Anna Levi

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients

In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

PURPOSE Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. PATIENTS AND METHODS We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). RESULTS In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. CONCLUSION Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Melphalan 200 mg/m 2 versus melphalan 100 mg/m 2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study

High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Thalidomide does not modify the prognosis of plasma cell leukemia patients: Experience of a single center

Plasma cell leukemia (PCL) represents the most advanced stage of multiple myeloma (MM) with the neoplastic cells circulating in the peripheral blood. Its diagnosis requires an absolute peripheral blood plasma cell count of 426 10/l or 420% of the differential white blood cell count [1]. PCL is classified into two clinical types: the primary type occurs in individuals without being preceded by MM, whereas the secondary one is a rare complication of the late-stage MM. Based on observations that in PCL the response to standard therapy is extremely poor and the use of Thalidomide (Thal) in advanced myeloma has resulted in marked responses even in patients with advanced diseases, including those who relapsed after high-dose chemotherapy [2], we decided to use this promising drug also in patients with PCL. According to the schedule reported by Singhal et al. [2], between March 2000 and July 2002, after written informed consent, five PCL (two primary and three secondary) patients were considered eligible for Thal treatment at our Institution. Thal was administered as single agent, according to a compassionate-use protocol. The starting dose of Thal was 100 mg daily for 2 weeks; subsequently, this dosage was increased by 100 mg every other week, to a maximum of 600 mg per day or according to the maximum tolerated dose. According to the International Stage criteria, two patients were in stage III (b2 microglobulin 45.5 mg/dl) and three in stage II (one for a b2 microglobulin of 4.2 mg/dl and two for serum albumin levels of 2.4 and 2.9 g/dl, respectively). No cytogenetics, labeling index or FISH data are available for these patients. Three were males and two females; median age was 68 years (range 51 – 72). Two cases were IgG, 1 IgA and two expressed light chains; one patient had serum creatinine 42 mg/dl. With regard to disease status, three patients (two primary and one secondary PCL) were refractory (defined as progression while on therapy) to prior chemotherapies and two were in relapse. All had been treated with at least two lines of treatment, including high-dose induction therapy for one of them, and were included in this study after 14 months (range 8 – 41) of median follow-up. All patients received Thal for at least 1 month and were, therefore, evaluable for response. No patient responded, although a reduction of circulating PC was observed in two. Survival was very short, all patients died after 40, 45, 60, 75 and 120 days of Thal treatment, respectively. During the same time period we treated with the same protocol 75 MM patients (33 refractory to prior chemotherapies and 42 in relapse). The median age was 63.5 years (range 33 – 84); 47 patients were IgG, 20 IgA and eight had light chain MM. Highdose induction therapy was utilized for 29 of them and the MM patients were included in this study after 36 months of median follow-up from diagnosis. The median daily dose of Thal administered to all patients was 400 mg (range 100 – 600 mg). Among the 75 MM patients, 67 received Thal for at least 1 month and were evaluable for response; the remaining eight patients were not evaluable because four

Lenalidomide and low-dose dexamethasone for newly diagnosed primary plasma cell leukemia.

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Treatment of 72 newly diagnosed Waldenström macroglobulinemia cases with oral melphalan, cyclophosphamide, and prednisone: Results and cost analysis

Current treatment regimens for Waldenström macroglobulinemia (WM) are based on the use of oral alkylating agents. Recently, however, other more costly agents have been proposed for the treatment of WM. In the current study, the authors report on results obtained using oral melphalan, cyclophosphamide, and prednisone (MCP) to treat 72 patients with WM, and they compare these results (and the associated costs) with those observed using more aggressive protocols.

IgM multiple myeloma: report of four cases and review of the literature.

The differential diagnosis between multiple myeloma (MM) and Waldenströms macroglobulinemia (WM) is generally well defined. Consistent with a diagnosis of MM is the presence of a non-IgM monoclonal gammopathy associated to multiple osteolytic lesions and plasma cell infiltration of the bone marrow. Characteristic of WM is the presence of an IgM monoclonal gammopathy associated to lymphoadenopathy, hepatosplenomegaly, anemia and hyperviscosity syndrome in the presence of a monoclonal lymphoplasmacytoid proliferation in the bone marrow. Nonetheless, few cases of IgM myeloma have been reported that display clinico-pathologic features intermediate between MM and WM. Here, this study describes four of 317 (1.2%) patients with an IgM monoclonal gammopathy in whom the morphologic and clinical features were consistent with a diagnosis of IgM myeloma.

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

BackgroundImmunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes.Design and methodsSeventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group.ResultsMedian age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT.ConclusionsDespite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.

Arterial and venous thrombosis in patients with monoclonal gammopathy of undetermined significance: incidence and risk factors in a cohort of 1491 patients.

Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of thrombosis. We carried out a retrospective multicentre cohort study on 1491 patients with MGUS. In 49 patients (3·3%) MGUS was diagnosed after a thrombotic event. Follow‐up details for a period of at least 12 months after diagnosis of MGUS were obtained in 1238 patients who had no recent history of thrombosis (<2 years) prior to diagnosis, for a total of 7334 years. During the follow‐up, 33 of 1238 patients (2·7%) experienced thrombosis, with an incidence of 2·5 arterial events and 1·9 venous events per 1000 patient‐years. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors [hazard ratio (HR) 4·92, 95%confidence interval (CI) 1·42–17·04], and of venous thrombosis in patients with a serum monoclonal (M)‐protein level >16 g/l at diagnosis (HR 3·08, 95%CI 1·01–9·36). No thrombosis was recorded in patients who developed multiple myeloma (n = 50) or other neoplastic diseases (n = 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M‐protein concentration exceeded >16 g/l.

Extramedullary Liver Plasmacytoma a Rare Presentation

Liver plasmacytoma is a very rare form of solitary plasmacytoma, in fact the presence of plasma cells in the liver is generally associated with a more aggressive form of multiple myeloma. We report an unusual case of liver plasmacytoma without systemic disease, diagnosed by percutaneous needle biopsy of the hepatic lesion, treated with six courses of melphalan and prednisone who achieved a good clinical remission after five years of follow-up.