Patients with POEMS Syndrome Have High Bone Turnover and Increased Circulating Angiogenic Cytokines; Should Angiopoietin-2 and Bone-Specific Alkaline Phosphatase Be Used As Minor Criteria for the Diagnosis of the Disease?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 806-806 ◽  
Author(s):  
Evangelos Terpos ◽  
Meletios Athanasios Dimopoulos ◽  
Stephanie Harel ◽  
Francis K Buadi ◽  
Dimitrios Christoulas ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Markers ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Bone Specific Alkaline Phosphatase ◽  
High Bone ◽  
Sclerotic Bone Lesions ◽  
Angiopoietin 2 ◽  
Minor Criteria ◽  
Angiogenic Cytokines

Abstract Abstract 806FN2 POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E) and skin changes (S). The majority of patients have sclerotic bone lesions, although the underlying mechanisms are still unclear. Increased circulating vascular endothelial growth factor (VEGF) is another feature of the disease. However, there is almost no information on the role of other angiogenic molecules in POEMS biology. The aim of the study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology. We retrospectively studied 61 POEMS patients (40M/21F, median age 52 years) who were diagnosed between 1996 and 2010 and were treated and followed in Mayo Clinic Rochester (MN, USA), Hôpital Saint-Louis, Paris (France) and in Alexandra Hospital, Athens (Greece). We evaluated the following indices of bone remodeling and angiogenesis in all patients at diagnosis and in 22 of them one month after front-line treatment: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker CTX; iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin]; and v) angiogenic cytokines [VEGF, angiogenin (ang), angiopoietin (angp)-1 and -2]. These molecules were also measured in 60 newly diagnosed, untreated MM patients (34M/26F, median age: 54 years) and 44 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, defined as osteosclerotic bone lesions in plain radiography and high T-score of lumbar spine DXA (median: +3.6, range: +2 to +7.9). All POEMS patients presented with P and M, while 90% had E, 83% had S, 61% had O and 32% had papilloedema. One or more documented sclerotic bone lesions in plain X-rays were observed in 78% of patients (diffuse lesions in 44%), while 43% of patients had also an osteolytic component. Seven patients had Castleman disease. At diagnosis, compared to controls, POEMS patients had increased levels of bALP (mean ± SD: 48.3 ± 22.9 IU/L vs. 21.6 ± 8.2 IU/L; p<0.001), CTX (0.97 ± 0.94 ng/ml vs. 0.33 ± 0.24 ng/ml; p<0.001), Dkk-1 (p<0.001), sRANKL (p<0.001) and sRANKL/OPG ratio (p<0.001). Patients with diffuse osteosclerosis had increased levels of Dkk-1 compared to others (p = 0.05), suggesting a balance effect to increased formation activity. Patients with POEMS had increased levels of bALP and decreased levels of CTX compared to MM patients (p<0.001 and p = 0.03, respectively), while they had increased levels of CTX and sRANKL/OPG ratio compared to HbS/beta-thal patients (p = 0.001 for both comparisons). There were no other differences regarding bone markers among studied groups. Regarding angiogenic cytokines, at diagnosis, POEMS patients had elevated VEGF (1232 ± 565 pg/ml vs. 195 ± 211 pg/ml; p<0.001), ang (266 ± 82 ng/ml vs. 190 ± 45; p<0.001) and angp-2 (3.5 ± 2.2 ng/ml vs. 1.2 ± 0.6 ng/ml; p<0.001) and decreased angp-1 (p =0.05) and angp-1/angp-2 ratio (reflects increased angiogenic capacity; 9.1 ± 8.8 vs. 44.8 ± 76.1; p<0.001) compared to normal controls. We found no strong correlations between the levels of VEGF, ang and angps. When compared to MM patients, POEMS patients had increased circulating VEGF (p = 0.001) without any difference regarding the other angiogenic cytokines. Response to therapy was accompanied by a dramatic reduction of VEGF only (551 ± 541 pg/ml compared to baseline 1800 ± 1510 pg/ml; p = 0.003). Receiver-operating characteristic (ROC) curve analysis showed that high levels of angiopoietin-2 (≥ 2.3 ng/ml) and high bALP (≥ 38 IU/l) each have a 95% specificity for patients with POEMS syndrome. These results suggest that patients with POEMS syndrome have high bone turnover with increased bone formation as compared to healthy subjects, to MM patients, who have reduced bone formation, and to osteosclerotic HbS/beta-thal patients, who have diminished bone resorption. Importantly, our analysis supports the use of angp-2, bALP along with VEGF as minor criteria for the diagnosis of POEMS. Successful treatment reduced VEGF, which seems to be a suitable marker for the follow-up of POEMS patients. Furthermore the imbalance of angp-1/angp-2 pathway may indicate possible targets for the development of novel agents against POEMS. Disclosures: No relevant conflicts of interest to declare.

High Bone Turnover and Increased Angiogenesis Cytokines in Patients with POEMS Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3525-3525
Author(s):  
Evangelos Terpos ◽  
Meletios A. Dimopoulos ◽  
Ersi Voskaridou ◽  
Angela Dispenzieri
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Type I Collagen ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Type I ◽  
Tnf Α ◽  
Sclerotic Bone Lesions ◽  
Angiogenic Cytokines

Abstract POEMS syndrome is defined by the presence of peripheral neuropathy (P), monoclonal plasma cell disorder (M), organomegaly (O), endocrinopathy (E), and skin changes (S). Virtually all patients will have sclerotic bone lesions, although the mechanisms of their development have not been clarified to-date. Increased plasma level of VEGF is another characteristic of the disease. However, there is very little information for the role of other angiogenic molecules in POEMS pathogenesis. The aim of this study was to evaluate bone metabolism and angiogenic cytokines in POEMS and compare the results with multiple myeloma (MM) and osteosclerotic patients of other etiology. Seven patients with POEMS at diagnosis (6M/1F; median age: 49 years) were evaluated. A series of bone remodeling indices were measured: i) bone resorption markers [C- and N- telopeptide of type-I collagen (CTX and NTX), TRACP-5b], ii) bone formation markers [bone-alkaline phosphatase, osteocalcin (OC), and C-terminal propeptide of type-I collagen (CICP)], and iii) osteoclast regulators [soluble RANKL, osteoprotegerin (OPG), MIP-1α, and TNF-α]. Furthermore, the following angiogenic cytokines were measured in the plasma of POEMS patients: VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and bFGF. All above molecules were also measured in 25 newly diagnosed, untreated MM patients (14M/11F, median age: 64 years) and 20 healthy controls. Bone markers were also evaluated in 24 patients with HbS/beta-thalassemia (10M/14F, median age: 43 years) who presented with osteosclerosis, i.e. osteosclerotic bone lesions in plain radiography and a median T-score of lumbar spine Bone Mineral Density of +3.6 (range: +2 to +7.9). All POEMS patients had P, O, E, S, edema and thombocytosis; 6 had E and 2 Castleman’s disease. Six patients had sclerotic bone lesions, while 4 had also a lytic component in their bone lesions. POEMS patients had increased levels of sRANKL (p=0.003), OPG (p=0.008), TNF-α (p=0.001), NTX (p<0.001), CTX (p=0.001) and CICP (p=0.001) compared with controls. Interestingly, NTX levels were even higher in POEMS than in MM patients (p<0.01). NTX and CTX were elevated in POEMS compared with osteosclerotic HbS/β-thal patients (p<0.01), who had reduced bone resorption compared with controls. POEMS patients had increased levels of OC and CICP compared with MM (p=0.02 and p=0.003, respectively), and increased levels of OC compared with osteosclerotic HbS/β-thal patients (p<0.01). In terms of angiogenic cytokines, POEMS patients had increased levels of all studied cytokines compared with controls (p<0.01). All POEMS patients had at least 1.8-fold higher value of VEGF-A (the major angiogenic component of VEGF) compared with the higher value observed in controls. Furthermore, VEGF (p=0.03), VEGF-A (p<0.001), angiogenin (p<0.001), and bFGF (p=0.01) were higher in POEMS than in MM. The ratio of Ang-1/Ang-2 was very low in POEMS compared with both controls and MM. These results suggest that POEMS patients have increased bone turnover in contrast to MM patients who have reduced bone formation and osteosclerotic HbS/β-thal patients who have diminished bone resorption. Furthermore the imbalance of Ang-1/Ang-2 pathway and the increased levels of angiogenic cytokines, even compared with MM, may indicate possible targets for the development of novel agents against POEMS.

Increased Angiogenesis and Enhanced Bone Formation in Patients with IgM Monoclonal Gammopathy and Urticarial Skin Rash: New Insight Into the Biology of the Schnitzler Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1802-1802
Author(s):  
Evangelos Terpos ◽  
Bouchra Asli ◽  
Dimitrios Christoulas ◽  
Jean-Claude Brouet ◽  
Efstathios Kastritis ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Skin Rash ◽  
Bone Pain ◽  
Serum Levels ◽  
Bone Lesions ◽  
Schnitzler Syndrome ◽  
Sclerotic Bone Lesions ◽  
Angiogenic Cytokines

Abstract Abstract 1802 Schnitzler syndrome is a rare plasma cell disorder which is characterized by the presence of a monoclonal IgM component in association with a chronic urticarial skin rash and at least 2 of the following criteria: fever, joint and/or bone pain, organomegaly (enlarged lymph nodes, spleen and/or liver), increased neutrophil counts and increased ESR. Abnormal bone findings with imaging evidence of osteosclerosis are also frequent. The pathogenesis of this syndrome is unclear and there is no information on bone remodeling and angiogenesis in these patients. To address this issue we studied 13 patients (12M/1F, median age 55 years, range: 39–79 years) with a well characterized Schnitzler syndrome. Patients were diagnosed between 1989 and 2009 and were treated and followed in Hôpital Saint-Louis, Paris (France) and in the University of Athens (Greece). We evaluated the following serum indices of bone remodeling and angiogenesis at diagnosis and after treatment: i) osteoclast regulators [soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker C-telopeptide of collagen type-1 (CTX); iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]; and v) angiogenic cytokines [vascular endothelial growth factor (VEGF), angiogenin (ang), angiopoietin (angp)-1 and -2]. The above molecules were also measured in 24 gender- and age-matched controls. All patients presented with urticaria and monoclonal IgM(kappa) component (median M-peak 0.79 g/dl; range 0.1–2.36 g/dl), while 10 (76%) patients had fever, 9 (69%) had joint and/or bone pain, 5 (38%) had lymphadenopathy and 2 (15%) had splenomegaly. Four patients had documented sclerotic bone lesions in plain X-rays. A technetium bone scintigraphy was performed in 11 patients; all of them had high uptake in at least one site. At diagnosis, 11/13 patients received various symptomatic therapies, including low dose corticosteroids that were ineffective. Two patients at diagnosis and 6 after initial symptomatic therapy were treated with the quinolone antibiotic pefloxacin, while 7 patients were treated with the interleukin-1 inhibitor anakinra (including 3 previously treated by pefloxacine) usually with a complete and sustained efficacy on clinical manifestations of the disease. In a median follow up time of 10 years (range 1–20 years), 3 patients developed overt Waldenström macroglobulinemia (WM) at 5, 7 and 20 years post diagnosis. At diagnosis patients had increased serum levels of bALP (mean±SD: 36.5±15.0 IU/L vs. 26.8±7.1 IU/L; p=0.049), osteocalcin (20.5±18.6 ng/ml vs. 7.4±3.5 ng/ml; p<0.001), Dkk-1 (49.9±13.0 pmol/L vs. 30.9±11.1 pmol/L; p<0.001) and OPG (6.7±1.3 pmol/L vs. 3.5±1.8; p<0.001) compared to controls, while there were no differences between patients and controls for sRANKL and CTX. The increase of Dkk-1 may suggest a balance effect on osteoblast increased activity, while the lack of increase in osteoclast function is in accordance with data on idiopathic osteosclerosis. At diagnosis, patients had also elevated VEGF (809±598 pg/ml vs. 263±257 pg/ml; p=0.001) and ang (221±96 ng/ml vs. 169±33; p=0.013) and decreased angp-1 (18.7±9.1 ng/ml vs. 25.4±10.9 ng/ml; p=0.048) and angp-1/angp-2 ratio (13.9±8.7 vs. 63.4±102.1; p=0.005). Patients presenting with fever had reduced angp-1 levels (14.8±5.2 ng/ml) compared to others (32.7±10.3 ng/ml; p=0.03). Interestingly, patients who progressed to WM had also decreased levels of angp-1 (10.2±7.5 ng/ml) compared to others (21.2±8.2 ng/ml; p=0.04) and angp-1/angp-2 ratio (5.3±4.6 vs. 16.5±8.0; p=0.04), suggesting that low angp-1/angp-2 ratio at diagnosis, which reflects increased angiogenesis, may indicate a predisposition for evolution of the gammopathy towards an overt WM. After successful treatment, VEGF levels decreased (387±207 pg/ml) compared to baseline (770±456 pg/ml; p=0.04). In conclusion our analysis shows increased serum levels of angiogenic cytokines in Schnitzler syndrome and documents enhanced bone formation which appears not to be balanced by a comparable increase in bone resorption; this result may explain the presence of sclerotic bone lesions in this entity. Successful therapy with either anakinra or pefloxacin is associated with reduction of the major angiogenic cytokine VEGF. Disclosures: No relevant conflicts of interest to declare.

Engraftment Syndrome Is Common in Patients with POEMS Syndrome Undergoing PBSCT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2995-2995
Author(s):  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Shaji K. Kumar ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Volume Overload ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Post Transplant ◽  
Gm Csf ◽  
Engraftment Syndrome ◽  
Sclerotic Bone Lesions ◽  
Definition Of ◽  
Discharge From Hospital

Abstract Background: POEMS syndrome is a devastating syndrome, characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis, & high VEGF. We noted an unexpectedly high transplant related morbidity, which we have since postulated to be ES. Methods: 30 patients with POEMS were treated with PBSCT at Mayo Clinic Rochester. We retrospectively studied outcomes, with an emphasis on treatment related morbidity. Two definitions of ES were used: Spitzer (BMT 2001) and Maiolino (BMT 2003). Results: Two-thirds were male. Median age was 48, range 20–70. Time from first symptoms and diagnosis was 26 and 4 months, respectively. To mobilize stem cells, CTX/G-CSF was used in 5 & G-CSF in the remainder. Conditioning was Mel200 (n=19), Mel140 (n=10), and BEAM (n=1). Post-transplant 15 had GM-CSF begun day+6. Only 10% remained outpatient, and median time to discharge from hospital was transplant day 17 (range 0–175). Factors predicting for later dismissal included age (p=0.04), abnormal CXR 7 to 17 days post transplant (p<0.0001), & bolus corticosteroids (CS) beyond day 12 post-transplant (p=0.006). Ninety-three percent had fever, although only 9 had bacteremia. Eight satisfied criteria for ES according to Spitzer and 14 according to Maiolino. Another 3 patients received steroid bolus days 8, 12, and 11 for presumed ES but did not meet criteria because of delayed ANC recovery (days 16, 18, and 20, respectively). Of the 5 patients requiring endotracheal intubation, 3 satisfied Maiolino’s criteria for ES. Although these 3 received bolus CS during their course, administration was delayed at 18, 14, and 18 days. The patient whose CS bolus antedated intubation only received prednisone 30 mg/day. In toto, fourteen patients received bolus CS (daily doses between 20 and 1200 mg prednisone equivalents) commencing day 8 to 59. Those 7 patients who received CS before day 13 did better than the 7 who received them day 13 or later (Table). Conclusions: It is essential to recognize that nearly 50% of patients satisfied formal criteria for ES as defined by Maiolino. In these patients ES may run a self-limited course or lead to catastrophe. No Steroid (n=16) Steroid ≤ D12 (n=7) Steroid > D12 (n=7) P *Engraftment syndrome according to definition of Maiolino (M) or of Spitzer (S). ES M / S, n* 5 / 2 4 / 4 5 / 2 NA Wt change, % 0.6 (−.4.2–6.7) 6.7 (3.6–27.2) 11.2 (–2.1–23.2) 0.005 Rash, % 27 71 43 0.13 Diarrhea, % 73 86 86 0.71 Tmax, C 39 (37.8–41) 40.1 (39–41.1) 38.9 (38.7–40.8) 0.08 1st fever, day 10 (6–15) 8 (7–9) 12 (8–146) 0.007 Abn CXR1, % 13 71 71 0.03 Ventilator, % 0 14 71 0.004 First WBC, day 12 (8–21) 14 (12–14) 14 (12–17) 0.03 ANC500, day 15 (12–29) 16 (14–115) 18 (15–45) 0.08 PLT20, day 12 (8–41) 20 (11–115) 24 (9–170) 0.05 PLT50, day 15 (11–192) 32 (16–115) 56 (13–551) 0.03 RBCs, units 3 (2–8) 6 (4–31) 11 (6–64) 0.0008 PLTS, aph. units 2 (1–9) 9 (4–51) 18 (4–60) 0.0004 Hosp dsm, day 15 (13–36) 21 (15–69) 41 (16–175) 0.009

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.

The Clinical Utility of Bone Resorption and Bone Formation Markers in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5373-5373
Author(s):  
Shahdabul Faraz ◽  
Roger N Pearse ◽  
Sujitha Yadlapati ◽  
David Jayabalan ◽  
Adriana C Rossi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Board Of Directors ◽  
Bone Markers ◽  
Bone Marker ◽  
Advisory Committees ◽  
Bone Specific Alkaline Phosphatase ◽  
Bone Formation Markers ◽  
Impending Fracture

Abstract Introduction: While bone resorption markers such as urinary N-terminal telopeptide (NTx) have long been used in research, serum C-terminal telopeptide (CTx) has become the preferred marker of bone status in multiple myeloma (MM). A full understanding of the clinical utility of CTx, as well as the bone formation markers osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), in MM is still lacking. In this study, we evaluated levels of CTx, OC, and BSAP in a cohort of MM patients to better understand their roles. Methods: One set of CTx, OC, and BSAP data was obtained by random sampling in patients during a 60-day window at the Weill Cornell Medical College Myeloma Center. Bone marker changes were assessed with respect to type of myeloma therapy, response status, use of anti-resorptive therapy, and presence of osteolytic lesions or fractures. Additionally, we tested the ability of the bone markers to isolate a high fracture risk group, as defined by radiologic evidence of impending fracture. The Wilcoxon-Mann-Whitney test was used to assess clinical variables, and a 2-sided t value of less than 0.05 indicated statistical significance. Results: 50 patients were identified with bone marker data, of which 47 had MM and 3 had MM precursor diseases. The mean age was 64 years, with 25 males and 25 females. All three markers CTx (p=0.001), OC (p=0.004), and BSAP (p<0.001) significantly decreased with myeloma therapy initiation. Only CTx, however, was significantly lower in patients who achieved a partial response or greater, compared to non-responders (p=0.010). Moreover, only CTx decreased significantly in patients using anti-resorptive therapy within one year of bone marker date (p=0.006). Both CTx (p=0.011) and BSAP (p=0.005) were significantly higher in patients with more than 5 osteolytic lesions compared to those without such lesions. Additionally, only CTx predicted which patients were at risk for impending fracture (p<0.001). Of 8 patients in this high-risk group for fractures, 2 developed new pathological fractures within 1 month of the CTx test. CTx values were significantly higher in patients who were taking both proteasome inhibitor (PI) and alkylating agents compared to those only taking PIs (p<0.001). Choice of PI also affected levels of bone markers, with patients receiving bortezomib having significantly higher levels of CTx (p=0.019) than those on carfilzomib. BSAP levels were similarly higher, with a trend toward significance (p=0.064). Discussion: Of the evaluated bone markers, only CTx correlated with response to anti-MM therapy and risk of impending fracture. Additionally, CTx reflects the extent of bone disease. CTx levels decreased with use of anti-resorptive therapy within one year of bone marker date, but not with longer time points. This suggests the clinical benefit of at least annual dosing of anti-resorptive therapy and indicates the dynamic nature of this marker. The high CTx values in the PI plus alkylating group may also suggest that PI alone is more effective in addressing bone disease in such patients. Differences in CTx between individual proteasome inhibitors points to agent-specific effects of PI on bone remodeling, which warrant further investigation. The potential increase in BSAP with bortezomib versus carfilzomib treatment is consistent with recent findings, which show that bortezomib promotes osteoblastic differentiation and bone formation. As opposed to our CTx data, OC and BSAP did not prognosticate disease response or future fractures or correlate with use of anti-resorptive therapy, suggesting limited utility of these bone formation markers in MM. Table 1. Bone Marker Category MM Therapy Initiation MM Therapy Responders ART Use Within 1 Year ART Use Before 1 Year Lytic Lesions Present 5+ lytic Lesions Present Risk of Future Fracture PI Plus Alkylator CTx Bone Resorption ↓↓ ↓ ↓↓ NS ↑ ↑↑ ↑↑ ↑↑↑ OC Bone Formation ↓↓ NS NS NS NS NS NS NS BSAP Bone Formation ↓↓ NS NS NS ↑ ↑↑ NS ↑ Abbreviations: CTx, C-terminal telopeptide; OC, osteocalcin; BSAP, bone-specific alkaline phosphatase; MM, multiple myeloma; ART, anti-resorptive therapy; NS, not significant; PI, proteasome inhibitor. Single arrow represents a change by a factor of less than 2. Double arrows represent a change by a factor of greater than 2. Triple arrows represent a change by a factor of greater than 3. Disclosures Pearse: Celegen: Consultancy. Rossi:Calgene: Speakers Bureau. Mark:Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau. Lane:Agnovos Healthcare, LLC: Consultancy; Bone Therapeutics: Membership on an entity's Board of Directors or advisory committees; CollPlant Holdings, Ltd.: Consultancy; D'Fine, Inc.: Consultancy; Gradtys: Membership on an entity's Board of Directors or advisory committees; ISTO Technologies, Inc: Membership on an entity's Board of Directors or advisory committees; Kuros: Membership on an entity's Board of Directors or advisory committees; Royal Consulting & Marketing: Consultancy.

scholarly journals An Atypical Case of POEMS Syndrome Associated with Autonomic Dysfunction

2019 ◽  
Vol 13 (1) ◽  
pp. 92-95
Author(s):  
Mariana B. Hämmerle ◽  
Karina L. Pires ◽  
Márcia B. Hammerle ◽  
Pedro de Mello Vianna P. Galvão ◽  
Lavinia L. Bergier ◽  
...  
Keyword(s):  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Extended Period ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Vascular Endothelial ◽  
Sensorimotor Polyneuropathy ◽  
Protein Levels ◽  
Elevated Protein ◽  
Sclerotic Bone Lesions ◽  
Endothelial Growth Factor

A 52 year old patient showed, for two years, symptoms compatible with sensorimotor polyneuropathy preventing him from walking. An electroneuromyography found a demyelinating pattern suggesting Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). The patient did not respond to corticosteroid therapy and later suffered sexual Dysfunction, Swelling, Lymphadenopathy, Hypotension, astrointestinal dysmotility, urinary retention and neuropathic pain. Analysis of the Cerebrospinal Fluid (CSF) revealed elevated protein levels and Computed Tomography (CT) scan found sclerotic bone lesions. High Vascular Endothelial Growth Factor (VEGF) levels and the results of Lambda light-Chain monoclonal gammopathy in urine protein Electrophoresis Suggested a Diagnosis of POEMS syndrome. The most striking feature, in this case, was the patient’s heightened and atypical polyneuropathy without axonal injury even after an extended period of time, and significant and atypical dysautonomia.

Lenalidomide Therapy in Nine Patients with POEMS Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3872-3872 ◽  
Author(s):  
Arnaud Jaccard ◽  
Julie Abraham ◽  
Christian Recher ◽  
Remy Dulery ◽  
Isabelle Guichard ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Plasma Cells ◽  
High Dose Chemotherapy ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
High Dose ◽  
Advisory Committees ◽  
Sclerotic Bone Lesions ◽  
Vegf Level

Abstract Abstract 3872 Poster Board III-808 Introduction POEMS syndrome is a rare disease characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis, and high serum VEGF level. Efficient treatments consist in irradiation for patients with localized solitary plasmocytoma and high-dose chemotherapy with autologous stem cell transplantation for appropriate candidates without a focal lesion. Conventional myeloma chemotherapy can only control the disease in a limited number of patients. Results of monoclonal anti-VEGF antibodies, which seem to be attractive due to the role of VEGF in this disease, are controversy with efficacy in 3 patients but treatment related deaths in 2 other patients. Thalidomide effectiveness has been reported in Japanese patients but enthusiasm for its use is tempered by the high incidence of thalidomide-induced peripheral neuropathy. Lenalidomide, which efficacy has been described in one observation (Dispenzieri, Blood 2007 110: 1075-1076), has the advantage of being anti-angiogenic, cytotoxic to malignant plasma cells and with a much lower risk of peripheral neuropathy. We reported here a multicentric French experience with this drug in POEMS syndrome. Patients and Methods There were 3 women and 6 men treated with Lenalidomide in 7 French centres. Median age was 60 (41-76). All patients had sensitive polyneuropathy with motor deficiency in 5 patients. A monoclonal component was present in all cases (IgA lambda in 7 patients, IgG lambda and lambda light chain only in 1 patient each). Other manifestations of POEMS syndrome included sclerotic bone lesions in 6 patients, endocrinopathies in 7 patients, skin changes in 8 patients, oedema in 7 patients, organomegaly in 5 patients, papilledema in 5 patients, thrombocytosis in 3 patients. VEGF serum level was elevated in 4 among 5 patients with a dosage. Previous treatments were high-dose chemotherapy with autologous stem cell transplantation in 3 patients, Melphalan-Prednisone in 3 patients because of advanced age, and prolonged steroid treatment in 2 patients. One patient received Lenalidomide as primary treatment before high-dose therapy. Lenalidomide was given during 21 days each month and sequentially associated with dexamethasone, 5 patients received 25 mg/day and 4 patients received 10 or 15 mg, for a median of 5 cycles (1 to 11). Results Serious side effects were noted in 3 patients with 2 hematologic toxicities (grade III and IV) and a cutaneous allergy. Six patients could be evaluated for hematologic response and all responded, complete response in 3 patients and partial in 3 (>25%). Clinical responses occurred early, before 3 months of treatment, in 6 cases among 8 (1 patient is not yet evaluable), with a marked improvement in performance and in neurological syndrome. Other manifestations of POEMS syndrome improved, especially oedema in 5 cases among 6. VEGF level (normal value < 500 pg/ml) could be serially measured in 4 patients with a normalization in 1 patient and a significant decrease in 3 patients, median 7100 pg/ml (2100-10100) before treatment to 887 pg/ml (304-3270). In 1 of these 3 patients VEGF level increased to initial value while he was still taking Lenalidomide. A second patient experimented a relapse 5 months after ending Lenalidomide, he is still in good response after Lenalidomide reintroduction. With a median follow-up of 12 months (1-26) all patients are alive. Conclusion Lenalidomide seems to be a very promising therapy in POEMS syndrome. It should be tested in larger studies in patients with a systemic disease, who are not able to receive high dose therapy, in relapsing patients and before high dose treatment to avoid transplant related morbidity, particularly engraftment syndrome. Disclosures: Jaccard: Celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees and Speakers Bureau. Moreau:Celgene: Membership on an entity's Board of Directors or advisory committees. Fermand:Celgene: Speakers Bureau.

scholarly journals How I treat POEMS syndrome

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5650-5658 ◽  
Author(s):  
Angela Dispenzieri
Keyword(s):  
Plasma Cell ◽  
Cell Clone ◽  
Treatment Strategies ◽  
Castleman Disease ◽  
Poems Syndrome ◽  
The Other ◽  
Bone Lesions ◽  
High Dose ◽  
Sclerotic Bone ◽  
Sclerotic Bone Lesions

Abstract POEMS syndrome is a paraneoplastic syndrome whose acronym stands for less than half of the defining features of the disease, that is, polyradiculoneuropathy, organomegaly, potentially including coexisting Castleman disease, endocrinopathy, monoclonal plasma cell neoplasm, and skin changes. The other important features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, elevated VEGF, and abnormal pulmonary function. The diagnosis is based on having both the polyradiculoneuropathy and the monoclonal plasma cell disorder, and at least 1 of the other 3 major criteria (Castleman disease, sclerotic bone lesions, or elevated VEGF) and at least one minor criterion. The diagnosis is often delayed with intervening incorrect diagnoses of chronic inflammatory demyelinating polyradiculoneuropathy, myeloproliferative disorder, and monoclonal gammopathy of undetermined significance. Prompt treatment directed at the underlying plasma cell clone produces dramatic responses in the majority of patients. Although there are no randomized clinical trial data to direct best therapy, for patients with disseminated disease, high-dose chemotherapy with peripheral blood transplantation has yielded durable benefit, whereas radiation therapy is typically effective for patients with a more localized presentation. More universal recognition of and more scientific inquiry into the underpinnings of the disease will provide direction toward the best treatment strategies in the future.

scholarly journals Age-Related Association of Calcitonin with Parameters of Anthropometry, Bone and Calcium Metabolism during Childhood

2020 ◽  
pp. 1-10
Author(s):  
Juliane Sonntag ◽  
Mandy Vogel ◽  
Mandy Geserick ◽  
Felix Eckelt ◽  
Antje Körner ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Growth ◽  
Venous Blood ◽  
Physiological Role ◽  
Blood Levels ◽  
Childhood And Adolescence ◽  
Procollagen Type ◽  
Child Study ◽  
Age Related ◽  
High Bone

<b><i>Introduction:</i></b> The thyroid parafollicular hormone calcitonin (CT) shows particularly high blood levels in early childhood, a period of high bone turnover, which decrease with increasing age. Data about the physiological role of CT during infancy, childhood, and adolescence are contradictory or lacking. <b><i>Objective:</i></b> We hypothesize that CT demonstrates age-related correlations with parameters of bone growth and turnover as well as with parameters of calcium homeostasis. <b><i>Methods:</i></b> 5,410 measurements of anthropometric data and venous blood samples were collected from 2,636 participants of the LIFE Child study, aged 2 months–18 years. Univariate correlations and multiple regression analysis were performed between serum CT and anthropometric indicators (height standard deviation scores [SDS] and BMI-SDS), markers of calcium (Ca) homeostasis (Ca, parathyroid hormone, 25-OH vitamin D, and phosphate [P]), bone formation (procollagen type 1 N-terminal propeptide [P1NP], osteocalcin), and bone resorption (β-CrossLaps). <b><i>Results:</i></b> CT was significantly associated with Ca (β = 0.26, <i>p</i> &#x3c; 0.05) and P1NP/100 (β = 0.005, <i>p</i> &#x3c; 0.05) in children aged 2 months–1.1 years. These relations were independent of age and sex and could not be confirmed in children aged 1.1–8 years. Independent of age, sex, puberty, P, and height SDS CT showed a significant positive relation to Ca (β = 0.26; <i>p</i> &#x3c; 0.001) in children aged 8–18 years. <b><i>Conclusions:</i></b> Our findings suggest a unique association between CT and Ca in periods of rapid bone growth and point to a possible involvement of CT in promoting bone formation during the first year of life.

scholarly journals Raloxifene Has No Efficacy in Reducing the High Bone Turnover and the Risk of Spontaneous Vertebral Fractures after Denosumab Discontinuation

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Elena Gonzalez-Rodriguez ◽  
Delphine Stoll ◽  
Olivier Lamy
Keyword(s):  
Bone Loss ◽  
Bone Turnover ◽  
Aromatase Inhibitors ◽  
Vertebral Fractures ◽  
Bone Markers ◽  
Rebound Effect ◽  
High Bone Turnover ◽  
Antiresorptive Agent ◽  
High Bone

At denosumab discontinuation, an antiresorptive agent is prescribed to reduce the high bone turnover, the rapid bone loss, and the risk of spontaneous vertebral fractures. We report the case of a woman treated with aromatase inhibitors and denosumab for 5 years. Raloxifene was then prescribed to prevent the rebound effect. Raloxifene was ineffective to reduce the high bone turnover and to avoid spontaneous clinical vertebral fractures. We believe that among the antiresorptive treatments, the most powerful bisphosphonates should be favored, and their administration adapted according to the serial follow-up of bone markers.

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