an appraisal of bendamustine for the treatment of advanced MM is not appropriate (6). The use of bendamustine in the treatment of relapsed MM is not licensed and therefore has not been appraised by NICE, nor by the AWMSG or the SMC. The following treatments have been recommended by NICE as options in the relapsed setting: 1. Bortezomib monotherapy is recommended as an option for the treatment of progressive MM in people who are at first relapse having received one prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation, under specified circumstances (7). 2. Lenalidomide in combination with dexamethasone is recommended as an option for the treatment of MM only in people who have received two or more prior therapies (providing the cost of treatment beyond 26 cycles is met by the manufacturer) (8).

3 Epidemiology The costing statement for the NICE guidance on lenalidomide in the treatment of relapsed MM states that the prevalence of MM in England is 0.02% (6,615 cases). It is assumed that 39% of these patients have relapsed disease and that 65% of these have received two or more prior therapies, which means that around 1,669 of the prevalent population are eligible for lenalidomide. The incidence of MM is 0.01% (3,243 new cases per year). Using the same assumptions as above, 819 of these patients will be eligible for lenalidomide (8). Bendamustine in combination with thalidomide and dexamethasone may be an option for patients who progress beyond lenalidomide- or bortezomib-based therapy, or may be used earlier in patients who are unsuitable for either of these therapies. Assuming that 50% of the population eligible for lenalidomide go on to receive fourth-line treatment, then this would work out as an incidence of 0.75 per 100,000 and a prevalence of 1.5 per 100,000. Published data for bendamustine, thalidomide and steroids in relapsed/refractory MM The published evidence for bendamustine plus thalidomide and corticosteroids (dexamethasone or prednisolone) in the treatment of relapsed/refractory MM is limited to three small retrospective studies (n=23, n=30, n=9) and one Phase I clinical trial. Grey-Davies et al retrospectively analysed the outcomes of 23 patients with relapsed/refractory MM who were treated with 28-day cycles of bendamustine (60mg/m 2 on days 1 and 8 [and 15 in first 10 patients; stopped subsequently due to haematological toxicity]), thalidomide (50-200mg daily) and dexamethasone (20mg on days 1, 2, 8, 9, 15, 16, 21 and 22) as part of a compassionate use programme in the UK between December 2008 and April 2010 (9). Patients were heavily pre-treated, with a median of five (range 3-7) previous lines of therapy. All had previously received thalidomide and the majority had also received bortezomib (n=21), lenalidomide (n=20), and HDT with autologous transplant (n=19). A median of three cycles of treatment were administered (range 1-6). A complete response (CR) was seen in one patient (4%), a partial response (PR) in 5 (22%), minimal response in 4 (17%) and stable disease (SD) in 4 (17%). As stable disease was considered by the authors to be a valid therapeutic goal in these patients, clinical benefit (at least SD) was seen in 61% overall. The median time to best response was 3 months (range 1-5). The median progression-free survival (PFS) for the overall group was 3 months (range 1-12) and the median OS was 13 months (range 1-17). As would be expected, OS was longer in those responding to treatment (15 months in those with at least SD versus 3 months in those progressing; p<0.001). Nine patients had grade 3/4 cytopenia at baseline (8 thrombocytopenia; 5 neutropenia) and an additional nine developed grade 3/4 haematological toxicity (5 thrombocytopenia; 7 neutropenia). Seven patients required hospitalisation for infection (5 of whom had progressive disease). Packed red cells (1-18 units), platelet transfusion (1-18 units) and G-CSF support was used in 15 patients each. Most nonhaematological toxicity was related to thalidomide, dexamethasone, or disease progression. The authors say that this regimen can be safely delivered to this patient group, with careful management, and they recommend that a 3-month trial be considered in those who have exhausted other treatment options. Ramasamy et al presented the results of a retrospective UK audit of use of bendamustine in combination with thalidomide (50-150mg daily) and steroids (dexamethasone-dosing equivalent of up to 160mg per cycle) for relapsed/refractory myeloma at the International Myeloma Workshop in (10). All 30 patients analysed had previously received treatment with both bortezomib and lenalidomide, and were refractory to their last treatment, and the majority had also received prior thalidomide (80%) and autologous transplant (80%). Bendamustine was administered on days 1, 8 ± 15 with a cumulative dose of up to 200mg/m 2. Six patients did not complete the first cycle of chemotherapy (reasons not stated) and these were excluded from the analysis. A median of 5 (2-9) cycles of therapy were administered in the evaluable patients, with an ORR of 41.7%. Median PFS was 2.4 months (0-11 months) and OS was 7.6 months ( months). Haematological toxicity was frequent, with grades 3/4 anaemia in 40%, neutropenia in 65%, and thrombocytopenia in 47%. Ramasamy et al retrospectively audited the use of a similar regimen in the treatment of nine patients with MM and renal impairment (CKD stage 3-5), four of whom had relapsed disease (two were refractory to their last treatment) (11). All of those with relapsed disease had undergone prior autologous transplant and one had relapsed following an allogeneic transplant. Two had received previous thalidomide and three prior lenalidomide, and one had been pretreated with bortezomib. The regimen consisted of bendamustine (120mg on day 1), thalidomide (100mg daily) and low-dose dexamethasone (20mg on days 1, 8, 15 and 22) given every 28 days; 4 of the 9 patients received the total of six cycles (no median stated).

4 This led to a CR in 3 (33%), a PR in 2 (22%) and SD in 2 (22%). One patient with CR was consolidated with an autologous transplant. Five of the seven patients with CKD stages 4 and 5 achieved a haematological response of PR or greater and three of the four patients receiving haemodialysis (HD) prior to receiving MM therapy became HD-independent. A significant renal improvement was observed in four patients. Anaemia was reported in 8 patients (1 grade 3/4), thrombocytopenia in 2 (both grade 3/4) and neutropenia in 5 (1 grade 3/4; nil febrile). Nonhaematological toxicity seen in at least two patients included somnolence, nausea, parasthesia, infection, and tremors. The authors suggest from their findings that bendamustine could be safely used in combination with thalidomide in patients with advanced stage CKD. Phase I study Ponisch et al conducted a Phase I study (n=28) which evaluated a fixed dose of bendamustine (60mg/m 2 on days 1, 8 and 15) and prednisolone (100mg orally on days 1, 8, 15 and 22) with escalating doses of thalidomide (50mg, 100mg or 200mg on days 1-28) in patients with relapsed or refractory MM following conventional chemotherapy or HDT with stem cell support (12). All patients had adequate WBC ( 3x10 9 /L) and platelet counts ( 75x10 9 / L) at baseline. They had received a median of 2 (range 1-6) previous treatments but there had been minimal prior use of thalidomide (2 patients) or bortezomib (4 patients) [patients were enrolled in so their previous treatment exposure would have been different to that used in current clinical practice]. The median duration of treatment was 5.5 cycles (range 2-10) and maximal response was achieved after a median of 4 months (range 1-6 months). A total of 24 patients responded after at least two cycles - 4 (14%) with CR, 6 (21%) with very good PR and 14 (50%) with PR - and the overall median PFS and OS was 11 (95% CI ) and 19 ( ) months, respectively. The two patients previously exposed to thalidomide had a PR and minimal response. Grade 3/4 neutropenia was reported in 12 patients, grade 3/4 leucopenia in 10, grade 3/4 anaemia in 5, and grade 3/4 thrombocytopenia in 2 patients. No grade 3/4 non-haematological adverse effects were reported. The authors say that doselimiting toxicity was not reached at any thalidomide dose studied and therefore the maximum tolerated dose was not defined. Ongoing Phase II study The optimal dose of bendamustine when combined with thalidomide and dexamethasone in the treatment of relapsed/refractory MM is yet to be defined and is being investigated in an ongoing Phase II study (MUKone) (13). Published data for bendamustine plus corticosteroids in relapsed/refractory MM The published evidence for bendamustine plus corticosteroids in the treatment of relapsed/refractory MM is limited to two retrospective audits; in one (n=39) it was given in combination with steroids in 69% of patients and in the other (n=110) it was routinely administered with prednisolone. Michael et al This retrospective study looked at the outcomes of patients with advanced MM (n=39) who were treated at a single institution with bendamustine between 2000 and 2005 (14). It included patients identified from pharmacy records to have received bendamustine (80-150mg/m 2 on days 1 and 2 of each cycle) for progressive disease after achieving a remission or stable disease to the previous therapy (46%) or for disease that was refractory to salvage therapy (54%). Patients had received a median of 2 (range 1-5) prior lines of therapy, including thalidomide (59%), HDT and ASCT (64%), and a second high-dose chemotherapy regimen as salvage therapy (23%). Bendamustine was given in combination with corticosteroids (prednisolone 100mg/day on days 1 to 5 or dexamethasone 40mg/day on days 1 and 2) in 69% of patients and as monotherapy in 31% of patients. Treatment cycles were repeated at a median time of 28 days (range: 14 to 90 days) until remission or disease progression (median number of cycles: 3; range 1-10). The main results reported were as follows: One patient (3%) experienced a very good PR and 13 patients (33%) had a PR, resulting in an ORR of 36%. Additionally, 7 patients (18%) had a minor response. The PR rate was not statistically significantly different in patients who received bendamustine with corticosteroids compared with monotherapy (40% vs. 25%) or in patients who received higher (120 to 150 mg/m 2 ) compared with lower ( mg/m 2 ) bendamustine doses (38% vs. 33%). The median event-free survival and overall survival times were 7 and 17 months, respectively. Serious adverse effects (grade 3 and 4) were primarily haematological and included neutropenia (41%), thrombocytopenia (26%), and anaemia (10%). Grade 3 and 4 infection occurred in 15% of patients overall; however, patients who received bendamustine with corticosteroids experienced more all grade (33% vs. 0%; p=0.04) and grade 3 or 4 (22% vs. 0%) infections compared with patients who received bendamustine monotherapy.

5 The authors comment that the 36% rate of PR is similar to that seen with other salvage therapies used in MM, including the novel agents (e.g. thalidomide; bortezomib). There were however no CR achieved and this is considered to be a key determinant of long-term outcome for salvage therapies. The event-free survival observed in this study is similar to that seen with bortezomib (event-free survivals for thalidomide and lenalidomide in the relapse setting have however apparently been longer). They comment on the favourable toxicity profile of bendamustine seen even in this heavily pre-treated population. Although the authors say that the lack of any difference in response between those receiving monotherapy and those receiving it in combination with steroids is noteworthy, this was a subgroup analysis including small patient numbers, conducted as part of a retrospective study, and therefore is hypothesis-generating only. Damaj et al This retrospective study describes experience from the use of bendamustine in the treatment of relapsed/refractory MM as part of a compassionate use program in France between April 2007 and December 2009 (15). The median number of previous treatments was 4 (range 1-9) and included steroids, alkylators and bortezomib in all, lenalidomide in 85%, and thalidomide-based therapy and anthracyclines in around half of the patients. In addition, 66 patients had received a previous autologous stem cell transplant. Bendamustine was administered at a dose of mg/m 2 for a median of four (range 1-13) 28-day cycles in combination with prednisone (variable doses used; range not stated). The recommended dose of bendamustine was mg/ m 2 on days 1 and 2 in combination with prednisone in 28-day cycles, but this could be modified according to the physician s choice. A total of 110 patients received at least one dose of bendamustine and were included in the analysis. The authors report that the overall response rate (CR or PR) was 30%, including a CR in 2 patients (2%). Disease stabilisation was seen in 20%, while 50% did not respond to bendamustine. Of note, 27% and 31% of the patients who were refractory to lenalidomide or thalidomide and bortezomib as their last therapy, respectively, responded. After a median follow-up of 10 months, the median duration of response had not been reached, and 66% of responding patients remained in response more than 6 months from the beginning of bendamustine therapy. The median PFS and OS for the entire cohort were 9.3 months and 12.4 months, respectively. The authors note that this is the largest retrospective series reported to date on the use of bendamustine in relapsed/refractory MM. These patients were heavily pre-treated and the majority were refractory to their last line of therapy, and all had been exposed to all available effective drugs prior to treatment with bendamustine [similar to the case being considered]. They acknowledge that the retrospective nature of the study is associated with a number of limitations (including the use of various doses and various steroid combinations), but they consider their findings to be encouraging (they also note that the response rate compares favourably with those seen in association with use of other agents in the relapsed/refractory setting). Further data on bendamustine-containing regimens from compassionate use programs The findings of retrospective studies looking at the use of bendamustine in patients with relapsed/ refractory MM as part of two other compassionate use programs (in Spain and Italy) were presented at the 2012 ASH Annual Meeting. The Spanish study included 72 patients who had received a median of 4 (1-11) previous salvage therapies (16). They were treated with a range of bendamustine-containing regimens (with bendamustine dosed at mg/m 2 on days 1 and 2 of each cycle) but only overall responses of the entire group are presented in the abstract. With a median of 2 (1-9) cycles of treatment, the overall response rate was 30%, including a CR in 11% and a PR in 13%. Minimal response was seen in a further 6% and SD in 17%. The most common adverse effect was haematological toxicity, with grade 3-4 neutropenia in 32%, grade 3-4 thrombocytopenia in 30% and grade 3-4 anaemia in 17%. Other toxicities included grade 3-4 infections in 27% of patients and grade 3-4 asthenia in 12%. The Italian study included 78 patients who had received a median of 4 (range 1-10) previous lines of therapy (17). The majority (97%) had previously received bortezomib, 94% immunomodulatory drugs (IMIDs; thalidomide or lenalidomide), 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, and 64% had undergone stem cell transplantation (mainly autologous). 73% of patients were resistant to the last therapy received, while 27% had relapsed. In around half of patients, bendamustine was administered in combination with bortezomib (23%), IMIDs (21%) or a combination of both (3%). With a total of 236 cycles administered (median 3, range 1-9 per patient), there were 3 CR, 1sCR, 1 very good PR and 16 PR, for an ORR of 29%. The ORR was 10% (4/39) in bendamustine single agent +/- steroids, 38% (5/13) in bendamustine plus bortezomib and 62% (10/16) in bendamustine plus IMIDs subgroups, respectively. The rate of response was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months.

6 After a median follow-up of 8 months, median PFS was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non-responders, range 0-27). Grade 3-4 haematological and non-haematological toxicities occurred in 56% and 15% of patients, respectively. Cost The UK compassionate use study described the use of the following schedule: bendamustine 60mg/m 2 on days 1 and 8, dexamethasone 20mg on days 1, 2, 8, 9, 15, 16, 21 and 22, and thalidomide mg daily (28-day cycles). Based on this, the cost per cycle for an average of 1.8m 2 BSA is as follows (the cost of dexamethasone has not been considered as this will be minimal): Bendamustine: 60x1.8 = 108mg per dose = 1x100mg vial and 1x25mg vial = 415 incl. VAT; for two doses (one cycle) this would be 830 Thalidomide: Assuming 100mg daily, this would be 2x28x50mg capsule pack = 715 incl. VAT per 28-day cycle Based on the assumptions of the eligible population detailed in the epidemiology section, use of this regimen would be associated with a non-recurrent cost of 13,905 per 100,000 (to treat the prevalent population) and a recurrent cost of 6,950 per 100,000 per year (to treat the incident population). Patients who have relapsed after bortezomib, an alkylator (melphalan or cyclophosphamide) and an IMiD may receive a range of possible treatments. As an example, if this regimen is compared to the use of the same regimen without bendamustine (thalidomide plus dexamethasone; recommended as one of many salvage options in the NCCN guideline), then there would be an additional nonrecurrent cost of 7,470 per 100,000 and a recurrent cost of 3,735 per 100,000 per year. Service implications There are a range of possible regimens that are used in the relapsed/refractory setting. The use of bendamustine instead of an oral regimen would be associated with two additional outpatient visits per cycle for intravenous administration. A total of six cycles would therefore cost 9,270. Summary of Costings Drug Indication Incidence (number of patients per 100,000 eligible for this treatment) Average duration of treatment (taken from trial data) Cost per month/ cycle Cost per 100,000 population per month/ cycle Cost per 100,000 for average treatment duration Bendamustine dexamethasone and thalidomide Relapsed multiple myeloma (fourthline) 0.75 Six cycles 1,545 1,160 6,960 Details of search strategy: EMBASE: exp BENDAMUSTINE/ AND exp *MULTIPLE MYELOMA/ MEDLINE: bendamustine.af AND exp *MULTIPLE MYELOMA/ Other sources checked: In-house enquiry database; Electronic Medicines Compendium (accessed 1/3/13); National Electronic Library for Medicines (accessed 4/3/13); NICE (accessed 4/3/13); British Committee for Standards in Haematology (accessed 1/3/13); National Comprehensive Cancer Network professionals (accessed 1/3/13); Martindale via (accessed 1/3/13); Micromedex Healthcare Series (accessed 1/3/13) The following studies were located but were excluded as they were not directly relevant to the intervention under consideration: studies of the first-line setting; bendamustine monotherapy in any setting; bendamustine in combination with lenalidomide (±steroids)

7 References 1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Multiple Myeloma (version 1, 2013) 2. Cancer Research UK myeloma statistics cancerstats/types/myeloma/ (accessed 19/12/12) 3. British Committee for Standards in Haematology in conjunction with the UK Myeloma Forum (UKMF). Guidelines on the diagnosis and management of multiple myeloma MYE- LOMA_Mngmt_GUIDELINE_REVISION_Sept_2 010.pdf 4. NICE: Bortezomib and thalidomide for the firstline treatment of multiple myeloma - Final scope (May 2009) pdf/ BortezomibThalidomideMultipleMylelomaScope.pdf 5. Levact SPC (last revised 3/8/2010) 6. Consultation on Batch 10 draft remits and draft scopes - Summary of comments and discussions at scoping workshops (July 2010) Batch10BlockScopingReport.pdf 7. NICE TA129 (October 2007): Bortezomib monotherapy for relapsed multiple myeloma publications.nice.org.uk/bortezomibmonotherapy-for-relapsed-multiple-myelomata NICE TA171 (June 2009): Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy publications.nice.org.uk/lenalidomide-for-thetreatment-of-multiple-myeloma-in-people-whohave-received-at-least-one-prior-ta Grey-Davies E et al (2012) Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. Br J Haematol; 156(4): Ramasamy K et al (2013) Bendamustine combination therapy in patients relapsed and/ or refractory to bortezomib and lenalidomide. Abstract presented at the International Myeloma Workshop, (P-310) [supplied by Napp Pharmaceuticals Limited] 11. Ramasamy K et al (2011) Bendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal disease. British Journal of Haematology; 155(5): Ponisch W et al (2008) Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. British Journal of Haematology; 143: Bendamustine, thalidomide, dexamethasone dose escalation study in relapsed/refractory myeloma (MUKone study) Michael M et al (2010) Bendamustine in patients with relapsed or refractory multiple myeloma. Eur J Med Res; 15(1): Damaj G et al (2012) Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukemia & Lymphoma; 53 (4): Bueno BA et al (2012) Preliminary experience of the Spanish compassionate use registry of bendamustine in patients with relapsed and/or refractory multiple myeloma. Blood; 120(21) 17. Musto P et al (2012) Bendamustine as salvage therapy in multiple myeloma: A retrospective, multicenter study from the Italian compassionate use program in 78 heavily pre-treated patients. Blood; 120/21 Please direct any comments to Nicola Pocock, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: mailto:nicola.pocock@gstt.nhs.uk The document reflects the views of LCNDG and may not reflect those of the reviewers