Francesco Pisani

Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma

PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

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.

Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib–thalidomide–dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Spike-induced interference in auditory sensory processing in Landau-Kleffner syndrome.

OBJECTIVES Landau-Kleffner Syndrome (LKS) is an epileptic syndrome characterised by a deficit in language comprehension and production, paroxysmal epileptiform activity in the posterior temporal leads, and by the inconsistent presence of epileptic fits. Its interest lies in the fact that it stands as a model for the study of interference of epileptiform activity on cognitive function, although the pathophysiology of the decline in language skills that follows its onset has not yet been clarified. METHODS We have recorded spike-triggered auditory evoked responses in a group of 6 children with LKS, to investigate whether the occurrence of individual EEG paroxysms is able per se to induce a decline in the response of the auditory cortex. RESULTS Results have indicated that left hemisphere spikes are associated with a greater reduction in amplitude and an increase in latency of the NI, than spikes occurring in the right hemisphere. No stable change in the evoked response has been detected outside of the EEG paroxysm. CONCLUSIONS We postulate EEG interictal activity is able to induce impairment in processing auditory information and that this may play a role in the pathogenesis of language deficit in LKS.

Frontal Lobe Epilepsy Associated With Tuberous Sclerosis: Electroencephalographic-Magnetic Resonance Image Fusioning

We studied the topographic relationships between cortical and subcortical lesions shown on magnetic resonance images (MRI) and sources of epileptiform activity in a series of nine children with intractable epilepsy and tuberous sclerosis complex. Although video-electroencephalographic (EEG) monitoring was suggestive of a frontal seizure onset, interictal EEG was, in seven of nine cases, in the form of apparently bisynchronous discharges. In all cases, the use of a short time lag estimation procedure based on a nonlinear correlation function between surface recorded EEG signals allowed the detection of a lateralized onset of EEG paroxysmal activity. Furthermore, a computerized method based on a source localization EEG-MRI image fusioning procedure, has revealed a topographic concordance between well-defmed frontal cortical lesions shown on MRI and site of onset of paroxysmal discharges. Lennox-like EEG patterns frequently reported in children with tuberous sclerosis complex could be the result of the tendency of frontal tubers to induce secondary bilateral synchrony, with implications in the medical and eventually surgical management of the often drug-resistant associated seizures. (J Child Neurol 1998;13:33-38).

Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che‐1, a RNA polymerase II‐binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che‐1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress‐induced autophagy. Strikingly, Che‐1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response.

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.

Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: A single-center study

AIM To determine the incidence of and the risk factors for cytomegalovirus (CMV) symptomatic infection and end-organ disease after autologous stem cell transplantation (ASCT). METHODS A total of 327 consecutive non CD34(+) selected autografts performed from the Hematology and Stem Cell Transplantation Unit of Regina Elena National Cancer Institute of Rome (Italy) in the period comprised between January 2003 to January 2015, were reviewed. Over the 327 autografts, 201 were performed in patients with multiple myeloma, whereas the remaining 126 in patients affected by non-Hodgkins lymphoma and Hodgkins lymphoma. The patients who underwent an ASCT for an acute leukemia (n = 20) in the same period were excluded from this analysis. CMV DNA load in the blood has been determined by polymerase-chain reaction in the case of a clinical suspicion of reactivation, therefore, no routine monitoring strategy was adopted. In the presence of signs and symptoms of CMV reactivation an antiviral treatment was performed. RESULTS Overall, 36 patients (11%) required a specific antiviral treatment for a symptomatic CMV reactivation (n = 32) or an end-organ disease (n = 4). We observed 20 and 16 cases of CMV reactivation among lymphoma (16%) and myeloma patients (8%), respectively. Among cases of end-organ disease, 3 were diagnosed as interstitial pneumonia and one remaining case as hemorrhagic enteritis. All cases of CMV reactivation were observed in IgG seropositive patients, with no documented cases of primary CMV infection. All patients were treated with a specific antiviral therapy, with a global rate of hospitalization of 55%; four patients received intravenous immunoglobulins. Transplant-related mortality was significantly higher in patients who experienced a CMV reactivation (8.4% ± 4.7% vs 1.7% ± 0.8%; P = 0.047). In univariate analysis, a pre-transplant HBcIgG seropositivity, a diagnosis of T-cell non-Hodgkins lymphoma and higher median age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection requiring specific antiviral therapy (P < 0.001, P = 0.042 and P = 0.004, respectively). In multivariate analysis, only a pre-transplant HBcIgG seropositivity (OR = 8.928, 95%CI: 1.991-33.321; P = 0.023) and a diagnosis of T-cell non-Hodgkins lymphoma (OR = 4.739, 95%CI: 1.511-11.112; P = 0.042) proved to be independent predictors of a post-transplant clinically relevant CMV reactivation. CONCLUSION A symptomatic CMV infection can occur in about 11% of adult patients with lymphoma or myeloma undergoing ASCT. A pre-transplant HBcIgG seropositivity and a diagnosis of T-cell non-Hodgkins lymphoma should be considered as independent predictor factors of CMV reactivation.

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4–15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstroms macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O2 therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O2/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O2 hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.