Risk of second cancers in Waldenström macroglobulinemia.

BACKGROUND: An increased incidence of second cancers has been reported in lymphoproliferative disorders. PATIENTS AND METHODS: We 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. RESULTS: Twenty-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). CONCLUSIONS: WM 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.

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

BACKGROUND: There 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. PATIENTS AND METHODS: The 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. RESULTS: Overall, 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. CONCLUSIONS: The 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.

Low efficacy of thalidomide in improving response after induction in multiple myeloma patients who are candidates for high-dose therapy.

Giving the impact of complete response (CR) on outcome of multiple myeloma patients addressed to high-dose melphalan, we explored the role of a pre-transplant intensification with 3 months thalidome plus dexamethasone therapy (Thal-Dex), after pulse-VAD induction. Seventy-four multiple myeloma patients (MM pts) uniformly treated, were retrospectively studied. The response rate after pulse-VAD were: CR 6%, VGPR 40%, PR 23%, MR 23%, and progression 8%. The response rate after Thal-Dex were similar: CR 11%, VGPR 39%, PR 17%, MR 9%, and progression 24%. Giving no advantage in terms of response rate with an additive toxicity, Thal-Dex does not seem useful for intensification before transplant.

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma.

Osteonecrosis of the jaw (ONJ) is a reported complication of bisphosphonate use. The incidence ranges between 6 and 13% and seems to be higher in people treated with zoledronic acid (ZA) than with pamidronate. We retrospectively evaluated the incidences of ONJ and skeletal-related events (SRE) in 106 patients with multiple myeloma divided in two groups according to the schedule of administration of bisphosphonates: 51 received monthly administrations until tolerated (group A, standard schedule), 55 were treated monthly during the first year and then every 3 months (group B, reduced schedule). The incidence of SRE was similar (15.1 per 100 person years in group A and 17.7 in group B). ONJ occurred in seven patients, six in group A and one in group B (P=0.049). The risk of ONJ was eight-fold lower with the reduced schedule than with the standard schedule. The only significant risk factor for ONJ was the type of bisphosphonate (P=0.006). The incidence of ONJ was significantly higher with ZA than with pamidronate + ZA (9.1 vs 1.6 per 100 person-years). No ONJ was observed in patients treated only with pamidronate. A reduced schedule of ZA may be safer than the standard schedule while maintaining anti-resorptive efficacy.

Efficacy, toxicity and feasibility of a shorter schedule of DCEP regimen for stem cell mobilization in multiple myeloma.

From 2000 to 2004, 152 patients with multiple myeloma aged or=4 x 10(6) cells/kg. The proportion of patients in whom mobilization failed was similar in the two groups. The incidence of WHO grade III neutropenia was higher in group II, although the difference was not statistically significant; the percentage of patients requiring hospitalization for severe infections was similar in the two groups. The incidence of WHO grade IV thrombocytopenia did not differ between the two groups. The response rate was 72% in group I and 80% in group II with similar percentages of patients achieving good responses. DCEP-short is a good mobilizing regimen, sharing the same characteristics as infusional-DCEP: high mobilizing efficacy, low toxicity and good antitumor activity. This new schedule of DCEP does, however, allow complete outpatient management and so could be advantageously included in any high-dose therapy program.

Blood stem cell collections in multiple myeloma: definition of a scoring system.

The purpose of the study was to identify factors that could predict good yields of peripheral blood stem cells (PBSC) in multiple myeloma (MM). Fifty-one MM patients, nine with refractory disease and 42 in plateau phase, were mobilized with high-dose cyclophosphamide (HD-Cy) at 4 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/day. Clinical and laboratory parameters at the time of mobilization were analyzed for correlations with the number of CD34+ cells collected, with the colony-forming unit granulocyte-macrophage (CFU-GM) count, and the mononuclear cell (MNC) count. In univariate analysis, low WBC count, low platelet count, prior exposure to melphalan, and an interval >6 months from the start of treatment correlated with poor yields of CD34+ cells. Low platelet count, prior exposure to melphalan or to radiotherapy, and an interval >6 months from the start of treatment were associated with a low CFU-GM count. On the basis of these data, we defined a scoring system able to predict the yield of the mobilizing procedure. According to this system, the presence of more than one risk factor (low WBC and platelet counts, prior exposure to melphalan, interval from first chemotherapy >6 months) was predictive of insufficient collections when a conventional combination of mobilizing measures are used.

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.

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 (100 mg/day) and dexamethasone (20 mg 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 1st month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.

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, alpha(1)-microglobulin (alpha(1)-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 beta(2)-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 alpha(1)-M also with urea. By contrast, they showed a variable correlation with clinical parameters: alpha(1)-M correlated with bone marrow plasmacytosis (BMPC) ( p=0.02) and beta(2)-M ( p=0.000001), IgG with all three disease parameters (MC p=0.0005, BMPC p=0.009, beta(2)-M p=0.007), and Alb only with beta(2)-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, alpha(1)-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.

Biochemical markers of bone disease in asymptomatic early stage multiple myeloma. A study on their role in identifying high risk patients.

BACKGROUND AND OBJECTIVES: Skeletal involvement is typical of multiple myeloma (MM) and its occurrence increases with the progression of the disease. We performed a study to evaluate the clinical importance of osteocalcin (bone gla-protein, BGP) and bone alkaline phosphatase (b-AP) as indices of osteoblastic activity, and deoxypyridoline (DPD) as a marker of bone resorption. DESIGN AND METHODS: Fifty-two MM patients, 39 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 normal controls entered the study. Of the 52 MM patients, 10 showed lytic lesions at standard X-rays and 42 did not; 21 were untreated and 31 had been treated with chemotherapy (combined with bisphophonates in 15). Of these last, 12 had progressive disease and 19 were in plateau phase. RESULTS: DPD levels were higher in MM patients than in patients with MGUS or healthy controls (p = 0.0001 and p = 0.0008, respectively). No statistical differences were seen between patients with MGUS and healthy controls. BGP serum levels were significantly lower in MM patients than in MGUS patients (p = 0.001) or healthy controls (p = 0.001). b-AP was significantly higher in MGUS patients than in MM patients (p = 0.04). Biochemical parameters were analyzed in a continuous fashion and after dichotomization into low and high values with respect to normal ones. Abnormal high values of DPD showed statistically significant correlations with presence of osteolysis (p = 0.008), advanced stage (p = 0.03) and abnormal beta2-microglobulin (beta2M) values (p = 0.03), while DPD as a continuous variable correlated significantly only with the presence of osteolysis (p = 0.02). In contrast, neither BGP nor b-AP showed statistical correlations with the presence of lytic lesions, or with other clinical or laboratory parameters. In 15 patients followed with serial controls, modifications of DPD levels reflected bone disease status well. Of the 42 patients without radiologic evidence of skeletal lesions, 15 had abnormal DPD values. Spinal magnetic resonance imaging (MRI) showed initial lytic lesions in 10 of them. INTERPRETATION AND CONCLUSIONS: Biochemical markers of bone metabolism are useful in evaluating and monitoring skeletal involvement in MM patients. They may help clinicians to identify: 1) from among patients without radiologic evidence of lytic lesions, those who deserve more accurate radiologic examinations (namely MRI); 2) from among asymptomatic patients, and in association with spinal MRI, those patients at higher risk of progression who might benefit from early treatment.

Consolidation treatment with autologous peripheral blood progenitor cell transplantation in acute myeloid leukemia: a single center experience.

Several trials have suggested that intensive post-remission therapy may prolong the duration of complete remission (CR) in acute myeloid leukemia (AML). The purpose of this study was to evaluate the feasibility and the efficacy of high-dose cytarabine (HiDAC) consolidation chemotherapy followed by high-dose therapy and autologous infusion of peripheral blood progenitor cells (PBPC) mobilized by G-CSF in adult patients with AML in first CR. Fifteen consecutive AML patients underwent HiDAC consolidation chemotherapy, used as a method of in vivo purging, followed by G-CSF for the purpose of autologous PBPC collection. Eleven patients collected a median of 6.9x10(8)/kg peripheral blood mononuclear cells (MNC) (range 2.9-23) and a median of 6.67x10(6)/kg CD34+ cells (range 1.8-33.5) with a median of two aphereses (range 1-3). Two patients did not mobilize and two obtained an inadequate number of progenitor cells. The 11 patients with adequate collections received myeloablative chemotherapy followed by the infusion of PBPC. The median number of days to recover neutrophils and platelets was 12 and 13, respectively. After a median follow-up of 28.7 months (range 17.2-43.4), five out of 11 patients who underwent PBPC transplantation are still in CR, five have died in first relapse and one is alive in CR after relapse treated with salvage therapy and second PBPC infusion. These results demonstrate that HiDAC consolidation chemotherapy followed by autologous PBPC transplantation is a feasible procedure with minimal toxicity. Randomized studies should be performed to evaluate whether this form of consolidation may produce a significant improvement in leukemia-free survival.