clusions: These results demonstrate that relapsed multiple myeloma patients who respond to initial bortezomib treatment have a sustained susceptibility to bortezomib and do not experience uncommon toxicity to retreatment.

Bortezomib(Bo) was approved for therapy of relapsed Multiple Myeloma (MM) in 2003-for use in Germany 2004. There is growing evidence that combination of Bo with conventional chemotharapy agents could improve MM patients’ (pts) outcome(P.Richardson ASCO 2004). Bendamustin(Ben) is widely used for MM chemotherapy in Germany. In weekly low dose regimen it is well tolerated and highly effective in therapy of low grade lymphoma in elderly (K.Bremer ASCO2003, Abstract 2410). Ben has no cross resistances with other cytostatic drugs used in MM therapy, in low dose regimen it is well tolerated, has low bone marrow toxicity and no renal toxicity. We reported results of the combination therapy of the first 17 pts 2 years ago. Because of very good tolerability and high response rates we established the combination in our institution as a salvage-therapy for pts with relapsed MM after at least 2 previous chemotherapies. Till now we treated 40 pts - all white European-21 women, 19 men- median age 66 years (range 51–86). All pts had relapsed MM with clinical symptoms such as anemia, bone pain, progressive bone disease, several of the pts had renal failure (1 on hemodialysis). Previous therapies - median 4-(range 2–10)- included Melphalan, Dexamethason, VAD and sim. combinations, Cyclophosphamide, Bendamustin, Thalidomide, Bortezomib mono and in 3 pts tandem HD Melphalan. Therapy-regimen: Bortezomib 1–1,3 m/sqm d 1,4,8,11, Bendamustin 60mg/sqm d 1,8, Dexamethason 3x8mmg p.o. d 1–3 and 8–10 if tolerated, Ondansetron 8 mg i.v. d 1,4,8,11- q3w until best response- median number of cycles 4 (range 2–6). Early responses with symptom relief at begin of second cycle were frequently observed. Results (outcome according to SWOG criteria): ORR 85%, very good PR 25%(normal electrophoresis, normal level of free light chains in serum and urine), PR 47,5%, MR 12,5%. Remission duration in pts with at least PR- 8 Months (range 2–26 months)-19 pts are still alive. Toxicity: comprised fatigue and mostly mild thrombocytopenia without bleeding, reversible within 1 week. 8 pts had neuropathy and required symptomatic therapy with Gabapentine- most of them pretreated with Thalidomide. 9 pts had herpes zoster before aciclovir 3x400 mg daily was administered as prophylactic therapy. Conclusion: The therapy with combination Bortezomib- Bendamustin is highly effective, safe and well tolerated. The therapy is feasible in out-patient setting. The response rates suggest that the drugs act at least additive. We think therefore that further studies are warranted.

In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients. Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy. The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below. Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy (<= 6 months versus > 6 months) and by concomitant dexamethasone treatment. In patients with TFI > 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI <= 6 months (61.9%). Concomitant dexamethasone treatment was associated with a lower rate of clinical benefit (76.5%) than without (84.6%). For 44 patients (46.8%) a total of 125 adverse drug reactions (ADRs) were documented. 21 serious ADRs were documented in 11 (11.7%) patients. 30 patients had died at the time of analysis. 2 patients died due to adverse events (pneumonia and pulmonary oedema) assessed as at least possibly related to bortezomib. For one fatal outcome (pneumonia) causality assessment has not been provided. This binational retrospective survey suggests that the safety profile is in line with the current summary of product characteristics of Velcade and that high remission rates and durable TFIs can be achieved by bortezomib retreatment. A TFI > 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results. Initial bortezomib therapy (N=60) Bortezomib retreatment (N=60) * based on n=47 patients responding to bortezomib retreatment. Complete response (CR) 12 (20%) 8 (13.3%) Nearly complete response (nCR) 7 (11.7%) 3 (5%) Partial response (PR) 41 (68.3%) 27 (45%) Stable disease (SD) - (not allowed by selection criteria) 10 (16.7%) Progressive disease (PD) - (not allowed by selection criteria) 12 (20%) Median time to response 3.1 months 3.3 months* Median duration of response 6.9 months 6.1 months* Median treatment free interval 8.6 months 5.7 months

Bortezomib has been approved for recurrent or therapy-resistent multiple myeloma in 2003. There is growing evidence that combination therapy of bortezomib with other agents considerably improves results (Richardson P, ASH 2004). Bendamustine is an alkylating agent widely used in Germany for treatment of multiple myeloma and indolent lymphoma. There is no cross-resistance to other alkylating agents. Weekly low dose application is well tolerated and highly effective in elderly patients with pretreated indolent lymphoma (Bremer K, ASCO 2003, Abstract 2410). Treatment modalities: We treated 17 pts (8 female, 9 male, median age 70 yrs (range 51–82) with relapsed multiple myeloma. Previous therapies ranged from 2 to 7 (median 4), and included 15 x thalidomide, 2 x tandem high dose melphalan, 2 x bortezomib/dexamethasone. Therapy regimen: bortezomib 1 – 1.3 mg/m2 d 1,4,8,11; bendamustine 60 mg/m2 d 1+8, dexamethasone 3x8 mg orally d 1–3 and d 8–10: ondansetrone 8 mg intravenously d 1,4,8,11. Cycles were repeated q3w until best response. The median number of cycles applied was 4 (range 3 – 6). Results: Outcome was evaluated according to SWOG criteria. ORR: 88%; CR (neg. immunofixation): 12% (n=2); PR 58% (n=10); MR 18% (n= 3); NC 12% (n=2). Median remission duration was 6+ months (range 3–12+ months). Until today, we observed 4 recurrences after 3 – 8 months. Toxicity comprised mild fatigue and thrombopenia. Lowest platelet count was 55/pL without bleeding, spontaneously reversible within 1 week. Three cases of neuropathia occurred, with controllable symptoms, in patients pretreated with thalidomide or bortezomib mono. Conclusion: Combination therapy of bortezomib with low dose bendamustine is well tolerated, induces a high rate of responses in spite of unfavourable patient characteristics, leads to early responses and can be limited to 3 months (i.e., 4 cycles), and can be done in an outpatient setting. Thus, bendamustine is a very promising agent to enhance bortezomib action, which warrants further study.

Bortezomib (Velcade) has demonstrated highest single agent response rates in anti-myeloma therapy. There is no data from preclinical studies to suggest that resistance develops from repeated treatment with bortezomib. It was therefore of interest to investigate, whether repeated bortezomib treatment is safe, feasible and efficient. Here, we have retrospectively collected data from multiple myeloma patients who had previously responded to bortezomib (previous bortezomib treatment), presented with relapsed disease and who received bortezomib for a second time (retreatment). Treatment and retreatment had been on discretion of the physician according to prescribing information, and no diagnostic or therapeutic instructions were given during the course of this multicenter non-interventional survey (26866138MMY4014). Data from from a total of 15 centers and 65 patients were obtained: these patients had all received bortezomib and were eligible for safety analyses. Sixteen patients had to be excluded due to major protocol violations, leaving 49 patients for the modified intention to treat population. Patients had a median age of 66 years and had been treated with a median of 4 prior therapies before receiving bortezomib for the first time. Median cycle number for previous bortezomib therapy and retreatment was 5 and 4, respectively. The majority of patients (85.7%) received doses of 1.3 mg/m2 body surface area. Concomitant dexamethasone was given in 38.8% of patients with previous bortezomib treatment, and in 62.2% with retreatment. Six patients (12.2%) received various anti-myeloma therapies between bortezomib treatment and retreatment. Efficacy data is summarized below, revealing very encouraging responses and similar response durations for previous bortezomib therapy and retreatment. Thirty-three (50.8%) patients experienced a total of 109 adverse drug reactions (ADRs). Three (4.6%) patients experienced a total of 12 life-threatening or disabling ADRs and six (9.2%) experienced 13 severe ADRs (related to bortezomib = 6 SADRs). By the end of the documentation period, 21 patients had died (32.8%). This retrospective survey suggests that the safety profile of bortezomib retreatment is in line with the current SmPC of Velcade and that high remission rates can be achieved. It remains to be shown if these bortezomib retreatment results can be repeated in prospective trials and larger patient cohorts. Previous bortezomib treatment Retreatment Overall response rate 100% (per protocol) 63.3% Complete remission rate 12.2% 10.2% Time to response (median) 3.2 months 3.0 months Duration of response (median) 6.3 months 4.5 months Treatment free interval (median) 6.6 months 4.1 months Time to progression (median) 10.9 months 6.7 months