Silvia Mangiacavalli

Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients

BACKGROUNDnThere are few data on the incidence and prognosis of extramedullary (EM) multiple myeloma (MM). There are concerns about a possible increase of EM relapses with the expanding use of high-dose therapy (HDT) and biological agents.nnnPATIENTS AND METHODSnThe incidence of EM disease, its relationship with prior exposure to HDT or novel agents, and its prognostic impact were analyzed in 1003 MM patients. Based on the different therapies available, three periods were considered: 1971-1993, conventional-dose chemotherapy; 1994-1999, HDT for younger patients; and 2000-2007, introduction of novel agents.nnnRESULTSnOverall, 13% of patients had EM disease, 7% at diagnosis and 6% later. In the 2000-2007 period, there was a significant increase of EM involvement, at diagnosis (P = 0.02) and during follow-up (P = 0.03). The risk of EM spread was not significantly increased after HDT [hazard ratio (HR 0.6)], bortezomib (HR 1.62), or thalidomide/lenalidomide (HR 1.07). EM disease was associated with shorter overall (HR 3.26, P < 0.0001) and progression-free (HR 1.46, P = 0.04) survival.nnnCONCLUSIONSnThe incidence of EM disease has increased, probably due to the availability of more sensitive imaging techniques and the prolongation of patients survival. HDT or novel agents seem not to increase the risk of EM disease. EM involvement confers a poor prognosis.

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.

A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenströms macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia

Hydroxyurea is an antimetabolite agent used in the treatment of myeloproliferative disorders and sickle cell anaemia. Although hydroxyurea is relatively well tolerated, adverse effects often involve skin and mucous membrane during long‐term therapy. A group of 510 patients affected by chronic myeloid leukaemia from 1977 to 1998 has been considered. Only 158 patients were treated with hydroxyurea and fulfilled inclusion/exclusion criteria of this study. A spectrum of severe cutaneous and mucosal changes (inflammatory and neoplastic) was seen in about 13% of patients (21 patients out of 158) and was studied in detail. Cutaneous and mucosal atrophy were observed in all 21 patients. Skin atrophy was often characterized by numerous telangiectases, especially on legs and on sun‐exposed sites (16/21). Cutaneous, mucosal and nail hyperpigmentation was evident, albeit with variable extent, in 10 of the 21 patients. Severe stomatitis and glossitis with flattening of papillae were another common finding. Five patients, who received a particularly long treatment with hydroxyurea, developed squamous‐cell neoplasms on sun‐exposed sites (both squamous‐cell carcinomas and keratoacanthomas). Acral changes were characteristic and constant, including acral erythema (21/21), dermatomyositis‐like changes on the dorsa of hands (7/21), ulcers localized on acral areas of legs, on genitalia and oral mucosae (20/21). The frequency and the variety of these muco‐cutaneous changes are reported and the mechanisms by which hydroxyurea may induce this muco‐cutaneous syndrome‐like group of changes, are proposed.

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.

OBJECTIVEnBortezomib 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.nnnMETHODSnFive patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations.nnnRESULTSnPeripheral 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).nnnCONCLUSIONSnIn some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms.nnnSIGNIFICANCEnThis 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.

Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone

Deep venous thrombosis (DVT) has been variably reported in multiple myeloma patients during treatment with thalidomide alone or in combination with chemotherapy or dexamethasone. With the aim of investigating this complication, we performed, on a cohort of 13 relapsed refractory MM patients treated with low-dose thalidomide (100xa0mg/day) and dexamethasone (20xa0mg p.o./day for 4 days every 2 weeks), a serial evaluation of different laboratory parameters implicated in DVT. No significant abnormalities in all genetic, serologic, or plasmatic parameters studied were registered, apart from thrombomodulin which showed significant variations between baseline and 1st-month values and 1st- and 3rd-month values. In conclusion, the evidence of significant variations of thrombomodulin values in the 1stxa0month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.

Risk of second cancers in Waldenström macroglobulinemia

BACKGROUNDnAn increased incidence of second cancers has been reported in lymphoproliferative disorders.nnnPATIENTS AND METHODSnWe assessed the frequency, characteristics and predictive factors of second cancers in 230 patients with Waldenström macroglobulinemia (WM) and compared the incidence of second cancers in WM with that of an age- and sex-matched control population.nnnRESULTSnTwenty-two patients (10%) developed solid cancers and 10 (4%) second hematologic malignancies. In a competing risk model, the cumulative incidence of solid cancers was 12% at 10 years and 17% at 15 years while the incidence of hematologic malignancies was 6% and 8%, respectively. The overall risk of second cancer in WM was 1.69 times higher than expected (P = 0.002). WM patients were at increased risk for diffuse large B-cell lymphoma [standardized incidence ratio (SIR) 9.24, P < 0.0001], myelodisplastic syndrome/acute myeloid leukemia (SIR 8.4, P < 0.0001), brain cancer (SIR 8.05, P = 0.0004). The risk of a second hematologic malignancy was fourfold higher in patients previously treated, though not reaching statistical significance (P = 0.19).nnnCONCLUSIONSnWM patients are at higher risk of second cancers as compared with the general population. The sample size does not allow firm conclusions about the effect of therapy on the development of second cancers.

MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance

To the editor:nnMYD88 (L265P) is a recurrent somatic mutation in Waldenstrom macroglobulinemia (WM).[1][1][⇓][2][⇓][3]-[4][4] By means of allele-specific polymerase chain reaction (AS-PCR), the MYD88 mutation is detectable in almost all patients with WM and in roughly half the patients with IgM

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.

Emergent T‐helper 2 profile with high interleukin‐6 levels correlates with the appearance of bortezomib‐induced neuropathic pain

cell indices. There was no known family history of iron overload. HFE gene analysis revealed a normal genotype (C282C, H63H). Because the patient had elevated liver function enzymes (alanine transaminase [ALT] = 82 i/u per litre) he underwent a liver biopsy, which showed grade 4 reticulo-endothelial haemosiderosis (Fig 1). The biopsy also showed steatohepatitis which was felt to be the cause of his elevated ALT levels. The patient’s SLC40A1 gene was subjected to mutation analysis. High Resolution Melting Analysis (HRMA) revealed a mutation in exon 5 of SLC40A1 and the variant melt was sequenced using a Beckman CEQ8000 sequencer. A heterozygous missense mutation was detected as a result of a single base substitution (c.470 A>C) resulting in a change in the amino acid at codon 157 from Asp (GAT) to Ala (GCT). The mutation was designated: p.D157A (Fig 2A). This mutation is novel, however, another mutation at codon 157: p.D157G had been recorded as a cause of ferroportin disease (Hetet et al, 2003). After counselling and consenting, the patient’s daughter was screened and was also found to have an elevated serum ferritin of 1404 lg/l with a transferrin saturation of 18%. Her FBC was normal with normal red cell indices, and her liver function tests were entirely normal. SLC40A1 analysis revealed the same mutation (Fig 2B). The patient was started on a cautious venesection programme, with removal of 400 ml blood on 21 occasions. His ferritin levels fell to 2537 lg/l (c. 40% reduction). However, his venesections were becoming increasingly difficult to perform due to a progressive fall in haemoglobin and poor patient tolerance. A T2* magnetic resonance imaging (MRI) scan, at that stage, showed no evidence of cardiac or hepatic iron loading. In view of the normal T2* MRI it was decided to withhold the venesections and take a watchful approach to his management. T2* MRI of the proband’s daughter also revealed no evidence of cardiac or hepatic iron loading, and she is currently being managed expectantly. Many mutations have been implicated as causing ferroportin disease, and most of these mutations have been traced to exon 5 of the SLC40A1 gene (Lee & Beutler, 2009). The disease should be suspected in patients presenting with hyperferritinaemia and normal transferrin saturation. Genetic screening is available and has the potential of accurately identifying these patients. It may also help in counselling and screening their family members. As the disease often leads a benign course, a proper diagnosis can also help avoid unnecessary and prolonged venesection programmes.