ALBERT

Description: Multiple Myeloma (MM) is a malignant lymphoproliferative B-cell disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Acquired genomic aberrations have been shown to significantly impact response to chemotherapy and survival in MM. The aim of our study was to assess the clinical relevance of genomic abnormalities in 306 MM patients treated with high-dose chemotherapy (HDCT) and peripheral stem cell transplantation (PBSCT) in our center. We analyzed 171 males and 135 females with a median age of 60 years (range 25 – 73 years). According to the international staging system (ISS), MM patients were classified as stage I (46.6%), stage II (36.1%) and stage III (17.4%) at the onset of chemotherapy. All patients underwent frontline HDCT with 200 melphalan mg/m2 and PBSCT according or in analogy to the GMMG-HD3- or GMMG-HD4-trials. Interphase-FISH-analysis was performed on CD138-purified plasma cells using probes for chromosomes 1q21, 6q21, 8p21, 9q34, 11q23, 13q14.3, 15q22, 17p13, 19q13, and 22q11, as well as IgH-translocations t(4;14)(p16.3;q32.3) and t(11;14)(q13;q32.3). For the entire group, the median overall survival (OS) and progression-free survival (PFS) after HDCT was 6.4 and 2.2 years, respectively. Table 1. Chromosomal abnormalities with significant results (a-level=0.05) on PFS or OS (univariate analysis, unadjusted p-values) Aberration yes vs. no Frequency % 3-year PFS % P value 3-year OS % P value del(8p21) 19 26 vs. 37 0.01 58 vs. 78 0.02 del(13q14.3) 46 23 vs. 53

Description: Introduction: No standard treatment is available for relapsed or refractory amyloid light-chain (AL) amyloidosis. The efficacy of lenalidomide has been proven in patients (pts) with multiple myeloma (MM) but its role in AL amyloidosis is not yet defined. Two small phase II trials (Sanchorawala et al and Dispenzieri et al, Blood, 2007) showed that toxicity might be higher than in pts with MM and standard dosage (25 mg) had to be reduced. Patients: Since 2006 40 pts with relapsed or refractory AL amyloidosis were treated with lenalidomide/dexamethasone (LD) at our center. Administration of at least 6 cycles was planned. The starting dosage of L was 15 mg and was adapted to renal function (15 mg every 48 hours for creatinine clearance 〈 40 ml/min, 15 mg 3-times a week for dialysis patients). The starting dosage of D was 20 mg (day 1 – 4) in the majority of the pts. Prophylaxis against thrombosis and infections consisted of aspirine 100 mg (n=35) or low-weight molecular heparine (n=4) and ciprofloxacine, respectively. Median age of the 40 pts enrolled was 60.5 years (range, 45–74 years). 19 patients have relapsed or become refractory after treatment with high-dose melphalan and 21 pts after melphalan-based conventional chemotherapy. 21 pts had an impaired renal function (creatinine clearance 〈 40 ml/min; 9 pts on dialysis) at study inclusion. Before start of LD 17 of 31 evaluable pts had an elevation of both cardiac biomarkers (cardiac troponin and brain-natriuretic peptide, Mayo Stage II, Dispenzieri et al, JCO 2004), in 10 pts one marker was elevated (Mayo stage I). The median number of previous chemotherapy regimens was 2, the median number of previous therapy cycles was 5. The median time from diagnosis to start of LD was 24 months. Results: Median follow up is 4 months (range 1–18 months). The median number of administered LD cycles is 3 (range 1–12), 12 pts have received at least 6 cycles. 32 pts are alive. Hematological toxicity 〉 NCI grade 2 required dose reduction of L in 10 pts. Seven pts died early during LD therapy (4 with Mayo stage II, 3 with end stage renal disease). Three pts stopped therapy due to side effects after receiving less than 3 cycles. 24 pts are still on therapy with LD. Main non-hematological toxicities were fatigue 〉 NCI grade 2 in 14 pts, worsening of renal function in 7 pts with pre-existing renal failure (3 pts requiring dialysis) and infections 〉 NCI grade 2 in 2 pts. Three pts developed deep vein thrombosis (all with aspirine prophylaxis and additional risk factors for thrombosis); no bleedings were reported. Liver toxicity 〉 NCI grade 1 or worsening of polyneuropathy were not observed. Skin rash occurred in 3 pts. One pt achieved complete remission of the underlying gammopathy and 46% of evaluable pts had partial remission after a median of 3 LD cycles. Conclusion: 40 pts with AL amyloidosis were treated uniformly with dose-reduced LD. Using prophylaxis against infections and thrombosis the treatment was feasible and not associated with undue toxicities encountered in pts with far advanced disease. The worst toxicity was observed in pts with severe impaired renal and cardiac function. The optimal dosage for these pts should be further evaluated. The hematological remission rate of 50% is encouraging in this cohort of heavily pre-treated AL amyloidosis pts. A longer follow-up period is mandated to further evaluate the efficacy in organ responses.

Description: Lenalidomide (Len), an immunomodulatory drug, in combination with dexamethasone (Dex) is a new treatment option for patients (pts) with relapsed or refractory multiple myeloma (MM). Reimbursement and drug laws in Germany allow treatment before marketing authorization of a given drug, if no alternatives are available for life-threatening diseases. AIM: To evaluate efficacy and tolerability of MM pts treated with Len/Dex in the German named patient (pt) program. PATIENT AND METHODS: A comprehensive, previously tested, questionnaire was used to document data from consecutive pt series in five large and specialized university treatment centres. Response was assessed using the EBMT criteria. RESULTS: 55 pts were documented so far (median age, 63 yrs; 92% stage III Durie & Salmon). Pts were heavily pretreated: 30% had up to 2 previous therapy lines, 35% had three, 13% four and 21% more than four; the median no. was 3 (interquartile range, IQR 2–4). Pts had received a median of 16 (IQR 10–22) previous courses of chemotherapy. Forty-nine patients (89%) had previously received a stem cell transplant (SCT): 41 an autologous and an additional eight allogeneic SCT. That correlates with a 2-fold higher proportion of pts with prior SCT compared to the Len registration trial. Furthermore, the proportion of pts treated with the new drugs thalidomide or bortezomib was even 7–10-fold higher than in the registration trial. Best response could be assessed in 49 pts.: 4% CR, 32% PR, 19% MR, thereby showing an overall reponse rate of 55%. Four patients (8%) progressed during therapy and two (4%) died before response evaluation. The table shows response in different subgroups according to previous therapies. Response (CR/PR/MR) ranged from 88% (7/8) with only 1 previous treatment line shown in the table to 52% (16/31) with 2–3 and 43% (6/14) with 4–5. The most common adverse event III°/IV° was infection occurring in 21/55 (38%) patients. Thrombo-embolic events were observed in three patients (5%). Haematological toxicity grade IV° was seen in 11/46 (24%) patients, most common in course 1 of therapy. Five patients (9%) died during treatment, four due to infection (one in neutropenia) and one patient due to cerebral bleeding. 70% of patients were alive at last follow-up. CONCLUSION: In this pt cohort Len/Dex induced considerable antineoplastic activity despite extensive pretreatment. Toxicity was moderate and as expected for this risk-cohort. Nevertheless pts with more than 3 prior treatment lines should receive close clinical monitoring in order to prevent life-threatening infection. Response in different subgroups Over all response Prev. alloSCT Prev. ASCT Prev. thalidomide Prev. bortezomib 3 prev. treatment lines〉〉 n 49 8 40 30 39 19 CR/PR/MR 55% 50% 53% 50% 54% 42%