[Show abstract][Hide abstract] ABSTRACT: Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP) and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (p=0.2). The 5 and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (p=0.054). Overall, the 5 and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43% and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T.
Full-text · Article · Aug 2014 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.
Full-text · Article · Sep 2012 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Background. Multiple myeloma (MM) is mainly a disease of the elderly and it has become common to treat patients of ≥80 years of age. However, octoge-narians are often excluded from clinical trials due to comorbidities, very poor performance status or socioeconomic reasons. Aims. To describe the disease characteristics and identify prognostic factors in MM patients ≥80 years of age. Methods. We searched the database of the Greek Myeloma Study Group to identify patients with symptomatic myeloma who were ≥80 years of age at the time of initial therapy and who were treated in the novel agent era (between 1/1/2003 and 31/12/2010.) Results. Among 682 patients we identified 155 (23%) patients ≥80 years of age. Most octogenarians were males (57%) and had a poor ECOG performance status (PS ≥2) (60%); 70% had lytic bone dis-ease, 53% anemia (Hb<10 mg/dl), 17% low platelet counts (<130x109/L), 11%elevated serum LDH (≥300 IU/L), while 59% had ISS-3, 34% ISS-2 and only 7% had ISS-1 MM (p=0.001). RI was common: 31% had serum creatinine ≥2 mg/dl but 63% had an eGFR <60 ml/min and 32% an eGFR <30 ml/min. When compared to patients <80 years of age, octogenarians had more often poor PS (p=0.001), anemia (p=0.006), elevated serum creatinine and low eGFR (p<0.001), low serum albumin (p<0.001) and elevated beta2-microglobulin (p<0.001). Upfront therapy with novel agents was given in 49% of octogenar-ians vs. 70% of patients <80 years (p<0.001). Response to first line therapy (≥PR) was lower in patients ≥80 years (58% vs. 78%; p<0.001). The median survival of patients ≥80 years was 22 months vs. 46 months for patients 66-79 years and 81 months for patients ≤65 years (p<0.001). Among octogenarians, 14% died ≤2 months from initiation of therapy vs. 3% for patients ≤80 years. In the univariate analysis, poor PS (16 months vs. 29 months, p<0.001) and ele-vated LDH ≥300 IU/L (9.4 vs. 27.5 months, p=0.016) were associated with poor survival in octogenarians. There were no significant differences in the characteristics of patients who were treated with novel agents or with conven-tional chemotherapy (CC). The median survival of octogenarians who were treated upfront with CC was 17 months vs. 26 months (p=0.3) for those who received upfront novel agents. Early death rates were similar. In an analysis, that excluded patients who died early (<2 months), response to first line ther-apy was associated with improved survival (29 vs. 16 months, p<0.001). In mul-tivariate analysis, poor PS was the most important prognostic factor; upfront therapy with novel agents was independently associated with improved survival (HR: 0.64, 95%CI: 0.41-0.98, p=0.042), while male gender and ISS-3 MM were independently associated with poor survival. Conclusions. Patients ≥80 years of age with symptomatic myeloma often present with high risk features. Their median survival is <2 years and early mortality is high. Upfront use of novel agents is associated with significant survival benefit; however, reduced doses and aggressive supportive care are needed in order to reduce early mortality and to improve safety and patients’ survival.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) affects mainly elderly persons and because the population of octogenarians increases, it is common to treat patients ≥ 80 years of age. These patients are often not included in clinical trials; thus, there is limited data on their characteristics and treatment outcome.
We retrospectively analyzed 682 consecutive, unselected patients with newly diagnosed symptomatic myeloma who started treatment between January 1, 2003 and December 31, 2010.
We identified 155 (23%) patients ≥ 80 years of age. Compared to patients <80 years, octogenarians had poorer performance status (P < 0.001), anemia (P = 0.006), low serum albumin (P = 0.001), and advanced ISS (P < 0.001). The median survival of patients ≥ 80 years was 22 months, and 14% died within 2 months from therapy initiation. The median survival of patients ≥ 80 years who received upfront novel agents was 26 vs. 17 months for those who did not. ECOG performance status ≤ 1 and frontline use of novel agents were independently associated with better survival. Response to first-line therapy was associated with improved survival (29 vs. 16 months, P = 0.017).
Patients ≥ 80 years of age present with features of advanced myeloma and impaired performance status. The addition of novel agents may improve their outcome, but careful assessment and prospective clinical trials targeting the population of elderly patients are needed.
Full-text · Article · Apr 2012 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.
Full-text · Article · Feb 2012 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells are cytotoxic lymphocytes able to kill tumor cells and virus-infected cells. Human-resting NK cells can be activated by co-culture with NK-resistant CTV-1a cells. These tumor-activated cells (TaNKs) are cytotoxic to a range of NK-resistant tumor cells in vitro. This potential, however, has not been explored in multiple myeloma (MM). In this study, we demonstrate that TaNK cells from 21 MM patients lyse a variety of myeloma targets, including primary isolates of autologous and allogeneic CD138+ myeloma cells whilst sparing CD138-ve bone marrow cells. Myeloma patients' TaNK-induced lysis of the U266 cell line was significantly higher compared to normal controls (median-specific lysis 79.1% vs. 69.5%) (P = 0.003). In addition, TaNKs induced substantial lysis of autologous and allogeneic CD138+ myeloma cells (median-specific lysis 52.5% and 37.4%, respectively). The percentage of specific lysis did not correlate with important disease characteristics (ISS, age, and high-risk molecular abnormalities) or with the disease status and antimyeloma treatment, including novel agents and dexamethasone. In conclusion, tumor-primed NK cells are able to induce substantial lysis of myeloma targets including autologous and allogeneic CD138+ myeloma plasma cells and could be an additional therapeutic approach in MM, particularly in the era of novel agents.
Full-text · Article · Dec 2011 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: The International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum β2-microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include 'up-staged' MM patients in whom elevated β2-microglobulin reflects the degree of renal dysfunction rather than tumor load.
In order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria.
Forty-eight percent patients had stages 3-5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day.
ISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction.
[Show abstract][Hide abstract] ABSTRACT: The treatment of Waldenström's macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2-microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent-based regimens and most patients who started treatment after January 1, 2000 received rituximab-based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high-risk disease. Possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients.
Full-text · Article · Jun 2011 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these "poor-risk" patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.
[Show abstract][Hide abstract] ABSTRACT: Background. Renal impairment (RI) is a common complication of mul¬tiple myeloma (MM). Cystatin-C (Cys-C) is considered as a sensitive marker of glomerular filtration rate (GFR). A recent study in >37400 pa¬tients with chronic kidney disease (CKD) showed that estimating GFR (eGFR) based on serum creatinine(sCr)7 Cys-C7 age, gender and race (eGFR/Cys/Cr) provides the most accurate GFR estimates: eGFR=177.6 x Scr-0.65 x CysC-0.57 x age-0.20 x (0.82 if female) x (1.11 if black). How-ever7 this new formula has not been evaluated in MM. Aim. The aim of this study was to evaluate eGFR/Cys/Cr in newly-diagnosed MM pa-tients7 compare it with eGFR assessed by MDRD equation and explore possible correlations with clinical data; including survival. Methods. We studied 157 newly-diagnosed7 symptomatic, MM patients (87M/70F7 median age 68 years) before any kind of therapy and evaluated both eGFR/Cys/Cr and eGFR/MDRD. Serum Cys-C was determined by par¬ticle enhanced immunonephelometry (Bade Behring7 Liederbach, Ger¬many). Results. Serum Cys-C was increased in MM patients compared to 52 controls [median: 1.01 mg/L vs. 0.72 mg/L7 p<0.0001] and was signif¬icantly correlated to sCr (R2=0.497, p<0.001) and beta2-microglobulin (R2=0.42, p<0.001). Median values of eGFR/Cys/Cr (68.7 ml/min/1.73m2) were not different compared with those of eGFR/MDRD (66.1 ml/min/1.73m2). There was also no difference in terms of number of pa¬tients with RI of different stages between the two estimates (39% of pa¬tients had CKD 3-5 by the MDRD equation and 41% by the eGFR/Cys/Cr equation). However, in 15% of patients, there was a dif¬ference in CKD staging according to the two methods: 13 (8%) patients were CKD 3-5 by eGFR/Cys/Cr but CKD 1-2 by eGFR/MDRD7 while 10 (6%) were CKD 1-2 by eGFR/Cys/Cr but CKD 3-5 by eGFR/MDRD. eGFR/Cys/Cr was correlated with ISS (p<0.001). The median survival was 48 months (median follow-up: 20 months). In the univariate analysis, CKD 3-5 assessed by eGFR/Cys/Cr (HR-.2.937 p<0.001) was a stronger prognostic factor than CKD 3-5 assessed by eGFR/MDRD (HR:1.85; p=0.018). Elevated LDH,ISS stage, bone disease and myeloma subtype (light chain only MM vs. others) were also associated with sur¬vival in the univariate analysis. In ISS-2, eGFR/Cys/Cr could identify a subgroup of patients with poor survival: 19 patients with eGFR/Cys/Cr <68.7 rnVmin/1.73m2 had a median survival of 23.9 months, while the median survival of all other (n=32) has not been reached (p=0.003). How¬ever, eGFR/MDRD, either by using the median as a cutoff or by using the CKD stage, could not discriminate prognostic groups within ISS-2. In a multivariate analysis eGFR/Cys/Cr was the strongest prognostic factor for survival, either as continuous variable (HR 0.986; p-0.004) or as a di-chotomous at median (HR-.0.380, p=0.01); other factors included bone disease (HR 2.220; p=0.018) and LDH (HR 2.782; p=0.025). Summary/Conclusions. These results suggest that eGFR/Cys/Cr estimates RI comparable to eGFR/MDRD. However, only eGFR/Cys/Cr strongly correlates with survival, while it could identify a subgroup of patients with ISS-2 disease with poor outcome. This may be due to the better re¬flection of both renal function and tumor burden by eGFR/Cys/Cr, as Cys-C is also overproduced by myeloma cells.
[Show abstract][Hide abstract] ABSTRACT: High serum lactate dehydrogenase (LDH) is associated with features of advanced disease and inferior survival in multiple myeloma. It is however unclear whether LDH adds to the prognostic value of International Staging System (ISS) and whether it retains its prognostic significance in patients who are exposed to novel agent-based therapies.
To address these issues we analyzed 996 consecutive symptomatic patients who were included in the database of the Greek Myeloma Study Group and received frontline treatment between January 1, 1995 and December 31, 2008.
The median overall survival (OS) of all patients was 40 months with a clear improvement in those who started treatment after January 1, 2000 (49 vs. 31 months; P < 0.01). A multivariate model showed that LDH, ISS, performance status, age and platelet counts had an independent prognostic value for OS (P < 0.001 for all parameters). The median OS of patients with high (11% of patients) and normal LDH was 15 vs. 44 months (P < 0.001). High LDH was associated with inferior OS within all ISS groups: 22 vs. 76 months for high and normal LDH groups, respectively, in ISS-1 (P < 0.01); 11 vs. 40 months in ISS-2 (P < 0.001) and 17 vs. 27 months in ISS-3 (P < 0.01). The median OS of high and normal LDH groups among patients who received novel agents was 21 vs. 51 months, respectively (P < 0.001).
Lactate dehydrogenase is a readily available and inexpensive variable, which has a major impact on the survival of myeloma patients even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapies.
Full-text · Article · Aug 2010 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.
Full-text · Article · May 2010 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: Primary systemic light-chain (AL) amyloidosis is characterized by the deposition of immunoglobulin light chain-derived amyloid fibrils in various tissues leading to multiorgan dysfunction.
In order to define characteristics, treatment, and outcome of Greek patients with AL amyloidosis, we analyzed 112 unselected patients with AL from several hospitals.
The heart was involved in 59% of patients and kidneys in 71%. Patients were treated with several different treatment regimens; high-dose dexamethasone-based regimens were used as primary treatment in 43% and melphalan-based regimens in 37%, while 12% received up-front bortezomib with dexamethasone. A hematologic response to first-line therapy was documented in 50% (complete response, 14.5%), and organ responses were observed in 25% of patients, the latter being strongly associated with achievement of hematologic response. Median overall survival was 34.2 months and was independently affected by heart involvement, creatinine, age, involvement of > or = 2 organs, and bone marrow plasmacytosis > 30%. In patients with cardiac involvement, advanced age and extended bone marrow plasmacytosis were associated with an even worse outcome, while for patients without heart involvement, only bone marrow plasmacytosis was independently associated with survival. Hematologic response was associated with improved survival in patients with heart involvement but mostly in patients with less bone marrow infiltration.
In this first series of patients from Greece with AL amyloidosis, disease features and outcome appeared similar to those reported from tertiary centers. Heart involvement and bone marrow plasma cell infiltration comprise adverse prognostic factors but also indicate the heterogeneity of the disease and the need for individual treatment approaches.
No preview · Article · Feb 2010 · Clinical lymphoma, myeloma & leukemia
[Show abstract][Hide abstract] ABSTRACT: Anemia is a common side-effect of patients with multiple myeloma (MM) and lymphoma. The etiology is complex, but the main cause is the underlying mechanism of anemia of chronic disease, which is characterized among others, by impairment of iron metabolism and consequently iron restricted erythropoiesis (IRE), resulting from the up-regulation of the iron distributing regulator, hepcidin. Erythopoiesis-stimulating agents (ESAs) have been the standard of care since early 90's offering high response rates and improving the quality of life of the patients. However, the role of ESAs in the treatment of cancer-related anemia has been questioned recently, due to the growing evidence which support that ESAs may be associated with increased risk for thrombosis and may have a detrimental impact on patients' survival. Under the light of the recent considerations, the place of ESAs in the management of cancer-related anemia has been reassigned. Regarding the management of anemia in MM or lymphoma, the updated American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) 2007 clinical practice guidelines on the use of ESAs in cancer-related anemia, recommended that ESAs should be preferably omitted in patients planned to receive chemotherapy and applied in case that anemia does not improve over treatment. The quest for reliable predictors for response to ESAs and for indicators of IRE which plays a major etiological role for the development of anemia of cancer still remains an open issue. In the current review we present an update on ESAs use in anemia of MM and lymphoma.
No preview · Article · Oct 2009 · Cancer Treatment Reviews
[Show abstract][Hide abstract] ABSTRACT: The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate.
Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated.
We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP.
The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.
Full-text · Article · Oct 2009 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: : Results of studies using IFN-α treatment for maintaining remission and prolonging survival in multiple myeloma (MM) are in conflict and trials seeking optimum use for this biological response modifier are continuing. Between 1989 and 1993 a prospective randomized multicentre trial was undertaken to evaluate the role of the combination of IFN-α with chemotherapy (CT) in maintenance treatment of MM. For remission induction, in patients 65 yr or younger, we used VAD (group A) and for the remaining Melphalan and Prednisone (MP) (group B). For maintenance, patients were randomized to receive IFN-α 3times106 i.u. s.c. t.i.w. (group I) or alternating monthly cycles of IFN-α and CT. The CT cycles were also alternated (VAD, MP, CP) in an effort to prevent the development of multidrug resistance. Median survival of the two maintenance groups from randomization (36 months for group I and 31 months for group II, p=0.3) as well as response duration (13 months in group I and 15 months in group II, p=0.95) were similar. Toxicities were more pronounced both with VAD induction and in the combination maintenance arm. The addition of chemotherapy to the IFN maintenance regimen in MM did not have an advantage over IFN alone.
No preview · Article · Aug 2009 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: Hepcidin is a liver-derived hormone with a central role in iron regulation and in anemia of inflammation. Its correlations with disease variables, anemia response (AR), and responses to treatment have not been investigated in multiple myeloma (MM). A cohort of anemic MM patients undergoing treatment with immunomodulatory drug (IMiDs)-based regimens (n = 18) or conventional chemotherapy (n = 16) was studied. Overall, hepcidin decreased significantly between baseline and treatment Cycles 2 and 4 (P < 0.05), and this was more profound in the IMiDs group compared with the conventional group. Baseline hepcidin inversely correlated with baseline hemoglobin (Hb) and platelets (PLT) and positively correlated with b2M, ferritin, transferrin saturation (TSAT%), and International Scoring System (ISS) (P < 0.05). Abnormally high baseline hepcidin inversely correlated with duration of response (DOR) in all studied patients and in the conventional group. Abnormally high hepcidin before treatment Cycles 2 and 3 predicted for AR and disease response (DR), respectively, in all studied patients (P < 0.05). These results suggest that serum hepcidin correlates with significant MM variables and may serve as a surrogate marker for MM and as a predictor for response indicators.
Full-text · Article · Aug 2009 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Renal impairment is a common complication of multiple myeloma. Cystatin-C is considered an accurate marker of glomerular filtration rate in several renal disorders. Microarray analysis has revealed that cystatin-C is one of the most highly up-regulated genes in multiple myeloma. The aim of this study was to evaluate the serum levels of cystatin-C in myeloma patients, explore possible correlations with clinical data, including survival, and assess the effect of bortezomib on cystatin-C in relapsed multiple myeloma.
We measured serum cystatin-C in 157 newly diagnosed, previously untreated myeloma patients, in 28 patients with relapsed disease pre- and post-bortezomib therapy and in 52 healthy controls, using a latex particle-enhanced nephelometric immunoassay.
In newly diagnosed patients, cystatin-C was elevated and showed strong correlations with advanced ISS stage, extensive bone disease, high beta(2)-microglobulin, high serum creatinine, and low creatinine clearance. Multivariate analysis revealed that only cystatin-C and lactate dehydrogenase had an independent prognostic impact on patients' survival. The combination of cystatin-C and lactate dehydrogenase revealed three prognostic groups of patients: a high-risk group (both elevated cystatin-C and lactate dehydrogenase) with a median survival of 24 months, an intermediate-risk group (elevated cystatin-C or elevated lactate dehydrogenase) with a median survival of 48 months and a low-risk group (both low cystatin-C and lactate dehydrogenase) in which median survival has not yet been reached (p<0.001). Cystatin-C could also identify a subset of ISS-II patients with worse outcome. Relapsed patients had higher cystatin-C levels even compared to newly diagnosed patients. Treatment with bortezomib produced a significant reduction of cystatin-C, mainly in responders.
Serum cystatin-C is not only a sensitive marker of renal impairment but also reflects tumor burden and is of prognostic value in myeloma. Its reduction after treatment with bortezomib reflects bortezomib's anti-myeloma activity and possibly bortezomib's direct effect on renal function.