Laura Corvatta

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres

Summary. A retrospective survey was conducted over a 10‐year period (1990–99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non‐Hodgkins lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non‐productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar–interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0·006) and a radiological picture of diffuse lung involvement (P < 0·003) were negative diagnostic factors.

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy

Objectives:  Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side‐effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side‐effect.

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma

Abstract The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

A Predictive Model of Varicella-Zoster Virus Infection after Autologous Peripheral Blood Progenitor Cell Transplantation

Varicella-zoster virus (VZV) frequently causes severe infections in patients who have undergone bone marrow transplantation. The frequency of, characteristics of, and risk factors for this infection were studied in 164 patients undergoing autologous peripheral blood progenitor cell transplantation (PBPCT). Twenty-six patients (15.8%) developed VZV infection, and the actuarial risk was 10% at 1 year. No patient had visceral dissemination or died because of VZV, although one-third of the patients developed postherpetic neuralgia. By multivariate analysis, a CD4(+) lymphocyte count of <200 cells/microL (P<.0001; odds ratio [OR], 2.0) and a CD8(+) lymphocyte count of <800 cells/microL (P=.0073; OR, 2.0) at day 30 after transplantation were factors associated with VZV infection. Patients with both these adverse factors had an actuarial risk of VZV of 48% at 1 year. Patients with deficiency in both CD4(+) and CD8(+) lymphocytes are at high risk of VZV infection. These patients should be considered as candidates for preventive therapy, but whether for antiviral therapy or vaccination remains to be investigated.

Thalidomide-dexamethasone versus Interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive α‐interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty‐one patients were randomized in the IFN‐dexamethasone (ID) arm and 52 in the thalidomide‐dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2‐years progression‐free survival (PFS; 63% vs. 32%; P = 0·024) and overall survival (84% vs. 68%; P = 0·030) was observed in the thalidomide arm. In high‐risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm (P = 0·014). Low‐dose thalidomide plus pulsed low‐dose dexamethasone after conventional thalidomide combination‐based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.

Technetium-99m sestamibi scintigraphy is sensitive and specific for the staging and the follow-up of patients with multiple myeloma : a multicentre study on 397 scans

We evaluated the additional benefit of Technetium99‐sestamibi (99mTc‐MIBI) scanning in comparison with standard X‐ray techniques for multiple myeloma patients either at diagnosis or during follow‐up. Between February 2001 and January 2005, 397 whole body scans were acquired. On 229 scans performed at diagnosis, 146 (64%) were positive and 81 cases have discordant X‐ray results. The sensitivity of 99mTc‐MIBI and X‐ray were 77% and 45% respectively. As a result of 99mTc‐MIBI, 40% of asymptomatic myeloma patients were up‐staged. The positivity of 99mTc‐MIBI correlated significantly with all of the most relevant clinical and biological parameters. Multivariate analysis selected only high reactive C protein (P = 0·0005), bone marrow infiltration (P = 0·02) and bone pain (P = 0·002) as factors affecting 99mTc‐MIBI pattern. In 22 patients with solitary myeloma, 99mTc‐MIBI was positive in 86% of cases and detected more disease sites than X‐ray. Among 168 scans performed during follow‐up, 99mTc‐MIBI presented high specificity in patients showing a complete response (CR; 86%), and correlated with myeloma activity and with response to therapy. At multivariate analysis, a positive pattern correlated with bone marrow infiltration (P = 0·002) and disease status other than CR (P = 0·03). We conclude that 99mTc‐MIBI scanning is an additional diagnostic tool with a high specificity for the staging and the follow‐up of multiple myeloma patients.

An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma

Proteasome inhibition represents one of the more important therapeutic targets in the treatment of multiple myeloma (MM), since by suppressing nuclear factor-κB activity, which promotes myelomagenesis, it makes plasma cells susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor approved for MM therapy, has been shown to increase response rate and improve outcome in patients with relapsed/refractory disease and in the frontline setting, particularly when combined with immunomodulatory drugs and alkylating agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss. Ixazomib was found to overcome bortezomib resistance and to trigger synergistic antimyeloma activity with dexamethasone, lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a single agent, showing important activity in this difficult-to-treat plasma-cell dyscrasia. More frequent side effects observed during administration of ixazomib were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas severe peripheral neuropathy was rare. Here, we review the chemical characteristics of ixazomib, as well as its mechanism of action and results from preclinical and clinical trials.

Infectious complications in patients with multiple myeloma treated with new drug combinations containing thalidomide.

The literature provides scant data concerning infectious complications and their effect on the outcome of patients with multiple myeloma (MM) treated with new drug combinations. Despite no substantial myelotoxic effect, thalidomide increases the risk of severe infections in patients with MM. We studied 202 patients who received regimens containing thalidomide in order to assess the time, type, outcome, and factors affecting development of severe infections, role of antibiotic prophylaxis, and effect of severe infections on final outcome. Thirty-eight patients (19%) developed a severe infection early during induction therapy and most infections were pneumonia. Only one patient died due to septic shock during neutropenia. No significant differences were reported in terms of progression-free survival (PFS) and overall survival (OS) between patients developing a severe infection and those who did not. Multivariate analysis determined a monoclonal component >3 g/dL and platelets <130 000/μL as factors associated with increased risk of severe infection. Primary antibiotic prophylaxis significantly decreased the probability of severe infection only in patients having both the above risk factors. Patients with MM receiving thalidomide combinations with high tumor burden are at high risk of developing severe infections and require primary antibiotic prophylaxis, whereas in other patients it is questionable. However, patient final outcome was not affected by infection development.

Ixazomib for the treatment of multiple myeloma

Introduction: Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 (ixazomib) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss. Areas covered: In this review, the authors discuss the rationale for use of PIs. They then summarize the clinical development of ixazomib in MM, from initial Phase I to Phase II studies as a monotherapy and in combination with other chemotherapeutics. Expert opinion: Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.