ALBERT

Description: Background: Acute renal failure (ARF) is a frequent complication of multiple myeloma (MM) and most frequently due to clonotypic light chains (LC) causing cast nephropathy, which is associated with fast deterioration of renal function, increased risk for infections and shortened survival. Here we present the final results of a phase II study employing lenalidomide-dexamethasone as treatment for patients with acute light-chain induced ARF. Patients and methods: 35 patients with LC-induced ARF have been enrolled. Cast nephropathy was confirmed in all 15 patients who had a renal biopsy. Patients with previously unknown MM must have presented with eGFR 〈 50ml/min and serum creatinine ³2.0mg/dL, and those with previously established diagnosis must have had documented eGFR ³ 60ml/min and serum creatinine ≤1.2mg/dL within 6 weeks before deterioration of eGFR to 〈 50ml/min and of serum creatinine to ≥ 2mg/dL due to LC-induced kidney injury. Nine cycles of Lenalidomide, day 1-21, q28 days, with dose adaptation according to eGFR (eGFR 30 – 50ml/min: 10 mg daily, eGFR 〈 30ml/min without requiring dialysis: 15mg q 48 hrs., eGFR 〈 30ml/min requiring dialysis: 5 mg daily following each dialysis) and dexamethasone (Dex), 40 mg, day 1-4, 9-12 and 17-21 during the first cycle and thereafter 40 mg once weekly were planned. Renal response was defined as previously described (Dimopoulos et al, Clin Lymphoma Myeloma. 2009, Ludwig et al. JCO 2010). Results: Patient's median age was: 66 (45-87), 28 patients had newly diagnosed and 7 previously established MM. 5.7% had ISS stage II, 94.3% stage III. 18 patients had light chain myeloma, 14 IgG, and 3 IgA isotype. Adverse cytogenetics t (4; 14) ± del17q ± 1q21 were detected in 14/29 patients. 4/35 patients died and 5 discontinued therapy (3 due to AEs, 1 due to PD, and 1 due to withdrawal of consent) within the first 2 cycles, leaving 26 patients for per protocol (PP) analysis. Median follow up was 17.7 months. Responses were seen in 25/35 (71.4%) patients; 7 (20%) had CR, 3 (8.6%) VGPR, 14 (40%) PR, and 1 (2.9%) MR. Median time to first and to best myeloma response was 28, and 92 days, respectively. Median baseline concentration of involved FLC was 5.465mg/L (range: 147–42.700mg/L) and 8350mg/L (range: 234– 35.500mg/L) in patients reaching ≥PR and ≤MR, respectively, and decreased significantly to a median of 95.75mg/L (range: 11.3–5.630mg/L, p

Description: In this study we compare the efficacy and toxicity of double T with M 200 with triple T using M 100 in newly diagnosed pts with MM. 175 pts have as yet been enrolled and 135 have been randomized after VAD induction treatment and stem cell collection to either tandem or triple transplantation. Reasons for non-randomization were too early for T (n=22), PD after induction (n=5), early death (n=3), toxicity (n=3), pt. refusal (n=3), and others (n=4). Median age of the 135 pts randomized was 59 years (range: 27–70 years). Stage I: 8%, stage II: 17%, stage III: 75%, Paraprotein Isotypes: IgG: 55%, IgA: 25%, IgD: 2%, IgM: 1%, Light chain: 17%. Induction treatment: 3 cycles of VAD; stem cell priming: IEV (ifosfamide (2g/m2)-etoposide (150mg/m2), d1–3; epirubicin (50mg/m2), d1) and G-CSF (5mg/kg) from d4. Conditioning regimen: M 200 mg/m2 or M 100 mg/m2 plus G-CSF; day 5 until WBC 〉2000/ml. Pts with ≥ SD after T were subsequently randomized to interferon 3MU, TIW (Schering Plough) plus prednisone (25mg, po., TIW), or interferon alone. QoL was assessed with the EORTC QLQ C30 instrument. Chi2 test for trend was used for comparison of response and survival endpoints were estimated by the Kaplan-Meier product limit method. Response rates after VAD were CR: 11%, PR: 65%, SD: 22% and PD: 2%. Median time from start of VAD to start of T was 137 in the double and 139 days in the triple T arm. Response rates did not differ between pts treated with double or triple T (CR: 47% vs. 43%, PR: 47% vs. 47%, SD 2% vs. 6%, PD: 4% vs. 4%, p=0.60, respectively). Median PFS for both groups combined was 36 mos, but showed a tendency for shorter PFS in pts on triple T (23 mos. vs. 37.5 mos; HR 1.26, 95% CI: 0.72–2.23, p=0.21). Median of OS has not been reached yet, but did not differ between both groups. Hematological toxicity was similar in both groups. There was a tendency for more grade 2–4 mucositis and for grade 3–4 vomiting, nausea, and fatigue in the double T group. Global QoL (questions 29 and 30) was comparable between both groups, before (5 (2.5–6.5) vs. 5 (4.5–6)) and after double (5.8 (3–8.5) or triple T (6 (2.5–7)). In conclusion, triple T with intermediate dose M resulted in similar response rates, slightly shorter PFS but similar OS and was associated with less mucositis and slightly less vomiting, nausea and fatigue. Progression-free survival by randomization group Progression-free survival by randomization group

Description: Key PointsBendamustine-bortezomib-dexamethasone is active and well tolerated in relapsed/refractory myeloma.

Description: Abstract 943 Introduction: Bendamustine has emerged as attractive treatment option for low grade lymphomas and seems to exert synergistic activity with bortezomib. Here we evaluate the efficacy and tolerance of bendamustine in combination with bortezomib-dexamethasone in patients with relapsed/refractory multiple myeloma and focus on individual factors associated with outcome. Patients and Methods: 74 patients with relapsed/refractory MM have been enrolled. Median age: 65 years (range 40–86), male/female: 34/40, ISS stage I/II/III: 24, 30, and 20, respectively. ECOG status 0/I/II: 39, 32, and 3 patients, respectively. Previous treatment lines: 1–2: 48, 3–4: 21, 〉4: 5 patients, respectively. Full data documentation for response evaluation (≥ 2 cycles) is available for 66 patients. Treatment regimen: bendamustine 70 mg/m2 day 1+4, bortezomib 1.3 mg/m2days 1, 4, 8 and 11, dexamethasone 20 mg on days 1, 4, 8 and 11, repeated every 4 weeks. Planned number of treatment cycles was 8, with discontinuation after 4 cycles in case of no response. Kaplan Mayer curves were compared using the log-rank test and Cox regression was used for univariate and multivariate analysis of possible prognostic factors (FISH, age, LDH, Hb, Ca, pretreatment with lenalidomide, bortezomib and both lenalidomide+bortezomib). Results: After a median follow up of 8.9 months, myeloma response (ORR: CR+VGPR+PR) was noted in 43 (65.2%) of the 66 evaluable patients. 14 (21.2%) patients achieved CR/nCR, 11 (16.7%) VGPR, 18 (27.3%) PR, 10 (15.2%) MR, and 13 (19.7%) remained stable; PD was not observed within the first 4 cycles. Median time to response was 108 days (3.65 months). Responses (CR-PR) were seen in 14 of 24 (58.3%) of patients with FISH determined high risk [ampl.1q21, del17p, t (4; 14)] and in 23 of 33 (69.7%) with standard risk (del13 or no aberration) cytogenetics (p=0.84). ORR (CR-PR) was 69.7% (30 of 43) and 56.5% (13 of 23) in patients with 1–2 or 3–6 prior treatment lines, respectively (p=0.77). Median PFS was 9.7 months in the entire cohort and 12.9 and 7.8 months in patients with 1–2 or 3–6 prior treatment lines. Median overall survival in the entire cohort was 21 months. Univariate analysis showed a significant impact of pre-treatment with lenalidomide + bortezomib on response rate (p

Description: A single nucleotide polymorphism (SNP) responsible for lactase persistence (LCT −13910C〉T) changes intestinal microflora. Considering the influence of bacterial microflora on various immune effects, we tested DNA from 111 recipients/donors and analyzed whether this SNP interferes with survival and the incidence of acute graft-versus-host disease (aGVHD) after allogeneic hematopoetic stem cell tranplantations (HSCT). Median overall survival (OS) was significantly longer when donors had a CC genotype (not reached after 133 vs 11.1 months, P = .004). Multivariate analysis identified a donor T allele (hazard ratio 2.63, 95% confidence interval 1.29-5.33, P = .008) as independent risk factor for death. Surprisingly, recipient genotypes did not influence outcome and there were no differences regarding aGVHD. Transplantation-related mortality (TRM), relapse and pneumonia were significantly less frequent in patients with CC donors. These findings add to the growing list of non-HLA polymorphisms with impact on outcome after allogeneic HSCT.

Description: Previous studies showed a survival advantage of double over single transplantation in proportion of patients. In this study we aimed to explore whether triple transplantation with intermediate melphalan 100mg/m2 (M100) yields at least similar treatment results with less toxicity than double transplantation with melphalan 200mg/m2 (M200). 219 Patients were entered in the study and started on 3 cycles of VAD induction therapy followed by IEV (ifosfamide (2g/m2)-etoposide (150mg/m2), d1-3; epirubicin (50mg/m2) d1) and G-CSF (5mg/kg) from d4 for stem cell priming and collection. Thereafter, 178 patients were randomized to either double or triple transplantation with M200 or M100. Reasons for non-randomization were PD (n=21), toxic side effects during induction or insufficient mobilization (n=9), withdrawal of consent (n=3), too early (n=1), death (n=1), second neoplasia (n=1), protocol violation (n=2), other (n=3). Patients achieving better than PD had subsequently been randomized to prednisolone plus interferon-a2b (Schering Plough) 3MU TIW or to interferon only maintenance therapy. Median age was 58 years (range: 27–71 years, n=172). DS stage I: 7%, stage II: 18%, stage III: 75%, M-component: IgG: 60%, IgA: 24%, IgD: 1%, IgM: 1%, light chain: 11%, non-secretory:1%. QoL was assessed with the EORTC QLQ C30 instrument. Chi2 test for trend was used for comparison of response and survival endpoints were estimated by the Kaplan-Meier product limit method. Median follow up is 34 months. Response rates in 186 patients evaluable for response after VAD (≥ 2 cycles of VAD) were: CR: 10%, PR: 58%, SD: 21% and PD: 11%. Median time from start of VAD to start of transplantation was 141 in the double and 144 days in the triple transplantation arm. Response rates after transplantation did not differ between pts treated with double or triple transplantation (CR: 41% vs. 41%, PR: 50% vs. 49%, SD 8% vs. 8%, PD: 1% vs. 3%, p=0.91. Median PFS for both groups combined was 39 mos, but showed a tendency for shorter PFS in pts on triple transplantation (median 44 mos. vs. 38 mos; HR 1.18, 95% CI: 0.77–1.81, p=0.22). Median OS has not been reached as yet, but did not differ between both groups with 3-year rates of 85% and 81%, respectively, and a HR of 1.01. Except for more cases of grade 1 and 2 anemia in the triple transplantation arm, hematological toxicity was similar in both groups. There was a tendency for more grade 2–3 mucositis and grade 3–4 vomiting, nausea in the double transplantation group. In conclusion, triple transplantation with intermediate dose M resulted in similar response rates, slightly shorter PFS but similar OS and was associated with less mucositis and slightly less vomiting, and nausea. Figure Figure

Description: Abstract 2928 Introduction: Bendamustine, an alkylating drug with purine like activities may exert synergistic activity in combination with bortezomib. Here we analyze the efficacy and tolerance of bortezomib-bendamustine-dexamethasone with particular focus on possible discrepancies between patient and physician assessed neuropathic symptoms. Patients: 45 patients with relapsed/refractory MM have been enrolled. Median age: 64 years (range 40–86), male/female: 17/28, ISS stage I/II/III: 14, 16, and 15 patients, respectively. ECOG status 0/I/II: 25, 22, and 2 patients, respectively. Previous treatment lines: 1–2: 25, 3–4: 16, 〉4: 4 patients, respectively. Full data documentation for response evaluation (≥ 2 cycles) is available for 33 patients. Treatment regimen: Bendamustine 70 mg/m2 day 1+4, Bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, Dexamethasone 20 mg on days 1, 4, 8 and 11, repeated every 4 weeks. For assessment of neuropathic sides effects the FACT-GOG/NTX self assessment instrument was used. Efficacy: After a median follow up of 4.7 months, myeloma response (ORR: CR+VGPR+PR) was noted in 17 (51.5%) of the 33 evaluable patients. 5 (15% of) patients achieved CR, 2 (6%) VGPR, 10 (30%) PR; 10 (30%) MR, and 6 (18%) remained stable, while PD was noted in 6 (18% of) patients. Median time to response was 82 days. Responses were observed in 48.1% of patients previously exposed to bortezomib and in 47.1% pretreated with lenalidomide. Responses were seen in 53.8% of patients with high [ampl.1q21, del17p, t (4; 14)] and in 53.8% with standard risk (del13 or no aberration) cytogenetics. Median PFS is 9, 4 months; median overall survival is not reached at present (figure). Tolerance: The regimen was well tolerated with low incidence of infections and gastrointestinal toxicities. Hematological toxicity remained stable from baseline to cycle 4, with G4 anemia, leucopenia and thrombopenia being recorded in 〈 5%. Patient self reported neuropathic symptoms at baseline were recorded as G1–2 in 57% and as G3–4 in 17%, respectively. This pattern remained stable from cycle 1 to 4. In contrast, physician assessed neurotoxicity G1–2 was documented in only 18% of patients at baseline. During the following 4 cycles physician assessed PNP remained constant in almost all patients with only 3 patients developing G3 PNP. G4 PNP was not reported. Conclusions: The BBD regimen yielded a response rate of 52% and a PFS of 9.6 months in heavily pretreated myeloma patients. Substantial response rates were noted in patients pre-exposed to bortezomib (33.3%) and lenalidomide (36.4%) Patient self assessment of neuropathic symptoms revealed a much higher incidence of G1–2 and G3–4 symptoms than physician assessment. Physician assessment of neurotoxicity may underestimate neurologic symptoms associated with disease or neurotoxic treatment. Disclosures: Ludwig: Mundipharma, Janssen-Cilag: Research Funding, Speakers Bureau. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

Description: Abstract 4031 Introduction: Excessive production of free light chains with affinity for uromodulin results in protein aggregates and toxic injury of distal renal tubules. The ensuing renal failure is a significant risk factor for infections, dependency on chronic hemodialysis and reduced survival. Management of this emergency includes rapid confirmation of the diagnosis and prompt installment of effective anti-myeloma therapy. Here, we assess the efficacy of lenalidomide-dexamethasone for treatment of patients with LC-ARF. Patients and Methods: 32 patients with LC-ARF as formerly defined (J. Clin. Oncol. 2010 20; 28(30):4635-41) have been enrolled so far. Age (median): 66 years (range: 46–87 years), Gender: male/female: 17/15. All patients presented with ISS stage III. 26 (81.3%) had de novo MM and 6 (18.8%) previously treated, but relapsing disease. Median GFR was 19.9 ml/min (range 6.1 – 37.2 ml/min). ECOG performance status was 0 in 9, I-II in 18 and III-IV in 5 patients, respectively. Lenalidomide was given from d 1–21 with dose adaptation according to GFR as suggested in the prescribing information. Dexamethasone 40 mg was administered on d 1–4, 9–12, 17–20 during cycle 1; thereafter 1x/week. Cycles were repeated q 4 weeks. Results: Presently, 23 patients are evaluable for response (completed ≥2 cycles and fully documented). The median follow-up is 7.7 months, median number of cycles is 9 (range 2–9). CR was achieved in 5 (21.7%), nCR in 1 (4%), VGPR in 2 (8%) and PR in 13 (52%) patients, MR in 1 (3%), respectively, yielding an ORR (CR+nCR+VGPR+PR) of 91.3% for evaluable patients and 65.6% for the ITT population. Median time to first myeloma response was 28 (range 27–63 days) and to best response was 113 days (34–304 days). The cumulative incidence of all patients with myeloma and renal responses are shown in figure 1. Median PFS and OS were 13.8 and 31.2 months respectively in the evaluable patients and 7.4 and 31.2 months in the ITT population. Renal response was assessed as formerly defined (J Clin Oncol. 2010 20; 28(30):4635-41). 4 patients achieved CRrenal, 8 PRrenal and 3 MRrenal, yielding an ORRrenal in 15 patients (65.2% of the evaluable and 46.9% of the ITT population). Median time to first renal response was 28 (range: 27–34) days, and to best renal response 119 days (34–304 days). 5 of 13 dialysis dependent patients became dialysis independent. Median GFR of evaluable patients increased from 15.2 (range 6.1 – 35.1 ml/min) at baseline to a median best GFR of 31.4 ml/min (range 11.3 – 103.2 ml/min). In the 5 patients with CR a significant increase in GFR (median 26.7 to 60.9 ml/min) and in the 16 patients with nCR/VGPR/PR an increase from 13.5 to 30.1 ml/min was observed. Full documentation of adverse events is presently available in 32 patients. 5 patients died within the first 2 months, 2 (8.7%) each due to infection and cardiac arrest and 1 (4.3%) with apoplexia. Grade 3/4 anemia, thrombopenia and leucopenia, were seen in 17 (53.1%), 9 (28.1%), and 5 (15.6%) patients, respectively. Other common grade 3/4 toxicities were infection/sepsis in 13 (40.6%), and cardiac dysfunction in 8 (25%) patients, respectively. Exanthema G3 was seen in 3 patients (9.3%), pulmonary embolism, macula edema and multiple stroke syndrome in 1 (3.1%), potassium deficiency G3/4 in 5 (15.6%), and oral candidiasis in 2 patients (6.3%) each. Conclusions: LD showed significant anti-myeloma activity with an overall myeloma response rate (CR-PR) of 91.3% in the evaluable of 65.5% in the ITT cohort. Renal responses (CRrenal-PRrenal) were observed in 65.2% and 46.9% patients, respectively. Time to first myeloma and first renal response was fast (28 days each). The LD regimen with the lenalidomide dose adjusted to GFR was well tolerated. Updated results will be presented. Disclosures: Ludwig: Janssen Cilag: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria. Off Label Use: Lenalidomide was used of label in combination with dexamethasone in this phase II study in patients with acute light-chain induced renal failure.