Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.
Background The combination of immunomodulatory drugs (IMiDs(r)) and alkylating agents have significantly improved outcomes of patients with relapsed or refractory multiple myeloma (RRMM). Bendamustine, an agent sharing properties of alkylators and purine analogous, and lenalidomide, an immunomodulator drug, are highly effective for the treatment of lymphoprolipherative disorders. Some clinical trials have shown good responses to the combination of bendamustine with steroids and novel agents (thalidomide, lenalidomide and bortezomib) for the treatment of RRMM (Knop S 2005, Lentzsch S 2012, Pönisch W 2013), but further research is needed to confirm the best combination, the optimal schedule of administration, and to better define the safety profile. Method A multicenter phase I/II trial tested the combination of escalating doses of bendamustine and lenalidomide, and a fixed dose of dexamethasone (BdL) in repeating 4-weeks cycles as treatment for RRMM. The drug dosages were chosen taking into account the haematological toxicity of both, and that patients were heavily pretreated. The phase I trial was conducted using a 3+3 cohort design beginning at a dose level 0 of intravenous bendamustine 40 mg/m²/day, days 1 and 2, oral lenalidomide 10 mg/day, days 1-21 and oral dexamethasone 40 mg/day, days 1, 8, 15, and 22 every 4 weeks. Patients were treated for 4 cycles + 2 cycles if the response was stable disease (SD) or better. In the phase II study patients were treated at the maximum tolerated dose (MTD) to evaluate the antimyeloma activity of BdL. Endpoints of the study included safety profile, overall response rate (ORR), progression-free survival (PFS), duration of remission (DR) and overall survival (OS). Results A total of 41 patients (17 in phase I, and 24 in phase II) were enrolled between October 2011 and July 2013. Four patients withdrew their informed consent: 3 before starting treatment and 1 after the fifth cycle. Twenty-eight out of 37 are currently evaluable. Median age of these patients was 68 (43-87 years), with a male/female ratio of 12/16. Sixteen patients had IgG MM, 10 had IgA, and 2 patients had light chain MM. Median number of previous treatments was 3; 9 patients were previously treated with thalidomide and 6 with lenalidomide; 19 with bortezomib and 11 underwent autologous stem cell transplant. The MTD established by the phase I study was dose level 0. To date, with a median follow up of 10 months, ORR is 50% (3 CR, 2 VGPR, 9 PR) and 1 SD. The median OS has not been reached yet. One-year OS is 78% (95% confidence interval [CI], 57%-89%). Median PFS is 10 months (95% CI, 5-12 months) with one-year PFS of 40% (95% CI, 21%-59%). Median duration of remission is 9.6 months with one-year DR of 44% (95% CI, 12%-73%; Figure 1). Toxicity data was available for 32 pts. Grade 3/4 adverse events (AEs) observed in ≥ 10% of patients included neutropenia, thrombocytopenia and anemia. The major non-hematological toxicity was renal dysfunction (6%). A total of 8 pts died during the study: 5 due to toxicity and 3 for progression of disease. Conclusions This study confirms that the combination of bendamustine with lenalidomide and low dose dexamethasone is effective in RRMM patients, even when administered after regimens containing novel agents. The dose of bendamustine in our study is lower (40 mg vs. 75 mg) that of previously published data (Knop S 2005, Lentzsch S 2012, Pönisch W 2013). However, we would like to emphasize that in our both phase I and phase II study we observed a consistent toxicity even utilizing 40 mg of bendamustine and 10 mg of lenalidomide. The toxicity was mainly hematological. Thus far, age, number of previous treatments, or the previous use of alkylating agents did not correlate with observed toxicity. In conclusion with a 50% ORR and 3 CR this is a very promising therapeutic option in RRMM requiring careful management of the patients. Disclosures: No relevant conflicts of interest to declare.
1611 Introduction: For many T-cell lymphoma (TCL) patients (pts), current treatment strategies are largely ineffective. In particular, pts failing first line therapy are expected to have a dismal outcome but little is known about them. The purpose of this population-based study was to establish the outcome of TCL pts following relapse/progression. Material and methods: All TCL pts diagnosed in the province of Modena, Italy between January 1, 1997 and December 31, 2010 were identified from the archives of the Modena Cancer Registry that covers a population of approximately 600.000 people. Additional data on disease characteristics, treatment modalities, together with response assessments and outcome were actively retrieved and collected. Results: A total of 146 TCL pts were initially identified, and 18 excluded because of missing data; therefore 128 were available for the present analysis. The most common subtypes were Peripheral T-cell lymphoma not otherwise specified in 46 pts (36%), Anaplastic large T-cell lymphoma in 46 patients (36%) Angioimmunoblastic T-cell lymphoma in 15 (12%), and other subtypes in 21 (16%). The male to female ratio (M/F) for the entire population was 1.7 and the median age was 64 years (16–90). A total of 100 (78%) pts received initial treatment within 3 months of their diagnosis: 74 received combination chemotherapy (CT), 9 received radiation therapy (RT) only, 10 underwent surgery and 7 were addressed to high dose therapy and autologous stem cell transplant (ASCT) as part of initial therapy. Among the remaining 28 patients, 24 (19%) died within 3 months of their diagnosis and 4 (3%) received only palliative therapy because of their comorbidities. The majority of pts received anthracyclines (ADM) containing regimens as part of their initial therapy (71/74, 96%). At the end of first line treatment, 59 (59%) pts achieved complete remission (CR), 13 pts partial remission (PR), 8 pts stable disease (SD) and 20 cases had disease progression (PD). Overall, 59 pts presented relapse/progression; 23 (39%) of them died before receiving any salvage treatment, 14 pts received DHAP (7 of whom were subsequently addressed to ASCT), 8 received gemcitabine-containing regimens, 6 received ADM containing regimes and 8 other CT regimens; 2 patients were treated with RT. At a median follow-up for living patients after relapse/progression of 28 months (range 9–111 months), 49 patients died, and the cause of death was found to be lymphoma progression in all of them. The median overall survival (OS) following relapse/progression was 1.9 months. Among the 36 pts that received salvage treatment median OS was not reached for those who received ASCT and was 4.5 months for those who received conventional dose salvage treatment (p=0.003). A Cox regression analysis was performed in order to identify prognostic factors among these 59 pts: age at relapse (≥60 years, HR=2.35, CI95% 1.04–5.28, P=0.038) and advanced stage (HR=3.24, 1.31–7.98) were associated with a higher risk of death and salvage treatment ASCT was associated with a better survival (HR=0.04, IC95% 0.006–0.36). No other clinical characteristic (gender, histology, LDH and performance status) at diagnosis was associated with higher risk of death among relapsing/progressing patients. Conclusion: In the general population, outside clinical trials, the outcome of TCL pts is dramatically poor. First, about 20% of the whole cohort is not able to receive any kind of therapy mainly due to early death; second, the rate of pts failing first line therapy that could not receive any salvage therapy rose to 39%. As a result, progression during initial therapy or relapse after first line treatment entails a very dismal prognosis with less than 2 months of median survival. Only a few patients that could receive ASCT after relapse had promising chances of long lasting remission. Based on the results of this population based study, it is evident that there is urgent need for novel agents to be offered to TCL pts requiring second line treatment. Disclosures: No relevant conflicts of interest to declare.
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