Bone Involvement in Multiple Myeloma Patients Carrying the T (4;14) Chromosomal Translocation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4996-4996
Author(s):  
Patrizia Tosi ◽  
Carolina Terragna ◽  
Testoni Nicoletta ◽  
Elena Zamagni ◽  
Matteo Renzulli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Chromosomal Abnormality ◽  
Surrogate Marker ◽  
Chromosomal Translocation ◽  
Bone Involvement ◽  
Disease Stage ◽  
High Dose ◽  
Spine Mri

Abstract Chromosomal translocations involving the immunoglobulin heavy chain switch region (IgH) are quite common in multiple myeloma (MM), and some of them can reliably predict disease outcome. In particular, t(4;14) chromosomal abnormality is one of the most adverse prognostic factors for response duration and survival after high dose therapy and autologous stem cell transplantation. Despite the dismal prognosis, however, in this subset of patients, bone involvement, as evaluated by spine MRI, is relatively infrequent, at variance to what has been observed in other MM subtypes according to TC classification. In the present study we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared to negative patients. For this purpose, 50 newly diagnosed MM patients (32M, 18F, median age = 54 yrs) underwent evaluation of total skeletal X-ray, whole spine MRI and, at the same time, quantification of markers of bone resorption (urinary NTX, PYR and DPYR and serum crosslaps) and bone formation (bone alkaline phosphatase-BAP and osteocalcin) was performed. Using a real-time PCR assay to detect the presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), we found 15 patients carrying this chromosomal abnormality, 7 of whom (46%) were also positive for the deletion of chromosome 13, this abnormality was detected in 11/35 (31%) patients who proved negative for IgH/MMSET hybrid transcript. The two groups of patients did not differ significantly in terms of median age, distribution of M protein isotype and light chain, beta-2 microglobulin, bone marrow plasma cell infiltration and disease stage. Spinal MRI was negative in 3/15 (20%) t(4;14) positive patients as compared to 12% t(4;14) negative patients; skeletal involvement, however, was more pronounced in t(4;14) positive patients (median skeletal score = 6.24, as compared to 3.58 in t(4;14) negative cases, p= 0.00). These data were confirmed by the evaluation of bone resorption markers; specifically, serum crosslaps were significantly increased in patients with t(4;14) abnormality compared to negative individuals (7984 pmol/L±1682SE vs 5123pmol/L±783SE p=0.04). Conversely, no difference in bone formation markers was found in the two groups of patients. Our results indicate that, despite a spinal involvement at MRI that is comparable to what is observed in negative patients, individuals who are t(4;14) positive show a more pronounced bone resorption pattern, this in contrast to what has been reported so far, but in line with the aggressive features of the disease in these patients.

High Dose Simvastatin Has No Beneficial Effect on Markers of Bone Turn-Over in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4824-4824
Author(s):  
Teis E. Sondergaard ◽  
Per T. Pedersen ◽  
Thomas L. Andersen ◽  
Thomas Lund ◽  
Patrick Garnero ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Pilot Study ◽  
Bone Resorption ◽  
Bone Formation ◽  
High Dose ◽  
Osteoclast Activity ◽  
Bone Formation Markers ◽  
Bone Degradation ◽  
Activity Trap

Abstract Background: Bone degradation in multiple myeloma (MM) is a result of increased bone degradation by osteoclasts that is not compensated for by bone forming osteoblasts. Ideally new drugs used for treatment of MM should target not only the myeloma cells but also the imbalance between bone resorption and bone formation. Statins have been shown to inhibit myeloma cell proliferation and induce apoptosis in vitro. Furthermore statins have been shown to stimulate osteoblasts and inhibit osteoclasts both in vitro and in animal models. Statins are normally used at doses around 20–80 mg/day, but in order to reach serum concentrations that can match the in vitro experiments MM patients were treated with 15 mg/kg/day of Simvastatin (HD-Sim) divided in two daily doses in this study. This high dose has previously been found to be safe for MM patients (Haematologica 2006, 91,542–545) Patients and methods: Six patients with advanced MM have been included in this pilot study, 4 males and 2 females with an average age of 68 years and an average duration of disease of 43 months. The patients were treated with 2 cycles of HD-Sim for seven days followed by a break of 21 days in a 4-weeks cycle. Two of the patients were treated with bisphosphonates during the study, and 4 had previously been treated with bisphosphonates. Endpoints are change in concentrations of markers of osteoclast activity (TRAP) or bone resorption (CTX, NTX, ICTP) or markers of bone formation (Osteocalcin and PINP). Cholesterol, OPG and DDK-1 were also measured. Results: Two patients completed the protocol with two cycles of HD-Sim at full dose, 2 patients were reduced to 7.5 mg/kg/day simvastatin in cycle 2 due to nausea and diarrhea and 2 patients left the protocol after 3 weeks (deaths not related to high dose simvastatin). All patients experienced gastrointestinal toxicity grade 1–2. Myalgia and other muscular symptoms grade 1–2 were reported by 5 patients but were not associated with an increase in creatin kinase. TRAP and NTX activity in serum increased for all 6 patients during the seven days of treatment with HD-Sim indicating that bone resorption may have been stimulated rather than inhibited. The other markers of bone resorption and the bone formation markers showed no change. All patients responded with a significantly reduced level of cholesterol in serum. None of the patients showed any reduction in free monoclonal light chains or monoclonal proteins in serum during treatment with HD-Sim and 2 of the 4 patients completing the protocol showed progression of diseases. Conclusion: This pilot study of HD-Sim in advanced MM has been terminated due to lack of response and evidence from two markers of osteoclast activity (TRAP) and bone resorption (NTX) that HD-Sim may be harmful rather than beneficial in MM.

Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5117-5117 ◽  
Author(s):  
Patrizia Tosi ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Giulia Perrone ◽  
Michela Ceccolini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Formation ◽  
Induction Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Bone Formation Markers

Abstract Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

1989 ◽  
Vol 7 (12) ◽  
pp. 1909-1914 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
C Marcelli ◽  
P Dessauw ◽  
J Sany ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cell Mass ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Mass Reduction

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

High-dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse

2009 ◽  
Vol 8 (4) ◽  
pp. 435-442 ◽  
Author(s):  
Steven D. Bain ◽  
Mason C. Bailey ◽  
Darlene L. Celino ◽  
Megan M. Lantry ◽  
Martin W. Edwards
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
High Dose ◽  
Ovariectomized Mouse

Multiple Myeloma Profile In Latin America: Clinical and Epidemiological Observational Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5327-5327
Author(s):  
Vania T M Hungria ◽  
Angelo Maiolino ◽  
Gracia Aparecida Martinez ◽  
Carmino A De Souza ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Latin America ◽  
Clinical Features ◽  
Median Overall Survival ◽  
High Dose Chemotherapy ◽  
Patterns Of Care ◽  
Disease Stage ◽  
High Dose

Abstract Introduction Little is known about the incidence and clinical features of Multiple Myeloma (MM) in Latin America. A clinical registry of Latin American (LA) patients with MM represents an opportunity to gain insight into the prevalence of the disease in this region, the patterns of care and the current treatment status in different LA countries. Objective To characterize the demographic and clinical features of patients with multiple myeloma from five LA countries (Brazil, Argentina, Chile, Mexico and Peru) and to create a LA database on MM; in addition to investigating the patterns of care for MM patients in Latin America. Patients and Methods This is an observational, non-intervention study, with a prospective evaluation of data. Eligible patients were diagnosed with multiple myeloma, between January 1, 2005, and December 31, 2007, at any one of the participating centers, regardless of disease stage or treatment modality. The follow-up period extended to at least 5 years for each patient (December 31, 2012). Results Eight hundred and seventy six patients were included. The median age was 60 years old (25-97), 53.4% male and 46.6% female. The median follow-up was 31.4 months, and the median overall survival was 57 months. The median overall survival to patients who received high-dose chemotherapy was 77 months and for patients who received conventional chemotherapy was 48 months (p<0.001). The multivariate prognostic model included patient baseline variables that were associated with mortality in the Kaplan-Meier univariate analyses. Only hypercalcemia, DSS II and III, ISS stage III andnon- high-dose chemotherapy were independent predictors of mortality. Conclusion This current study, which is the largest case series of MM patients in Latin America, recognizes the feasibility of large, collaborative, observational studies among various tertiary-care hematology centers in Latin America. Note We will present more details related to the demographic and most frequently used treatments in Latin America for newly diagnosed and relapsed patients in these LA countries. Disclosures: No relevant conflicts of interest to declare.

A Multiple Myeloma Classification System That Associates Normal Bone Marrow B-Cell Subset Phenotypes with Disease Stage and Prognosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3352-3352 ◽  
Author(s):  
Hans Erik Johnsen ◽  
Julie Støve Bødker ◽  
Alexander Schmitz ◽  
Malene Krag Kjeldsen ◽  
Kim Steve Bergkvist ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Clinical Data ◽  
Cell Subset ◽  
Disease Stage ◽  
High Dose ◽  
Gene Probe ◽  
Cell Of Origin ◽  
Data Set ◽  
B Cell Subsets

Abstract Introduction Today’s diagnostic tests for multiple myeloma reflect the criteria of the updated WHO classification based on biological, morphological and clinical heterogeneity. It has been the concept behind the present study to extend our current biological classification and provide a new tool to generate insight into the stage of clonal differentiation and oncogenesis. The goal of the present study was to generate B-cell subset associated gene signatures (BAGS) from the BM hierarchy used to assign individual phenotypic cell of origin (pCOO) subtypes in patients and validate its pathogenetic impact by prognostic evaluation. Methods Bone marrows (BM, n=7) were harvested from sternum during cardiac surgery. B-cell subsets were phenotyped by Euroflow standard for multiparametric flow cytometry and FACS-sorted for microarray analysis on the Human Exon 1.0 ST Arrays platform. This combination allowed us to generate five BAGS for PreBI, PreBII, immature (Im), naïve (N), memory (M) B-cells, and plasma cells (PC) of normal BM. The BAGS classifier was based on all median-centred probe sets from the data set by regularized multinomial regression with 6 discrete outcomes corresponding to each B-cell subset and the elastic net penalty using the algorithm implemented in the R-package glmnet24. Each clinical data set was probe-set-wise adjusted to have a zero median and the same variance as in the BM data set. The associated cell of origin subset for each patient in each data set was predicted by the BAGS classifier by assigning the class with the highest predicted probability score above 0.45 and otherwise UC. All statistical analyses were done with R version 3.0.2. Survival analysis was performed by the Kaplan-Meier method and log-rank tests. Clinical data sets were from University of Arkansas for Medical Sciences UAMS (n=559), the Dana Farber Cancer Institute DFCI (n=170) both available on the GEO website. Results First, we verified the quality of the sampled B-cell subsets based on the expression patterns of differentiation marker genes. Next, we constructed the BAGS-classifier provided by 38-68 gene probe sets (n), capable of assigning samples to each of the six subtypes of PreBI (n=38), PreBII (n=82), Im (n=71), N (n=68), M (n=52) and PC (n=43). Second, we assigned individual myeloma cases in the 2 patient cohorts including a total of 729 myeloma patients. The resultant assignments generated patient BAGS subtypes with diagnostic frequencies of 0,5-0,6 % preBI, 7-8 % preBII, 27-30 % Im, 8-9 % N, 36-37 % M, 1-5 % PC and 15-16 % UC subtypes. The frequencies were not different between the cohorts. Third, the BAGS subtypes was associated significantly with overall survival (P = 8.6 x 10-5) for high dose melphalan and autologous stem cell transplanted UAMS patients1, as illustrated in Figure 1. The most significant impact was observed within the PreB-II (light blue) and M (acid green) subtypes conferred with significant inferior prognosis compared to the Im (amethyst), N (apple green) and PC (blue) subtypes. The PreB-II and M subtypes in the UAMS cohort were correlated to the ISS stage I-III with 33%, 49% and 69% of the cases, respectively. Fourth, we compared the BAGS subtypes and the TC classification2 with no observed correlations (results not shown). Conclusions Our data support a new COO defined BAGS classification based on the normal BM B-cell subset phenotypes with impact on staging and prognosis in multiple myeloma and a new diagnostic platform, which may result in more effective disease management. References 1) Zhan F, Huang Y, Colla S et al. The molecular classification of multiple myeloma. Blood. 2006 Sep 15;108(6):2020-8. 2) Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005 Jul 1;106(1):296-303. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Lung Transplantation in a Patient With Osteogenesis Imperfecta and Osteoporosis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A205-A205
Author(s):  
Lena Fan ◽  
Luke J Benvenuto ◽  
Margaret Nolan ◽  
Angela DiMango ◽  
Elizabeth Shane ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Osteogenesis Imperfecta ◽  
Lung Transplantation ◽  
Urinary Calcium ◽  
Multiple Drug ◽  
High Dose ◽  
Full Time ◽  
Restrictive Lung Disease

Abstract Background: Osteogenesis imperfecta (OI) and transplantation (TP) are independently associated with fractures. Yet reports regarding the skeletal effects of organ TP in OI are limited. We report the early skeletal outcomes in an OI patient with osteoporosis who underwent lung TP. Clinical Case: A 35-year-old man with moderate/severe OI and severe bronchiectasis was admitted for progressive respiratory failure and expedited lung TP evaluation. OI was diagnosed at age 10 after sustaining a hairline coccyx fracture when falling off a stool; scoliosis was diagnosed at age 14; additional fractures included ankle (18 y), toes (28 y) and rib (34 y). He had dentogenesis imperfecta, but no hearing loss, easy bruising or OI family history. Bronchiectasis also began at age 10 and progressed, with multiple drug resistant infections and glucocorticoid (GC) treatments. At admission, he was on 6L oxygen and bed-bound from dyspnea. Notably, he had been rejected twice for TP because of his bone disease. Admission medications included calcium, D3, famotidine, inhaled fluticasone, tobramycin, and tiotropium bromide. His exam was notable for height 5’5”, BMI 16.5 kg/m2, kyphoscoliosis, blue sclera and joint laxity. Labs were notable for (mg/dl): serum calcium 9.4, magnesium 2.4, phosphate 4.4; albumin 4.2 g/dl, alkaline phosphatase 75 U/L, 25(OH)D 34 ng/ml, sCTX 535 pg/ml, urinary calcium 370 mg/24 hr. DXA showed T-scores of -4.7 (lumbar spine), -3.3 (femoral neck), -3.2 (total hip), -2.6 (1/3 radius). Endocrinology was consulted about the skeletal risk of lung transplantation. Discussion and Follow-up:The patient’s manifestations of OI increased the risk of adverse skeletal outcomes. His high CTX suggested increased bone resorption, often seen with OI; bone formation was not directly measured but in OI is frequently reduced. Notably, his bronchiectasis was likely related to the OI: in addition to restrictive lung disease in OI, the abnormal type 1 collagen likely alters alveolar structure and elasticity. His risk for post-TP fractures was high given that the expected post-TP bone loss would likely be exacerbated by high dose GCs further increasing bone resorption and reducing presumed low bone formation. Nevertheless, because he had never sustained a major fracture even without OI treatment, the decision was made to proceed. He received zoledronate (ZOL) 5 mg IV and underwent an uncomplicated double lung transplant; initial high dose GCs were tapered to prednisone 10 mg/d. Three months later, he has steadily rising lung function, excellent functional status, and is working full time. A current sCTX of 73 pg/ml suggests that bone loss is not increased. Admittedly, the patient remains within the early high-risk fracture window. Yet this case is the first report to our knowledge which suggests that lung TP in an OI patient treated with ZOL did not lead to fracture in the early post-TP period.

Bone Remodeling in Patients with Relapsed/Refractory Multiple Myeloma Who Receive Lenalidomide-Based Regimens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4745-4745
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Efstathios Kastritis ◽  
Eirini Katodritou ◽  
Xenophon Papanikolaou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Response To Therapy ◽  
Type I ◽  
Fracture Group ◽  
Lytic Lesions ◽  
Tracp 5B

Abstract Lenalidomide in combination with dexamethasone is very effective for the management of refractory/relapsed multiple myeloma (MM). However, there is very little information for the effect of lenalidomide on bone metabolism in MM. We evaluated bone remodeling in 36 patients (22M/14F; median age 64 years) with refractory/relapsed MM who received lenalidomide-based regimens: 27 received the combination of lenalidomide at the standard dose of 25mg/day x 21 days, every 28 days, with either high (n=18) or low (n=9) dose dexamethasone, while 9 patients received the combination of lenalidomide/low dose dexamethasone plus bortezomib (BDR) at a dose of 1 mg/m2, iv, on days 1, 4, 8, 11 every 28 days. The following serum indices of bone turnover were measured on day 1 of cycle 1, and then on day 28 of cycle 3: osteoblast inhibitor dickkopf-1 (Dkk-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 20 healthy controls of similar gender and age. The median number of previous therapies was 3 (range: 2–7). At baseline, 9 patients had no lytic lesions (group A), while 3 patients had 1–3 lytic lesions (group B) and 24 patients had more than 3 lytic lesions and/or a pathological fracture (group C) in plain radiography of the skeleton. After 3 cycles of therapy the objective response (CR+PR) rate was 77% (21/27) in lenalidomide/dexamethasone patients and 55% (5/9) in BDR patients. MM patients at baseline had increased levels of Dkk-1 (p=0.002), sRANKL (p=0.04), and both markers of bone resorption (p<0.01) compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.01). Patients with advanced bone disease (group C) had increased levels of CTX (p<0.001), TRACP-5b (p<0.01), Dkk-1 (p=0.04) and reduced levels of OC (p=0.04) compared with all others. Moreover, serum levels of DKK-1 correlated with TRACP-5b (r=0.614, p<0.0001), CTX (r=0.29, p=0.03), sRANKL (r=0.423, p=0.001) and OPG (r=0.572, p<0.0001). The administration of lenalidomide-based regimens produced only a reduction of Dkk-1 (p=0.04) and TRACP-5b (p=0.03) after 3 cycles of therapy. Interestingly, patients who received BDR showed a dramatic reduction of sRANKL (p=0.02), sRANKL/OPG ratio (p=0.03) and Dkk-1 (p=0.02), which associated with an increase in both markers of bone formation (p=0.04). The % reduction of sRANKL and TRACP-5b and the % increase of bALP and OC was higher in BDR patients compared with others. There was no correlation between response to therapy and bone markers’ changes. In conclusion, the combination of lenalidomide plus dexamethasone seems not to have a clear effect on bone metabolism after 3 cycles of therapy, possibly due to administration of high dose dexamethasone in the majority of patients. BDR patients had a beneficial effect mainly on bone formation, reflecting the bone anabolic effect of bortezomib and/or the lower dose of dexamethasone given in these patients. Longer follow-up is needed to exact final conclusions for the effect of lenalidomide on bone metabolism in relapsed/refractory MM.

A Multi-Center Analysis of Renal Impairment as a Potential Prognostic Factor: Analysis in Multiple Myeloma Patients Treated with Standard or High-Dose Chemotherapy Followed by Autologous Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4830-4830
Author(s):  
Martina Kleber ◽  
Gabriele Ihorst ◽  
Christian Jakob ◽  
Peter Liebisch ◽  
Bernd Koch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Impairment ◽  
Renal Disease ◽  
Performance Status ◽  
High Dose Chemotherapy ◽  
Disease Stage ◽  
High Dose ◽  
Novel Therapy ◽  
Normal Ranges ◽  
Ckd Stage

Abstract Renal impairment (RI) of varying severity including end stage renal disease is a common manifestation of multiple myeloma (MM). Nevertheless, the influence of milder - and via creatinine (crea) determination invisible - RI as a risk factor in MM patients (pts) is less well defined. We have previously reported in 167 cancer pts that estimating the glomerular filtration rate (eGFR) as compared to serum crea- or cystatin-levels determines prognostically adverse risk groups (Ann Oncol18: 950–8, 2007). In order to analyze the frequency of RI stages in a homogenous pt group, we determined RI in 198 consecutive MM pts receiving standard (Std; n=103) or high-dose chemotherapy (hd-CTx; n=95) in a multi-center study. We analyzed disease-stage, sex, age, performance status, β2-microglobulin, serum crea and GFR calculated by both the four-component “Modification of Diet in Renal Disease” (MDRD) and Cockcroft-Gault (CG). Evaluated outcomes were overall survival (OS) and progression free survival (PFS). Of note, although median crea, MDRD- and CG-eGFR-values appeared almost normal with 0.9mg/dl, 87 and 82ml/min/1.73m2, respectively, RI as determined as advanced chronic kidney disease (CKD stage >3 = eGFR<60) was apparent in 25% of all pts. We also observed distinct differences in pts receiving Std vs. hd-CTx: the median age was higher with 67 years (y) in the Std vs. 57y in the hd-CTx group (p<0.05). Advanced disease, as defined as number of pts with Durie & Salmon stage II/III, was comparable in both groups (92 vs. 97%, respectively). Although the crea was still within normal ranges in the Std- (1mg/dl) vs. hd-CTx-pts (0.8mg/dl), MDRD- and CG-formulas uncovered relevant differences between both groups: both MDRD- and CG-eGFRs being significantly decreased in Std- vs. hd-CTx-pts (MDRD: 72 vs. 96; CG: 68 vs. 101, respectively; p<0.05). Correspondingly, more Std-pts showed a decreased eGFR <60 than hd-CTx-pts (34 vs. 14%). Comparing solely those Std vs. hd-CTx-pts with active, progressing and/or proliferating myeloma also ascertained significant eGFR-differences in terms of decreased MDRD- and CG-levels, as well as more pts with CKD stage 3–5 in the Std group. This suggests that these MM pts had a significantly different renal function in Std-pts, most reliably, however, only detected via eGFR and CKD staging assessment, rather than the serum crea alone. Associated with RI (eGFR <60), PFS and OS were significantly decreased as compared to eGFR values >60 with estimated median values of 15 vs. 20 months and 36 vs. 61.3 months, respectively (p<0.05). In line, PFS and OS for Std- and hd-CTx-pts for eGFR<60 were considerably lower as compared to pts with eGFRs>60. In conclusion, we highlight the importance of efficiently detecting RI by means of eGFR-assessment, which allows to detect MM pts with mild - and/or via crea determination invisible - RI. Our data demonstrate that eGFR-decline substantially diminishes PFS and OS in consecutive MM pts, and suggest that with RI, Std- as opposed to hd-therapies do not substantially improve PFS/OS, so that novel therapy approaches are especially needed for those pts with RI, not receiving hd-CTx. These findings should also hold true for other cancer pts.

Consolidation Therapy with Bortezomib, Thalidomide and Dexamethasone (VTD) Regimen After ASCT in Myeloma Patients Who Do Not Receive Bisphosphonates Reduces Bone Resorption and RANKL/OPG Ratio but Seems to Have No Effect On Bone Formation and Angiogenesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3863-3863 ◽  
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
Athanasios Papatheodorou ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Serum Levels ◽  
High Dose ◽  
Osteoblastic Activity ◽  
Bone Specific Alkaline Phosphatase ◽  
Bone Formation Markers ◽  
Tracp 5B ◽  
Angiogenic Cytokines

Abstract Abstract 3863 Poster Board III-799 Bortezomib (V) monotherapy is associated with increased osteoblastic activity, reduced osteoclast function and decreased angiogenesis in relapsed/refractory myeloma (MM). The co-administration of zoledronic acid in all reported studies to-date may suggest a synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not allowed the independent evaluation of V on bone metabolism. Furthermore, the combination of V with other agents, such as thalidomide (T), melphalan (M) and dexamethasone (D), although it reduced osteoclast activity, it did not enhance osteoblast function. We evaluated the effect of VTD consolidation on bone metabolism and angiogenesis in MM patients who underwent high-dose M followed by ASCT. In this prospective study, only patients in first remission or with primary refractory disease to one frontline treatment were included. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VTD consolidation. VTD started on day 100 after ASCT: V was administered at a dose of 1.0 mg/m2 on days 1,4,8,11; T was given at a dose of 100 mg/day, po, on days 1-21 and D at a dose of 40 mg/day on days 1–4 of a 21-day cycle. Patients received 4 cycles of VTD (first block), were followed without treatment for 100 days and then received another 4 cycles of VTD (2nd block). Patients were assessed for skeletal-related events (SREs) throughout the period of the study (12 months). Bone remodeling was studied by the measurement of the following serum indices before and after each block of VTD (4 measurements for each patient): i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Angiogenic cytokines such as VEGF, angiogenin (ANG), angiopoietin (Angp)-1 and -2, and bFGF were also studied on the same dates. So far, 32 patients have completed the first block of VTD, while 16 patients have completed both VTD blocks. Just before VDT administration, 10 patients were in CR (4 in sCR), 14 in vgPR and 8 in PR. Although most of these patients were rated as vgPR or better, they had increased serum levels of sRANKL (p=0.037), Dkk-1 (p=0.001), CTX (p=0.002), TRACP-5b (p<0.001), VEGF (p<0.001), bFGF (p<0.001), ANG (p=0.006) and reduced levels of Angp-1/Angp-2 ratio (p<0.001) compared to 18 healthy controls of similar age and gender, indicating sustained osteoclast and angiogenic activity despite minimal tumor load. Levels of sRANKL and Dkk-1 positively correlated with resorption markers (p<0.01). The first block of VTD resulted in a significant reduction of sRANKL (p=0.001), sRANKL/OPG (p=0.005), CTX (p=0.001), TRACP-5b (p=0.032), but also of bALP (p=0.022) and OC (p=0.02), while Dkk-1 and the majority of angiogenic cytokines showed no alterations (only Angp-1/Angp-2 ratio had a borderline increase, p=0.044). After the first block of VTD, 39% of patients improved their status of response; however alterations of the studied molecules were irrespective of further response or not improvement. Before the administration of the 2nd block of VTD, RANKL, RANKL/OPG and CTX were reduced compared to values after the first block of VTD (p=0.01, p=0.027 and p=0.005, respectively). These parameters were further reduced after the completion of the study (p<0.05). On the contrary, Dkk-1 was increased between the end of the first block of VTD and the initiation of the 2nd (p=0.008) but was reduced after the 2nd block of VTD (p=0.037). OC had no further alterations, while bALP was increased before the 2nd block of VTD (p=0.012) and showed no changes thereafter. VEGF, ANG, and Angp-1/Angp-2 were increased during the resting period between the two VTD blocks and remained unchanged thereafter. During the study period, only one patient developed a SRE (i.e. radiation to bone). As of July 2009, 8 of 32 patients have developed progressive disease. The median TTP after ASCT was 27 months (CI 95% 16.3-37.6). The results of this ongoing study suggest that VTD consolidation post-ASCT, without the presence of bisphosphonates, reduces RANKL and bone resorption and is associated with a very low incidence of SREs. However, bortezomib was not able to produce a significant anabolic effect on bones when combined with TD even in these patients with low myeloma burden, while its effect on angiogenic cytokines was modest. Disclosures: Terpos: Janssen-Cilag: Consultancy, Honoraria. Dimopoulos:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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