Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

Abstract Bortezomib has significant activity in multiple myeloma (MM). Its efficacy is increased with the addition of dexamethasone and doxorubicin in vitro, thus providing the rationale for combination regimens with these agents. The aim of this study was to evaluate the efficacy and safety of PAD regimen (bortezomib, doxorubicin, dexamethasone) in high-risk, newly diagnosed, MM patients and evaluate its effect on bone remodeling and angiogenesis. The inclusion criteria included newly diagnosed MM, ISS 2/3 disease or del13q detected by FISH. Patients received four 21-day cycles of PAD: bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; dexamethasone 40 mg on days 1–4 and 8–11; bolus doxorubicin 9 mg/m2 on days 1–4. All patients received monthly zoledronic acid and prophylactic dose of co-trimoxazole and acyclovir. Following peripheral blood stem cell (PBSC) collection, eligible patients received high-dose melphalan with PBSC transplantation. Effect of PAD on angiogenesis was evaluated by measuring serum levels of VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and basic fibroblast growth factor at baseline and on day 21 of cycle 4. Bone remodeling was studied by the measurement of serum indices: osteoclast stimulators [soluble RANKL, and osteoprotegerin (OPG)], bone resorption markers [C-telopeptide of collagen type-I (CTX), and tartrate resistant acid phosphatase-5b (TRACP-5b)], and bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin] at baseline and on day 21 of cycle 4. All above molecules were also measured in 22 healthy controls of similar age and gender. To-date, 23 patients (14M/9F, median age 60 years) completed 4 cycles of therapy: 12 (52%) had ISS stage 2 and 11 (47%) stage 3 disease. Del13q was detected in 12 patients. The majority of patients (n=12) had more than 3 lytic lesions and/or a pathological fracture in the plain radiography of the skeleton. The objective response rate was 95% (22/23 patients): CR 26%, vgPR 13% and PR 56%. Median time to response was 35 days. Grade 3/4 adverse events included infections (7 patients-30%; one died due to septicemia), lymphopenia (6-26%), thrombocytopenia (6–26%), neutropenia (4–17%), peripheral neuropathy (3–13%), fatigue (2–8%), and hyponatremia (2–8%). At baseline, MM patients had increased serum levels of CTX, TRACP-5b, OPG, angiogenin, and Ang-2 compared with controls (p<0.01), while the ratio of Ang-1/Ang-2 was reduced. The administration of PAD resulted in a dramatic reduction of bone resorption markers (p<0.01) and a borderline increase in bALP (p=0.09). PAD also produced a significant increase of Ang-1/Ang-2 ratio (p=0.006), which was normalized. No patient developed a skeletal related event during 4 cycles of therapy. Eight patients (34%) had a PBSC collection; the median number of CD34+ cells was 6.45x106/kg (range: 2.3-13x106cells/kg). In conclusion, PAD has significant activity in high-risk, newly diagnosed patients with MM, overriding del13q. This regimen reduces bone resorption and normalizes Ang-1/Ang-2 balance which is crucial for the process of angiogenesis in MM.

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Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor?

Blood ◽

10.1182/blood-2010-07-295105 ◽

2011 ◽

Vol 117 (6) ◽

pp. 2009-2011 ◽

Cited By ~ 80

Author(s):

Hervé Avet-Loiseau ◽

Florent Malard ◽

Loic Campion ◽

Florence Magrangeas ◽

Catherine Sebban ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Prognostic Factor ◽

Multivariate Analyses ◽

Independent Prognostic Factor ◽

Newly Diagnosed ◽

Cytogenetic Abnormalities ◽

Data Support ◽

Few Data

Abstract Many trials in myeloma are stratified on cytogenetic abnormalities. Among them, the most commonly chosen are the t(4;14), the del(17p), and the t(14;16). If data are well established for t(4;14) and del(17p), very few data support the use of t(14;16). To address this issue, we retrospectively analyzed 1003 patients with newly diagnosed myeloma for this abnormality. We identified 32 patients with the t(14;16). Compared with patients lacking the t(14;16), we did not observe any difference in overall survival (P = .28). Moreover, in multivariate analyses, the t(14;16) was not prognostic (P = .39). In conclusion, our data do not support the use of t(14;16)-specific probes in the diagnostic panels of multiple myeloma.

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The Ratio of Angiopoietin-1 to Angiopoietin-2 Is Reduced and Predicts Independently for Survival in Newly Diagnosed Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.1478.1478 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1478-1478

Author(s):

Meletios A. Dimopoulos ◽

Konstantinos Anargyrou ◽

Eirini Katodritou ◽

Efstathios Kastritis ◽

Anastasia Pouli ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Median Survival ◽

Bone Disease ◽

Univariate Analysis ◽

Disease Status ◽

Serum Levels ◽

Newly Diagnosed ◽

Angiopoietin 2 ◽

Angiopoietin 1

Abstract Angiogenesis represents an essential step of disease progression in several hematological malignancies, including multiple myeloma (MM). Angiopoietin-1 (Ang-1) and its natural antagonist angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie-2, are essential cytokines for angiogenesis process. Maturation and stabilization of the vascular wall are critically regulated by Ang-1 binding to Tie-2 receptor, while Ang2- antagonizes Tie-2 binding and induces vessel destabilization, which leads to the angiogenic sprouting. Vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF) are also potent stimulators of both physiological and pathological angiogenesis. The aim of this study was to evaluate the serum levels of the above angiogenesis cytokines and explore possible correlations with clinical data, including survival, in 143 newly diagnosed, untreated, MM patients (75M/68F; median age: 68 years, range: 40–94 years). According to ISS, 49 patients had stage 1, 46 stage 2 and 48 stage 3 disease. Serum levels of Ang-1, Ang-2, VEGF, VEGF-A (the major angiogenesis component of VEGF), angiogenin, and bFGF were evaluated using ELISA methodology (R&D Systems, Minneapolis, MN, USA, for all, except VEGF-A: Diaclone, Bensancon, France). MM patients had increased serum levels of Ang-2 (p<0.0001), angiogenin (p<0.0001), VEGF (p=0.033) and VEGF-A (p=0.010) compared with 25 controls of similar age and gender. Ang-1 levels were not different between patients and controls; thus the ratio of Ang-1/Ang-2 was reduced in MM (p<0.0001). Ang-1/Ang-2 ratio correlated with ISS (p=0.022) and beta2-microglobulin (p=0.03), while angiogenin showed strong correlations with ISS (p<0.0001), bone disease status (p=0.01) and hemoglobin (p=0.01). Interestingly, VEGF levels correlated with both Ang-1 (p<0.0001) and Ang-2 (p<0.0001) as well as with bFGF (p<0.0001) and LDH (p=0.01) serum levels. The median survival of all patients was 47 months and the median follow-up was 20 months. The univariate analysis revealed that ISS stage (p=0.001), serum LDH (p=0.001), serum beta2-microglobulin (p=0.0002), bone disease status (p=0.0007), serum creatinine (p=0.045), and the ratio of Ang-1/Ang-2 predicted for survival. Patients with serum Ang-1/Ang-2 of below or equal to the median value (4.8) had a median survival of 25 months, while patients with Ang-1/Ang-2 values of above the median value of 4.8 had a median survival of 53 months (p=0.0065). The multivariate analysis revealed that only serum LDH (p=0.003), Ang-1/Ang-2 ratio (p=0.005) and bone disease status (p=0.015) could independently predict for survival. These results reveal for the first time in MM patients the correlation of reduced Ang-1/Ang-2 ratio with advanced disease and highlight the role of Ang-1/Ang-2 pathway in the biology of plasma cell growth as reflected by its influence on survival. These observations reveal Ang-1/Ang-2/Tie-2 system as a possible target for the development of novel anti-myeloma agents.

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The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma

Blood ◽

10.1182/blood-2018-04-842880 ◽

2018 ◽

Vol 132 (1) ◽

pp. 59-66 ◽

Cited By ~ 25

Author(s):

Leo Rasche ◽

Edgardo J. Angtuaco ◽

Terri L. Alpe ◽

Grant H. Gershner ◽

James E. McDonald ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Independent Prognostic Factor ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Focal Lesions ◽

Poor Outcome ◽

Extramedullary Disease ◽

Key Points

Key Points The presence of ≥3 large focal lesions is associated with poor outcome in newly diagnosed myeloma patients. The prognostic impact of multiple large focal lesions is independent of R-ISS, GEP70, and extramedullary disease.

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Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7605 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7605-7605

Author(s):

H. Ege ◽

M. Gertz ◽

S. N. Markovic ◽

M. Q. Lacy ◽

A. Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Mayo Clinic ◽

Lymphocyte Count ◽

Staging System ◽

Absolute Lymphocyte Count ◽

Independent Prognostic Factor ◽

Newly Diagnosed

7605 Background: In the setting of autologous stem cell transplantation (ASCT) in multiple myeloma (MM), it has been shown that peripheral blood absolute lymphocyte count (ALC) on day 15 is an independent prognostic factor for clinical outcomes. Recently the International Staging System (ISS) for MM has been developed as a simple staging system to assess survival in newly diagnosed MM patients. The role of ALC on survival in newly diagnosed MM patients is unknown. Methods: Between 1994 and 2002, 1,835 consecutive MM patients were evaluated at the Mayo Clinic, Rochester. Of these patients, we retrospectively analyzed 584 MM patients that were originally diagnosed and followed at the Mayo Clinic. The primary end point was to assess the role of ALC at the time of MM diagnosis on overall survival (OS). OS was measured from the date of diagnosis to time of death or last follow-up. ALC was analyzed as a continuous variable and dichotomized based on finding the optimal cut point based on the log-rank statistic. ALC was then compared to the ISS. Results: The median age of the cohort was 67 years (range: 29–94 years), including 234 females and 350 males. The median follow-up was 32 months (range: 1–136 months). The median ALC at diagnosis was 1.2 x 109/L (range: 0.12–5.44 x 109/L). ALC, as a continuos variables was identified as a prognostic factor for OS (HR= 0.466, 95%CI= 0.396–0.547, p < 0.0001). MM patients with an ALC ≥ 1.3 x 109/L experienced a superior OS compared with MM patients with an ALC < 1.3 x 109/L (55.5 months versus 22.6 months, p< 0.0001). In the multivariate analysis, ALC was independent prognostic factor when compared to the ISS (HR = 0.580, 95%CI=0.518–0.647, p< 0.0001). Conclusions: Our study shows that ALC at diagnosis for MM is an independent prognostic factor for OS, suggesting how the host immune status plays a critical role in the survival of patients with MM. No significant financial relationships to disclose.

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