ALBERT

Description: In vitro evidences suggest that bisphosponates (BP) may exert some anti-myeloma activities. Indeed, the use of BP has been associated with better survival in selected subgroups of myeloma patients. We have previously reported that pamidronate, a second generation BP, is not useful to prevent or to delay the need of chemo-radiotherapy in patients with early stage or smouldering myeloma, who do not require specific treatments at diagnosis, although such a therapy may reduce skeletal events at the time of disease progression (Musto et al, Leuk Lymphoma2003; 44: 1545). Based on this limited evidence, the recently updated ASCO guidelines still not recommend the use of BP in this specific setting of patients (Kyle et al, J Clin Oncol2007; 25: 2464). On June, 2001, we started a randomised clinical trial comparing zoledronate (ZOL), a third generation, more potent BP, vs simple observation in patients with monoclonal gammopathy fulfilling the diagnostic criteria of stage IA, IIA or smouldering myeloma, not requiring further treatments. These criteria substantially correspond to the current definition of “asymptomatic myeloma”, recently suggested by the International Myeloma Working Group (IMWG, Br J Haematol2003; 121: 749). Accrual was completed on June, 2004. One-hundred-sixty patients were enrolled and randomised (1:1) to receive (n. 80) or not (n. 80) ZOL (Zometa, Novartis Pharmaceuticals. Origgio, Italy) for one year, on an out-patient basis, at the dose of 4 mg as 15′ i.v. single monthly infusion. The two groups were comparable at baseline for time from diagnosis, levels and type of M-component and percentage of bone marrow plasma cells. The most frequent adverse effects observed in ZOL-treated patients were moderate, not clinically relevant hypocalcemia (15 patients: all received oral substitutive therapy and continued the treatment) and fever (7 patients, one of whom stopped drug administration after two cycles). One patient developed reversible osteonecrosis of the jaw, none evidenced renal failure under ZOL therapy. Eight patients (two in the ZOL-treated group and six within controls) died due to unrelated reasons or were lost at follow-up after 6–26 months. No significant reduction of M-component (〉 25%) was observed throughout the study in both groups. After a median follow-up of 55 months (range 36–72), there were 35 (46%) progressions to “symptomatic” myeloma in the ZOL group and 37 (50%) within the controls (p n.s.). Median time-to-progression was 42.2 and 40.7 months, respectively (p n.s.). Bone lesions and/or hypercalcemia at the time of progression were significantly lower (17/35, 48.5%) in ZOL-treated patients than in controls (30/37, 81%) (p 〈 0.02). These mature data suggest that the monthly use of ZOL for one year in patients with early-stage, asymptomatic myeloma is safe, reduces the development of skeletal events at progression, but does not decrease the number of evolutions and does not prolong the time to transformation into “overt” myeloma.

Description: Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM), with peculiar clinical and biological characteristics, which represents about 2–4% of all MM. PCL exists in two forms: primary PCL (about 60% of cases) presents “de novo”, without previous evidence of MM; secondary PCL, which accounts for the remaining 40%, consists of a leukemic transformation occurring in about 1% of patients with a previously diagnosed MM. We have recently shown that bortezomib is an effective agent for the treatment of both primary and secondary PCL, mainly in the setting of pre-treated disease (Musto et al, Cancer 2007). In the present study we conducted a multicenter retrospective survey focused on unselected patients with a diagnosis of primary PCL who had received bortezomib exclusively as first line therapy for the treatment of their disease, outside of clinical trials. To-date, 15 patients, diagnosed according to International Myeloma Working Group criteria, have been collected, 12 of whom (seven male and five female, 49 to 77 year-old) have been so far evaluated for response. Circulating plasma cells ranged from 3 to 95 × 10e9/L. Seven patients had an IgG M-component, two had IgA, two light chains, while one patient was not secretory. Five patients had concomitant extramedullary disease. Unfavourable cytogenetic abnormalities were observed in 4 out of 7 patients with available karyotype. Bortezomib was generally given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Minor modifications were performed, according to tolerance. Three patients received dexamethasone (VD), two dexamethasone and thalidomide (VTD), six doxorubicin and dexamethasone (PAD), and one oral melphalan and prednisone (MPV) in combination with bortezomib, for 2–6 cycles. Three patients underwent autologous, two allogeneic and one a sequence of autologous followed by non-myeloablative allogeneic stem cell transplantation after induction therapy. One out of five eligible patients failed to collect peripheral blood stem cells. Grade 3–4 hematological, neurological, infectious and renal toxicities occurred in 6, 2, 1 and 1 patient, respectively. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. According to the International Uniform Response Criteria, 4 partial remissions (reduction of M-component 〉 50%), 5 very good partial remissions (reduction of M-component 〉 90%, with positive immunofixation), and 3 complete remissions (negative immunofixation) were achieved (100% overall response). In all patients circulating plasma cells disappeared. One patient with pre-existing renal damage died of progressive disease after 3 months, developing more severe renal failure. Another patient died in CR 6 months after diagnosis, while performing allogeneic stem cell transplantation. Three patients relapsed after 5–8 months and 2 of them died with progressive disease within 4 months from relapse. The remaining 8 patients are alive, and 6 of them maintain their remission phase after 9 to 19 months. One-year progression-free survival and overall survival were 50% and 66.6%, respectively. Primary PCL is usually characterized by poor prognosis. Global response rate to standard chemotherapy is less than 50% and median survival is only 7 months. Stem cell transplantation may be more effective in some, but not all cases. Our findings suggest that, in these patients, the front-line use of bortezomib induces a very high rate of good quality responses, whose duration, however, may be short. This suggests that, in primary PCL, bortezomib should be integrated within more intensive therapeutic programs, including other active drugs and, when possible, stem cell transplantation.

Description: Darbepoetin (DPO), a long acting erythropoiesis stimulating protein, is effective in inducing erythroid responses in 40–71% of anemic patients with myelodysplastic syndromes (MDS) when given at fixed doses of 150–300 mcg once-a-week. Of interest, some of these responses have been reported in MDS patients previously treated with (and occasionally unresponsive to) recombinant erythropoietin (r-EPO). We aimed to explore, on a compassionate basis, the effects of a higher DPO dose, administered with longer intervals, specifically in this last setting of patients. A single s.c. injection of DPO at the dose of 500 mcg s.c. was given every 3 weeks (Q3W) in fifteen anemic MDS patients, who had a history of an unsuccessful prior treatment with alpha or beta r-EPO (total weekly doses of r-EPO received: 30.000–80.000 U, for at least 8 weeks), both primary resistant or with loss of efficacy after an initial response. Informed consent was obtained in all cases. Nine patients were male, six female; mean age was 71 years (range 62–82). According to WHO classification, there were 5 RA, 3 RARS, 6 RCMD and 1 RCMD-RS. IPSS score was low in 6 patients and intermediate-1 in the remaining 9 subjects. Baseline Hb levels ranged from 6.2 to 9.1 g/dl, twelve patients being transfusion-dependent. All patients were treated with at least 3 DPO doses (nine weeks of therapy) and were evaluable for short term response and safety. No relevant adverse effect attributable to DPO was recorded. According to recently revised IWG criteria, three patients (20%) achieved an erythroid response. Transfusion-independence was obtained in one of two transfusion-dependent responders. All responses occurred after 2 doses of DPO in patients with baseline endogenous EPO below 200 miu/ml, two of whom previously treated with r-EPO 10.000 U s.c. t.i.w, while one had received 40.000 U s.c. b.i.w. Erythroid responses were maintained prolonging intervals between two DPO administrations up to 6 weeks. Based on the previously described possible synergism between r-EPO and myeloid growth-factors in MDS and to the concomitant presence of symptomatic neutropenia, five patients non-responding to DPO alone received Peg-filgrastim, a novel, pegylated form of granulocyte-colony stimulating factor (G-CSF) with prolonged terminal half-life, at the dose of 6 mg s.c. every 3 weeks, in combination with DPO, for an additional period of 9 weeks. The treatment was well tolerated, but no improvement in Hb levels or reduction in transfusional support was observed. A significant increase in peripheral blood WBC count occurred in all patients treated with Peg-filgrastim. In this preliminary experience, DPO given at the fixed dose of 500 mcg Q3W was effective in some anemic MDS patients considered unresponsive to r-EPO. However, it should be taken into account the fact that at least two of responders had probably previously received r-EPO at sub-optimal doses (less than 40.000 U per week). The adjunct of Peg-filgrastim in this setting of patients resulted in an improvement of neutropenia, without effects on Hb levels.

Description: Mantle-cell lymphoma (MCL) is recognized as a distinct clinico-pathologic entity, accounting for 3–10% of all non-Hodgkin’s lymphomas, with median overall survival not exceeding 3–4 years. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The neoplastic cells are characterized as CD20+ CD5+ CD23−, with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. The current, most diffused regimens for the treatment of MCL include either R-CHOP or R-HyperCVAD, followed by autologous stem cell transplantation or observation, depending on the patient’s eligibility. However, considering that MCL is frequently diagnosed in elderly subjects with relevant co-morbidities, high dose chemotherapy or the use of drugs with potential cardiotoxicity, such as anthracyclines, may result not feasible in a significant proportion of patients. In this setting, recent data suggest that the proteasome inhibitor bortezomib is well tolerated and has significant single-agent activity in patients with MCL. Thus, we evaluated safety and efficacy of the RBC regimen, a 21-day cycle, anthracycline-free combination of rituximab (375 mg/m(2) on day 1), bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11) and hyper-fractionated cyclophosphamide (600 mg/m(2)/d given as a double, three-hour infusion on days 1–3) in “true” (≥ 75 year-old) elderly patients with advanced MCL. Diagnosis was made according to standard histological, phenotypic and molecular criteria. The results of an early analysis on feasibility in the first six patients enrolled (3 male, 3 female) are reported here. Mean age was 79.8 years (range 75–84). All patients had stage IV disease, evidencing extranodal localizations (n. 2) or marrow/leukemic involvement (n. 4). IPI score was 2 in three patients, 3 in two patients and 4 in one patient. Three patients received RBC as first line therapy, the others were treated at relapse after (R)-CHOP- like regimens. Hematological toxicities consisted in grade 1 (n. 2) and grade 2 (n. 1) thrombocytopenia, while one patient experienced grade 3 neutropenia, requiring G-CSF support. No extra-hematological toxicities higher than grade 1 were observed. Full doses of RBC were constantly administered. One patient, who presented with a WBC count 〉 200.000/μl, died during the first cycle due to progressive disease; another patient showed an initial response in extranodal sites and then progressed before the fourth planned cycle. The remaining four patients received six cycles: one patient achieved a partial response and three obtained a complete response, one of whom showing a molecular remission using PCR for t(11;14) bcl-1/IgH determination. All responders (66.6%) maintain their remission phase 7–10 months after the start of RBC treatment. Although very preliminary, these results indicate that RBC regimen is feasible, well tolerated and may be effective (including the possibility to obtain molecular response) in very elderly patients with advanced MCL. Larger and more mature data will be presented at the Meeting.

Description: Abstract 4951 Background Primary Plasma Cell Leukemia (PPCL) is an aggressive, rare variant of multiple myeloma, with clinical, molecular and phenotypic peculiarities, which accounts approximately for 2% to 4% of all myeloma diagnoses. The prognosis of PPCL patients is usually poor, with less than half of patients responding to conventional chemotherapy and a median survival of 7 months. Even by using autologous or allogeneic transplant procedures, survival generally does not exceed three years. Bortezomib has recently provided some promising results in this setting, but, given all the above, new treatments for PPCL are greatly awaited. Lenalidomide is a new immunomodulating agent with great efficacy in multiple myeloma, especially when associated with dexamethasone or other drugs. There are, indeed, some sporadic case reports of PPCL patients treated with lenalidomide as salvage therapy, but no data are currently available on the use of this drug as first line therapy in this disease. Patients and Methods On March, 2009, we started an open label, prospective, multicenter, exploratory, single arm, two-stage study aiming to evaluate safety and antitumor activity of the lenalidomide/low dose dexamethasone combination (Rd), as first line therapy in patients with PPCL. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were TTP, PFS, OS, percentage of eligible PPCL patients able to collect peripheral blood stem cells and to undergo autologous or allogeneic stem cells transplantation after Rd, serious and severe adverse event rate. According to this study protocol, all eligible, newly diagnosed adult patients with PPCL receive Lenalidomide at a dose of 25 mg daily for 21 days every 28 days. Oral dexamethasone is administered at a dose of 40 mg daily on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, patients who achieve at least PR and not eligible for autologous or allogeneic stem cell transplantation, continue with Rd until clinically appropriate (disease progression, unacceptable toxicity, patient's decision to leave the protocol). In these patients, a maintenance dose of lenalidomide alone equal to 10 mg/die days 1-21 every month is considered after at least 8 full dose Rd cycles. Patients responding after 4 Rd cycles and eligible for transplant procedures, proceed according to single Centre transplant policy. Patients not responding after 4 cycles or progressing under Rd treatment are considered off-study. Appropriate contraception methods and anti-thrombotic prophylaxis are planned. Results Four enrolled patients (1 male, 3 female, mean age 65 years, range 58-69) are currently evaluable for early response. All had unfavourable cytogenetics, including del13, t(4;14), t (14;16), or a complex karyotype. Circulating plasma cells ranged from 4.4 to 9.2 ×10e9/l. One patient had at baseline a moderate degree of renal failure (serum creatinine levels 2 mg/dl). After at least 2 Rd cycles (range 2-4), two PR and two VGPR were achieved (overall response rate 100%), with disappearance or near complete reduction of circulating plasma cells in all cases. The most relevant toxicities were grade 3 neutropenia and pneumonia, occurring in one patient and resolved by appropriate lenalidomide dose reduction, introduction of G-CSF and antibiotic therapy. One patient died in PR, due to causes unrelated to PPCL or treatment. As, according to the Simon, two-stage design adopted, more than two responses occurred within the first ten patients enrolled (stage 1), a total of 22 PPCL subjects will be accrued to complete the stage 2 of the trial. Conclusions These findings, though very preliminary, suggest that the combination of lenalidomide and dexamethasone may be a safe and promising initial therapy for PPCL patients, which can rapidly control the disease and could permit to perform following single patient-adapted therapeutic strategies. An update of this study, including molecular data, a larger number of patients and a longer follow-up, will be presented at the Meeting. Disclosures Musto: Janssen-Cilag: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide is approved in Italy for advanced multiple myeloma, not for plasma cell leukemia. This is a clinical trial registered at AIFA (Italian regulatory Agency for Drugs), EudraCT No. 2008-003246 28. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Morabito:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.

Description: Primary plasma cell leukaemia (PCL) is an aggressive variant of multiple myeloma characterized by poor prognosis. Global response rate to standard chemotherapy in primary PCL is less than 50% and median overall survival only 7 months. Even by using transplant procedures, survival does not exceed three years. Among new drugs for PCL, thalidomide has provided conflicting results, while bortezomib is emerging as a possible effective agent. The role of lenalidomide in PCL is still unknown. A 76-year-old man referred to our Institution on January, 2007, because of fatigue, anemia and leucocytosis. Performance status was 2 on ECOG scale and clinical examination revealed an intumescence of the left thigh. Hb was 8,7 g/dl, WBC count 21,8 × 109/l, and PLT count 392 × 109/l. Morphologic examination of the peripheral blood smear revealed the presence of 60% circulating plasma cells which resulted CD 38+, CD138+, CD19−, CD20− and CD 56− at cytofluorimetric analysis. A 3.3 g/dl, IgG lambda monoclonal component (MC) was identified by immunofixation. Serum beta2-microglobulin was 4.8 mg/dl, LDH 1018 U/L. Renal and liver functions were normal, as well as clotting tests and electrolytes. Bone marrow cellularity was completely replaced by anaplastic plasma cells showing chromosome 13 deletion. Magnetic resonance evidenced a large mass (cm 25 × 6) of the left thigh with soft tissues involvement (biopsy: plasmacytoma). Osteolytic bone lesions were detected at level of skull, mandible and ribs. A diagnosis of primary PCL was made. The patient was enrolled into a national clinical trial and treated with a six-week VMP cycle including bortezomib (1,3 mg/m2 i.v. d 1, 4, 8, 11, 22, 25, 29, 32), melphalan (9 mg/m2 p.o. d 1–4) and prednisone (60 mg/m2 p.o. d 1–4). Monthly infusions of zoledronic acid were also administered. After 4 cycles the patient achieved a very satisfactory response, with MC reduction 〉 90%, complete disappearance of marrow and circulating plasma cells, and total regression of the thigh mass. Grade 3 neurological and grade 2 haematological toxicities were concomitantly observed. On May, 2007, the patient relapsed when still under VMP therapy, showing a progressive increase of the MC (4 g/dl) and WBC count (38.3 × 109/l), associated with the presence of 70% peripheral blood plasma cells and the development of multiple muscle and subcutaneous nodules in both legs. Due to the presence of prior neurological toxicity which excluded the use of thalidomide, the patient received, on a compassionate basis, lenalidomide 25 mg/for 21 days plus dexamethasone 40 mg d 1–4, for a 28-day cycle. During the first cycle, an immediate and impressive response was obtained, with complete regression of extramedullary tumors, disappearance of circulating plasma cells and significant (〉 75%) decrease of MC. No relevant side effects were observed. So far, the patient has received two additional cycles with further improvement of the response and is currently continuing the treatment. To the best of our knowledge, this is the second patient with PCL successfully treated with lenalidomide. The duration of response is at present unknown, so that this very preliminary result requires caution. However, the effect of lenalidomide in our patient, who was resistant to a combination of bortezomib, melphalan, and prednisone, is encouraging and suggests the possibility to plan specific clinical trials with this drug in PCL.