Patrizia Zappasodi

Bortezomib-induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients

Peripheral neuropathy (PN), with neuropathic pain as main symptom, represents the dose-limiting toxicity of the proteasome inhibitor bortezomib. Aim of this study was to compare the incidence, risk factors, severity and outcome of PN and neuropathic pain in patient treated with bortezomib up-front or at relapse. We studied 55 patients with multiple myeloma (MM) who received bortezomib as first line therapy and 70 pre-treated patients who received bortezomib in relapse or progression. Regarding PN, no differences were found among untreated and pre-treated patients in the incidence (55% vs 52%, p=0.43), severity (NCI grade 3-4 9% vs 14%, p=0.27), and outcome (improved/resolved 90% vs 91%, p=0.58). Concerning neuropathic pain, the incidence was lower (50% vs 81%, p=0.008) and solved earlier (35 days vs 91 days, p=0.02) in untreated compared with pre-treated patients. Untreated patients needed dose modification less frequently (36% vs 73%, p=0.012). No correlation was found between development of PN and prior exposure to potentially neurotoxic drugs such as thalidomide, vincristine, and cysplatin. Age represented the main risk factor for PN (p=0.036) with an increase in risk of PN amounting to 6% per year of age. In conclusion, incidence, severity and outcome of bortezomib-related PN are similar in untreated and pre-treated MM patients except for neuropathic pain which has lower incidence and shorter duration in untreated patients with less frequent need for bortezomib discontinuation. Age emerges as the most relevant risk factor for peripheral neuropathy, with a risk increase for PN of 6% per year of age.

Immune-mediated neuropathies in myeloma patients treated with bortezomib.

OBJECTIVE Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. METHODS Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. RESULTS Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

Urinary proteins in multiple myeloma: correlation with clinical parameters and diagnostic implications

Renal failure is one of the worst complications occurring in multiple myeloma (MM) patients. It does not affect survival if reverted by a prompt chemotherapy before the damage becomes irreversible; therefore, the early diagnosis of renal dysfunction is crucial. High and low molecular weight urinary proteins have proved to be helpful in diagnosing initial renal damage since they are more sensitive than urea and creatinine serum levels or creatinine clearance. We studied the renal function of 111 MM patients through serum creatinine, urea, urinary IgG, α1-microglobulin (α1-M), and albumin (Alb). Two successive controls were made in a subset of 30 patients, categorized in three groups (improved, stable, worsened) according to the behavior of tumor burden markers (bone marrow plasmacytosis, monoclonal component, and β2-microglobulin). In every group, we evaluated the behavior of urinary proteins. Renal dysfunction evaluated with serum parameters was present in 19 patients (17%), while if studied with urinary proteins was revealed in 71 patients (64.5%). Urinary proteins statistically correlated with each other. They correlated with creatinine, IgG, and α1-M also with urea. By contrast, they showed a variable correlation with clinical parameters: α1-M correlated with bone marrow plasmacytosis (BMPC) (p=0.02) and β2-M (p=0.000001), IgG with all three disease parameters (MC p=0.0005, BMPC p=0.009, β2-M p=0.007), and Alb only with β2-M (p=0.0004). In the subset of 30 patients followed with two successive controls, urinary proteins showed a parallel behavior with the indices of tumor burden. In conclusion, IgG, α1-microglobulin, and albumin are reliable and sensitive to precociously reveal renal damage, and we recommend their routine use for the definition and monitoring of renal function in multiple myeloma patients, mainly those in early stage, to better identify initial signs of progression.

Assessment of renal function in patients with multiple myeloma: The role of urinary proteins

Abstract Renal failure (RF) in multiple myeloma (MM) is considered an ominous complication even though, when timely therapy is started in patients with minimal damage, a high percentage of cases can achieve a regression. The evaluation of renal involvement usually relies on serum creatinine or its clearance, but these parameters have proved to be inadequate to identify initial damage. The aim of this study was to assess the role of the following urinary proteins in diagnosing renal impairment at an early stage: high-molecular-mass proteins (transferrin, IgG, albumin) as markers of glomerular damage, and low-molecular-weight proteins and parenchymal enzymes [α1-acid glycoprotein (AGP), α1-microglobulin (α1M), retinol-binding protein (RBP), β2-microglobulin (β2M), lysozyme (LZ), and N-acetyl-β-d-glucosaminidase (NAG)] as indicators of tubular disorder. Thirty MM patients (nine at disease onset and 21 previously treated) were included in the study. No correlation was found between the urinary proteins and the phase or the stage of the disease. By the Spearman test, Bence Jones proteinuria correlated significantly with the 24 h proteinuria (p=0.01) and β2M (p=0.02), and weakly with the α1M. Serum creatinine concentrations and urea correlated with most of the analytes evaluated: RBP correlated well with urea (p=0.004) and creatinine (p=0.004); IgG (p=0.006) albumin (p=0.009), AGP (p=0.04), and NAG (p=0.02) correlated with serum creatinine. Significant statistical correlation was found between all the analytes except LZ and the creatinine clearance. Twelve of the 30 MM patients (40%) showed abnormal values of urinary proteins. Four of these patients showed overt renal failure with significant modification of the serum parameters and of creatinine clearance, three showed an isolated decrease of creatinine clearance, and five did not present any alteration of serum or urinary parameters. This testifies to the utility of urinary proteins in highlighting renal damage even in cases where the customary serum indicators of renal disorder are normal. In conclusion, our results demonstrate that AGP, RBP, NAG, transferrin, and IgG are good indicators of renal damage. They do not correlate with the severity of the disease, but they seem to be helpful in identifying a subset of patients with initial renal dysfunction.

Bortezomib plus dexamethasone is highly effective in relapsed and refractory myeloma patients but responses are short-lived.

Objectives:  Bortezomib has proven to be effective as single agent in myeloma patients. Aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with dexamethasone in a cohort of multiple myeloma (MM) relapsed/refractory patients treated in a single center.

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.

Mucocutaneous paraneoplastic syndromes in hematologic malignancies.

Hematologic malignancies can be accompanied by cutaneous manifestations, known as paraneoplastic syndromes, which usually present different patterns from their idiopathic counterparts. These disorders can either precede, occur concurrently with, or follow the diagnosis of a neoplastic disease. They often represent the first clinical sign of an underlying neoplasm or the earliest symptom of relapse of a previous cancer. 1

Urinary proteins and renal dysfunction in patients with multiple myeloma

Besides bone pain, pathologic fractures, anaemia, and recurrent infectious diseases, renal failure is one of the most serious complications in multiple myeloma patients. Its incidence is generally underestimated because of the low reliability of the parameters routinely used for the evaluation of renal dysfunction. Other laboratory tests in the literature are reported to be more suitable to better define the extension of the renal impairment, namely urinary proteins or creatinine clearance. We here report on the clinical implication of urinary parameters in defining the renal function in myeloma patients.

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.

Long-term outcome in relapsed and refractory multiple myeloma treated with thalidomide. Balancing efficacy and side-effects

A total of 303 MM patients were retrospectively reviewed to evaluate long-term efficacy and toxicity of thalidomide alone or in combination with steroids. Overall response rate was 57% (CR/VGPR 12%). Median TTP, PFS and OS were 13.4 months, 20.6 months, and 26.2 months, respectively. PFS and OS were significantly different according to response (p < 0.0001), with better outcome in patients achieving CR/VGPR (PFS and OS 35.4 months and 63 months, respectively). PFS and OS of patients achieving SD or PR were overlapping (p = 0.3). The addition of steroids significantly increased the response rate (p = 0.01). The most clinically relevant complications were neuropathy (40%), constipation (26%), thromboembolic events (7%). Thalidomide was reduced for toxicity in 68 patients (24%) and permanently discontinued in 36 (12%). In conclusion, thalidomide produces high response rate in relapsed/refractory MM. The best outcome is observed in patients with good quality response, but even patients with suboptimal response may obtain durable survival.