Federica Cocito

Monoclonal gammopathy of undetermined significance: a new proposal of workup

Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) require quantification of bone marrow plasma cells (BMPCs) and skeletal survey to discriminate between MGUS and multiple myeloma (MM). By contrast, recent published guidelines suggest that these procedures could be avoided in the presence of serum monoclonal spike (M‐spike) of small amount (≤1.5 g/dL). Aim of this study is to better quantify the risk of missing a diagnosis of MM, not performing bone marrow aspirate and skeletal survey in patients with M‐spike ≤ 1.5 g/dL asymptomatic for bone pain.

Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide

Abstract Immunomodulatory drugs (IMiDs) may favor autoimmune disease (AD) occurrence. We conducted a retrospective study to evaluate AD occurrence among IMiD-treated patients with myeloma. Patients were grouped into three classes depending on the type of IMiD engaged. The first group included patients treated with thalidomide (Thal) (n = 474), the second group with lenalidomide (Len) (n = 140) and patients in the third group were first treated with Thal followed by Len (Thal-Len) (n = 94). Absolute risk of AD was 0.4% for patients treated with Thal, 4.3% for Len and 1.1% for Thal-Len. ADs manifested prevalently as autoimmune cytopenias (55%), although we observed one vasculitis, one optic neuritis, one Graves’ disease and one polymyositis. ADs occurred preferentially in the first months of IMiD treatment. A previous autologous transplant was shown to be a significant risk factor. All ADs were managed with IMiD discontinuation and steroids, resolving in a few weeks, except for Graves’ disease and polymyositis.

Changing pattern of presentation in monoclonal gammopathy of undetermined significance: a single-center experience with 1400 patients.

To assess whether the pattern of presentation and the outcome of monoclonal gammopathy of undetermined significance (MGUS) have changed over the last 3 decades, we evaluated 1400 patients, divided into 3 groups: group I (1975-1987), group II (1988-1997), and group III (1998-2007). We observed a significant increase in age (p = 0.001), IgM and biclonal MGUS (p = 0.003), hemoglobin (p < 0.0001), and albumin (p = 0.0001), and a significant reduction of monoclonal (M)-protein concentration (p < 0.0001), percentage of bone marrow plasma cells (p < 0.0001), and &bgr;2-microglobulin (p = 0.0001) over the 3 decades. The proportion of patients with M-protein <1.5 g/dL was significantly higher in group III (66%) than in group II (44%) and group I (26%) (p < 0.0001). By Kaplan-Meier analysis, group III had a significantly lower 5-year probability of transformation (5%) compared to group II (12%) and group I (22%) (p = 0.003). Patients with M-protein <1.5 g/dL had the same life expectancy as the general population (standardized mortality ratio 1.09; p = 0.41). In conclusion, we found that the pattern of presentation of MGUS has changed over time and now includes a higher proportion of patients with more favorable presenting features and probably a better outcome compared to patients presenting in the past. This changing scenario calls for revising the current concepts of the clinical significance of MGUS and the management of patients. Abbreviations: BMPC = bone marrow plasma cells, FLC = free light chains, M = monoclonal, MGUS = monoclonal gammopathy of undetermined significance, SMR = standardized mortality ratio.

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty‐eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow‐up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy‐related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575–580, 2016.

Correlation between burden of 17P13.1 alteration and rapid escape to plasma cell leukaemia in multiple myeloma

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Long Term Evaluation of the Impact of Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: A Cost-Effectiveness Analysis

Background High-dose therapy with autologous peripheral stem cell transplantation represents today the standard approach for younger multiple myeloma patients. This study aimed to evaluate the long term economic impact of autologous transplantation with respect to conventional therapy. Methods We retrospectively reviewed the charts of multiple myeloma patients diagnosed at our department between 1986 and 2003 and treated according to the therapy considered standard at the time of diagnosis. Analysis of costs was done by assessing resource utilization and direct costs were measured and monetized before proceeding with the analysis, based on public health service tariffs. Results Group A including 78 patients treated with Melphalan and Prednisone was compared with Group B including 74 patients who received an autologous transplant. The median overall survival was 3.2 and 5.4 years respectively (p = 0.0002). Mean cost per patient was significantly higher in group B with respect to group A (102373€ vs 23825€; p<0.001). The final quality-adjusted-life-year gain in group B patients as compared to group A was 1.73 QALY, with an incremental cost-effectiveness ratio of 45460€. With a threshold of 75000€ per QALY gained, the cost effectiveness acceptability curve indicated that the probability that autologous transplantation in multiple myeloma is a cost-effective intervention is 90%. Conclusions The cost of autologous transplantation remains high. The calculated incremental cost-effectiveness ratio, however, given the significant prolongation of overall survival obtained with autologous transplantation, is within an acceptable threshold. Notwithstanding, its high cost should be taken into account when considering the whole cost of multiple myeloma.

Good clinical activity and favorable toxicity profile of once weekly bortezomib, fotemustine, and dexamethasone (B-MuD) for the treatment of relapsed multiple myeloma.

Since multiple myeloma (MM) is still not‐curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B‐MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80–100 mg/m2 i.v.) on day 1. The original 21‐day schedule was early amended for extra‐hematological toxicity and a 35‐day schedule was adopted (Bortezomib 1.3 mg/m2 i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty‐four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m2. The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression‐free survival (PFS) was 19.1 months. B‐MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib‐naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B‐MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.

Implemented myeloma management with whole-body low-dose CT scan: a real life experience

Abstract A total of 318 consecutive myeloma patients underwent whole-body low-dose CT scan (WBLDCT) at baseline and during follow-up as a radiological assessment of lytic lesions in place of skeletal X-ray survey. After WBLDCT baseline assessment, 60% had bone involvement. The presence of lytic lesions represented the only met CRAB (hyperCalcaemia, Renal insufficiency, Anaemia, Bone lesions) criteria in 29% of patients. Patients presenting with extramedullary masses were 10%. Radiological progression was documented in 9% of the population with available follow-up. Additional pathological incidental findings were detected in 28 patients (14.5%), most located in the chest region (68%). In conclusion, our real-life data shows that WBLDCT scan represents a reliable imaging tool for decision-making process for multiple myeloma management in different disease phases, providing significant additional information on the presence of soft tissues plasmacytomas detection as well as the presence of pathological incidental findings.

Panobinostat in combination with bortezomib and dexamethasone as induction therapy in patients with multiple myeloma, candidates for autologous transplant

1 Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 2 Department of Internal Medicine – Clinic of Hematology, Ospedale Valduce, Como, Italy, 3 Division of Hematology, Policlinico Ospedale Maggiore, Italy, 4 Department of Oncology-Hematology, Ospedale di Circolo, Busto Arsizio, Italy and 5 Division of Hematology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy

Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study

Abstract 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/m2 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.