Regular assessment of serum vascular endothelial growth factor levels to monitor POEMS syndrome.

BACKGROUND: To investigate the utility of regular serum VEGF (sVEGF) levels assessment in the monitoring of POEMS syndrome. METHODS: We retrospectively reviewed data of 30 patients with POEMS syndrome whose sVEGF was tested regularly every 6 months. sVEGF levels after treatment were measured and correlated with disability (Overall Neuropathy Limitations Scale, ONLS), clinical impairment (measured with the modified Clinical Response Evaluation Scale, mCRES), and relapse-free survival. The ability of sVEGF to predict disease flares during remission and refractory disease was also analysed. RESULTS: Patients with normalised serum VEGF levels (< 1000 pg/ml) at 6 months showed prolonged relapse-free survival (at 3-year 94% for complete VEGF response, 57% partial, 0% none, p < 0.001) and greater later clinical improvement (median ΔmCRES complete VEGF response -5 vs partial -4, p = 0.019, and vs no VEGF response -2, p = 0.006). After remission, the sensitivity of 6-month sVEGF monitoring in predicting clinical relapse was 58% with a specificity of 100%. In patients refractory to treatment, the sensitivity in predicting further clinical worsening was 15%. In addition, in 25% of the patients in remission and 16% of those refractory to therapy, sVEGF levels only increased at the time of relapse. CONCLUSIONS: Regular sVEGF assessment is a valid biomarker in the prediction of disease reactivation in POEMS syndrome and was particularly useful during the phase of remission.

Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse.

Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66-86%) and 74% (95% CI: 64-85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.

Peripheral Blood Hemopoietic Stem Cell Mobilization Regimens in POEMS Syndrome: A Retrospective Study at 2 Hematologic Italian Centers.

Autologous peripheral blood stem cell transplantation should be considered first-line therapy in young patients with POEMS. The best protocol to collect peripheral blood stem cells remains to be defined, because of the disease rarity and the heterogeneity of published case series. We collected clinical and laboratory data from 25 patients undergoing mobilization, of whom 11 were mobilized using cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF) and 14 patients using G-CSF. The incidence of poor mobilization was low and not statistically different between the 2 groups. Both schemes (CY plus G-CSF versus G-CSF alone) were able to harvest a sufficient CD34+ cell dose.

Long-Term Follow-Up of a Donor versus No-Donor Comparison in Patients with Multiple Myeloma in First Relapse after Failing Autologous Transplantation.

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P < .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P < .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.

Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program.

Because of the rarity of the disease, randomized clinical trials for multicentric Castleman disease (MCD) remain a challenge and, as a consequence, there is no established standard of care. Siltuximab is a chimeric immunoglobulin G1κ monoclonal antibody against human IL-6 which was recently approved by FDA. Eligible patients in Italy were granted early access through a Named Patient Program (NPP). The aim of this observational multicenter retrospective study was to analyze outcomes and toxicity data of relapsed or refractory MCD patients treated with siltuximab in a real life context. All the 9 patients who received siltuximab in Italy under the NPP were enrolled. Median duration of treatment was 285 days (range, 104-1113 days). The global overall response rate was 33.3%. At the time of this analysis, none of the 3 responder patients had subsequently disease relapse: response duration was 20, 23, and 37 months, respectively. Grade 1 to 2 fatigue and pruritus were observed in 2 (22.2%) patients, and weight gain was reported in only 1 patient (grade 1); local edema was reported in 2 patients with a grade 2 presentation. The most common side effect was upper respiratory tract infection reported in 3 (33.3%) patients but in these cases was grades 1 to 2. No patient developed an infusion-related reaction. Our NPP data support siltuximab as single agent in the real-life experience of the treatment of relapse/refractory MCD patients in effectiveness, safety profile, and sustained disease control.

Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective, open-label trial.

Given its anti-angiogenic activity, lenalidomide may have a role in the treatment of POEMS (Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder and Skin changes) syndrome. This prospective, open-label, pilot study evaluated the combination of lenalidomide + dexamethasone (RD) in 18 POEMS syndrome patients (13 pre-treated, 5 newly-diagnosed but ineligible for high-dose therapy). Treatment consisted of six cycles of lenalidomide (25 mg/day for 21 days followed by 7 days rest) plus dexamethasone (40 mg/once a week). Patients responding after six cycles continued treatment until progression or unbearable toxicity. The primary endpoint was the proportion of patients with either neurological or clinical improvement. The RD combination was considered as deserving further evaluation if 9 of the first 15 patients responded. Ten responses were observed among the first 15 enrolled patients, meeting the primary endpoint. Fifteen of 18 patients (83%) completed six RD cycles: 13 (72%) patients responded and nine had both clinical and neurological improvement. Among the 15 patients who completed the six RD cycles, four were still on treatment after a 25-month follow-up. At 39 months of follow-up, all patients were alive with a 3-year progression-free survival of 59%. No patient discontinued RD for toxicity. Overall, the RD regimen showed a high incidence of prolonged symptoms improvement and was well tolerated in most POEMS patients.

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

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.

Response-adjusted ISS (RaISS) is a simple and reliable prognostic scoring system for predicting progression-free survival in transplanted patients with multiple myeloma.

Complete response (CR) is associated with better outcome in patients with multiple myeloma (MM) treated with autologous transplant even though the progression-free survival (PFS) can be very variable among patients with good response. No simple and reliable prognostic scoring system, able to predict the duration of response, are so far available. Aim of this study was to identify any correlation between baseline clinical findings, response after transplant and the length of PFS, and thus develop a prognostic model. The new prognostic model was developed in a learning cohort of 549 patients with MM transplanted in five Italian hospitals. The prognostic value of this new score was confirmed in a validation cohort of 276 distinct patients with MM transplanted in two different Italian hospital. Univariate and multivariate analyses were performed using Cox models. The most important independent baseline predictor of transplant outcome, together with response after transplant, was International Staging System (ISS). We thus incorporated response to transplant and baseline ISS in a new scoring system, named response-adjusted international scoring system (RaISS), that was able to classify patients in three risk groups (low, intermediate, high) with different probabilities of progression after transplant (median PFS 35.9-15.4 months). The prognostic value of this new score was confirmed in the validation cohort. In conclusion, RaISS is a new simple and easily available scoring system that, accurately defining the risk of progression, can allow to identify patients who could deserve further treatment after transplant (consolidation, maintenance).

Vertebroplasty for pain relief and spinal stabilization in multiple myeloma.

Mechanical stabilization of oncological vertebral fractures with cement augmentation is the first mechanism of pain relief, with or without restoration of vertebral body height. The aim of this study was to assess the safety and efficacy of vertebroplasty for painful vertebral body fractures in patients with multiple myeloma, in each phase of the disease. The authors reviewed a consecutive group of patients with multiple myeloma who underwent vertebroplasty at our Institute between November 2003 and December 2005. Twenty-eight levels were performed on 11 patients during 14 treatment sessions. All patients suffered from intractable back pain, and presented various lesion types (with and without fractures of posterior wall, and with and without epidural disease). The preoperative median visual analog scale (VAS) score was 7. The median duration of symptoms was 1.1 months. Eight patients were ambulating with orthopaedic devices (57%) in the pre-treatment period. Improvement or complete pain relief was observed in all patients (immediately in 8 cases, and after 2 days in 6 cases). The median VAS pain score decreased to 2. There was no symptomatic procedure-related complication. There were three cases (21%) of PMMA leakage: in the disc space in one case (7%), and in the anterior spinal canal in two cases (14%). Complete removal of orthopaedic devices was obtained in five patients (36%). No new deformation or collapse of the treated vertebrae was observed during the follow-up (range 1 day-25 months). In conclusion, vertebroplasty is a safe and efficient procedure in the treatment of painful vertebral body fractures in patients with multiple myeloma, without potential contraindications, such as fractures of the posterior wall or epidural disease. We also treated three and more levels in 28% of cases in a single session without complications. Due to the early pain relief and the low complication rate, it is possible to expand the indication to vertebroplasty for the prophylactic augmentation of those vertebral bodies at risk of fracture in which significant neoplastic substitution of the body is present.

Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy.

This retrospective study evaluated whether early 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) after two cycles of salvage chemotherapy (PET2) could predict survival after high-dose chemotherapy (HDC). Twenty-four Hodgkin lymphoma (HL) patients were included. PET2 was negative in 58% and positive in 42% of patients. Ninety per cent of patients (9/10) with positive PET2 relapsed after HDC while all but one patient with negative PET2 maintained a complete remission. The 2-year progression-free survival was 93% vs. 10% for patients with negative and positive PET2, respectively (P < 0.001). This study shows that interim PET can predict the outcome after high-dose chemotherapy in HL patients.

Melphalan, prednisone, and lenalidomide for newly diagnosed myeloma: kinetics of neutropenia and thrombocytopenia and time-to-event results.

BACKGROUND: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. PATIENTS AND METHODS: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. RESULTS: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%. CONCLUSION: MPR is a promising regimen with manageable hematologic toxicity.

Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Response to pre-transplant salvage chemotherapy remains the most important prognostic factor for outcome in refractory or relapsed Hodgkin's lymphoma. Results of a new induction regimen are reported in terms of response rates, toxicity, and stem cell mobilization. DESIGN AND METHODS: Ninety-one patients with refractory or relapsed Hodgkin's lymphoma were treated prospectively with a salvage regimen consisting of ifosfamide 2000 mg/m2 on days 1 to 4, gemcitabine 800 mg/m2 on days 1 and 4, vinorelbine 20 mg/m2 on day 1, and prednisolone 100 mg on days 1 to 4 (IGEV). RESULTS: Forty-nine patients (53.8%) achieved a complete remission and 25 (27.5%) a partial response for an overall response rate of 81.3%. In the multivariate analysis response to the last chemotherapy (p<0.0001) and involvement of > or =3 sites (p<0.049) were the most important prognostic factors for response. Adequate CD34+ cell collection was achieved in 78 out of 79 (98.7%) mobilized patients. So far, no treatment-related death has been documented. Thirteen (4.2%) and 27 (8.6%) out of 313 evaluated cycles had to be delayed or reduced, respectively, mainly because of neutropenia and thrombocytopenia. No grade 4 non-hematologic toxicity was observed, except for one episode of mucositis. INTERPRETATION AND CONCLUSIONS: The high response rate, in particular the complete remission rate, the low toxicity profile, and the very high mobilizing potential of the IGEV regimen strongly suggest that patients with relapsed/refractory Hodgkin's lymphoma may benefit from the use of this salvage induction regimen.

POEMS SYNDROME: an Update.

POEMS syndrome is a rare, chronic and disabling condition. The causes of this condition remain unknown; however, chronic overproduction of proinflammatory cytokines appears to be a major contributor. Early diagnosis is essential to start treatment before the clinical state of the patient becomes compromised. A complete evaluation of the disease at its onset is critical to the treatment decision. In localized disease, curative doses of radiation (50 Gy) is the recommended therapy. On the other hand, patients with disseminated disease should be given systemic therapy. Treatment-related morbidity can be minimized by an efficient induction therapy that modifies the cytokine status, improving clinical condition and control disease severity before mobilization and transplantation. Patients not suitable for hematopoietic stem cell transplantation (HSCT) are usually treated with alkylator-based therapy. Novel agents may also offer benefits to patients with a poor performance status or renal dysfunction, and induce transplantation eligibility. Given the biological characteristics of POEMS, immunomodulatory effects and the absence of neurotoxicity, lenalidomide appears to be an effective therapy for the treatment of POEMS, both as short induction therapy before PBSCT and in non-transplant eligible patients, as it showed high response rate and durable responses. At present, however, guidelines for the diagnosis and treatment of POEMS are not available and appear advocated.

Advances in the Treatment of Paraproteinemic Neuropathy.

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy. Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib. Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials.

Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function.

BACKGROUND: Multiple myeloma (MM) is a hematologic neoplasia characterized by the monoclonal proliferation of bone marrow plasma cells. Renal failure occurs in 20% to 30% of MM patients at diagnosis and in >50% with an advanced form of the disease. For those with advanced MM, often a high-risk group of patients with poor prognosis, salvage treatment for renal failure needs to avoid nephrotoxic drugs. CASE SUMMARY: We report a case of a 78-year-old white male (weight, 90 kg) presented to the Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy, with refractory MM immunoglobulin G kappa (IgGkappa), Durie-Salmon Stage IIA, with progressive renal failure after an oral melphalan, prednisone, and thalidomide regimen (4 mg/m2.d, 40 mg/m2.d for 7 days every 6 weeks, and 100 mg/d, respectively). The patient had documented increments of serum monoclonal component (M-protein), anemia, and renal failure with Bence Jones proteinuria (serum creatinine, 2.9 mg/dL; creatinine clearance, 30 mL/min; hemoglobin, 10.9 g/dL; serum IgGkappa M-protein, 3.9 g/dL; proteinuria 3.5 g/d;light-chain level in urine, 1.2 g/L). After 2 cycles with bortezomib at a reduced dose (1.0 mg/m2 twice weekly for 2 weeks followed by a 10-day rest period) to evaluate tolerability and renal toxicity, the patient completed another 3 cycles at the standard dose (1.3 mg/m2) in combination with dexamethasone (20 mg on the day of bortezomib administration and the day after). This led to an improvement of the renal function with a reduction of serum and urinary M-protein (serum creatinine 1.4 mg/dL; serum IgGkappa M-protein, 2.9 g/dL; proteinuria, 2 g/d; kappa light-chain level in urine, 0.7 g/L). The patient developed thrombocytopenia but did not suffer from some of the more severe adverse events associated with bortezomib, such as infection or peripheral neuropathy, even at full dose. CONCLUSION: We report an elderly patient with refractory MM and progression with renal failure who responded to bortezomib treatment. Bortezomib was well tolerated in this patient.

High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study.

PURPOSE: The prognosis of metastatic/high-risk localized small round-cell tumors (SRCTs) treated conventionally is dismal. In this phase II study, we explored a high-dose chemotherapy (HD-CT) approach and analyzed the clinical significance of fusion transcripts detection. PATIENTS AND METHODS: From June 1997 to November 1999, 28 SRCT patients (median age, 26 years; 14 peripheral primitive neuroectodermal tumors [pPNETs], seven rhabdomyosarcomas [RMSs], and seven desmoplastic small round-cell tumors [DSRCTs]) received induction chemotherapy with ifosfamide, epirubicin, and vincristine followed by HD-CT. Local treatment (radiotherapy and/or surgery) was performed when possible. Molecular analysis was performed on peripheral-blood and leukapheresis products by reverse-transcriptase polymerase chain reaction. RESULTS: Overall response (OR) was 65% (18 of 28), with 40% complete response and 25% partial response. According to histology, the OR rate was 86% in pPNET and 43% in both RMS DSRCT. With a median follow-up of 35 months, median overall survival was 16 months and median progression-free survival (PFS) was 10 months. PFS was statistically better in pPNET than other histologic types (P =.0045). No correlation was found between the fusion transcript and clinical outcome during follow-up. Furthermore, transcript detection in leukapheretic products was not of prognostic significance. CONCLUSION: Intensive HD-CT seems to enhance the response rate and survival when compared with conventional treatment in poor-prognosis pPNET. The poor results of this treatment in RMS and DSRCT do not support the inclusion of such an approach in these patient subsets. No definitive conclusions can currently be drawn concerning the clinical implications of the detection of fusion transcripts during treatment or follow-up.