The Combination of Bortezomib, Doxorubicin, and Dexamethasone (PAD) Is an Effective Regimen for High Risk, Newly Diagnosed, Patients with Multiple Myeloma, Reduces Bone Resorption and Normalizes Angiopoietin-1 to Angiopoietin-2 Ratio.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3596-3596 ◽  
Author(s):  
Evangelos Terpos ◽  
Sosana Delimpasi ◽  
Konstantinos Anargyrou ◽  
Ioannis Baltathakis ◽  
Efstathios Kastritis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Bone Resorption ◽  
Serum Levels ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Bone Resorption Markers ◽  
Tracp 5B ◽  
Angiopoietin 2 ◽  
Angiopoietin 1

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.

Increased Levels of Serum Tissue Inhibitor of Metalloproteinase-1 Correlate with Advanced Stage, Increased Bone Resorption, Lytic Bone Disease and Poor Survival in Newly-Diagnosed Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5143-5143
Author(s):  
Evangelos Terpos ◽  
Meletios A. Dimopoulos ◽  
Vikas Shrivastava ◽  
Kim Leitzel ◽  
Dimitrios Christoulas ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Median Survival ◽  
Serum Levels ◽  
Myeloma Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Bone Resorption Markers ◽  
Tracp 5B ◽  
The Mean

Abstract Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a natural metalloproteinase (MMP) inhibitor that binds to and inactivates mainly MMP-9. TIMP-1 has multifunctional roles in tumorigenesis: inhibition of the catalytic activity of metalloproteinases, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. In vitro studies have revealed that TIMP-1 is overexpressed in myeloma cell lines. Furthermore, TIMP-1 promotes myeloma cell invasion across basement membranes. The aim of this study was to evaluate the serum levels of TIMP-1 in newly-diagnosed, previous untreated myeloma patients and explore possible correlations with clinical and laboratory data, including survival. Fifty-five patients with newly-diagnosed myeloma (25M/30F, median age: 69 years) were evaluated. Eleven patients had stage 1 disease according to ISS, while 27 had stage 2 and 17 stage 3 myeloma. Serum TIMP-1 was determined before the administration of any therapy, including bisphosphonates, using ELISA methodology (Oncogene Science/Siemens HealthCare Diagnostics, Cambridge, MA, USA) along with a series of serum markers of bone metabolism: osteoclast regulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL), and osteoprotegerin (OPG)], osteoblast inhibitor dickkopf-1 (Dkk-1), bone resorption markers (N- & C-telopeptide of collagen type-I: NTX, CTX and ICTP; and tartrate-resistant acid phosphatase-isoform 5b, TRACP-5b), and bone formation markers (bone-specific alkaline phosphatase, bALP; and osteocalcin, OC). The above bone markers were also evaluated in 27 healthy controls of similar age and gender. The mean serum TIMP-1 level of all patients was 431.9 ng/ml (SD 198.1 ng/ml). Twenty-six patients (17M/9F; 47%) had elevated values of TIMP-1 (upper normal limit 324 ng/ml for males and 454 ng/ml for post-menopausal women). Patients had also increased levels of Dkk-1, sRANKL, sRANKL/OPG ratio and bone resorption markers (NTX, CTX, ICTP and TRACP-5b) (p<0.01 compared with healthy controls). TIMP-1 serum levels correlated with ICTP (r=0.514, p<0.001), beta2-microglobulin (r=0.414, p<0.01), albumin (r=-0.416, p<0.01), osteocalcin (r=0.325, p=0.01), CTX (r=0.314, p=0.01), NTX (r=0.306, p=0.02), and LDH (r=0.295, p=0.03). More importantly, TIMP-1 correlated with ISS (ANOVA p=0.005). Patients with ISS 3 disease had higher levels of TIMP-1 (mean±SD 557.8±234 ng/ml) compared with those who had ISS 1 (311±90.6 ng/ml; p=0.001) or ISS 2 disease (405.5±165.6 ng/ml; p=0.021). Furthermore, patients with lytic disease (n=43) had increased levels of TIMP-1 (457.7±205 ng/ml) compared with all others (313.6±107.6 ng/ml; p=0.05). The median follow-up was 31 months and 16/55 patients have died. The median survival has not been reached yet. Patients who had TIMP-1 level of above the mean value had a median survival of 37 months, while in all others the median survival has not been reached yet (p=0.04). Our study provides evidence for the first time that increased serum levels of TIMP-1 correlate with advanced myeloma, with increased bone resorption and with increased number of osteolytic lesions. Furthermore, elevated TIMP-1 was associated with inferior survival of MM patients. These results suggest that TIMP-1 may participate in myeloma pathogenesis and support that serum TIMP-1 deserves further study to determine its predictive and prognostic potential in a larger cohort of myeloma patients.

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

Blood ◽  
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.

scholarly journals 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

2011 ◽  
Vol 130 (3) ◽  
pp. 735-742 ◽  
Author(s):  
Evangelos Terpos ◽  
Konstantinos Anargyrou ◽  
Eirini Katodritou ◽  
Efstathios Kastritis ◽  
Athanasios Papatheodorou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Independent Prognostic Factor ◽  
Newly Diagnosed ◽  
Angiopoietin 2 ◽  
Angiopoietin 1

scholarly journals The Combination of Bortezomib and Lenalidomide (VR) Consolidation Post-ASCT, in the Absence of Dexamethasone and Bisphosphonates, Improves Response Rates and Bone Metabolism in Newly Diagnosed Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3462-3462
Author(s):  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Metabolism ◽  
Stable Disease ◽  
Newly Diagnosed ◽  
Infectious Episode ◽  
Short Period ◽  
Tracp 5B ◽  
Grade 3

Abstract Consolidation therapy post autologous stem cell transplantation (ASCT) with combinations of bortezomib with an IMiD (thalidomide or lenalidomide) and dexamethasone has been evaluated in patients with multiple myeloma (MM) in an attempt to deepen responses and to improve survival. Bortezomib, IMiDs and steroids have been usually administered in various combinations. However, it is not clear if the use of dexamethasone is needed in consolidation regimens. The primary endpoint of this prospective study was to explore the efficacy of VR consolidation without dexamethasone in newly-diagnosed MM patients who received bortezomib-based induction treatment and then underwent high dose melphalan (HDM) and ASCT. Secondary endpoints included: safety, time to progression (TTP), time to next treatment (TtNT), OS and the effects of VR on bone metabolism in the absence of bisphosphonates administration. Between January 2010 and November 2013, 59 consecutive patients (30M/29F, median age 54 year, range 37-68 years) who achieved at least stable disease post-ASCT were entered into this study. Consolidation consisted of 4 cycles of VR, which started on day 100 post-ASCT. Bortezomib was given at a dose of 1.3 mg/m2, iv (or sc when it was available), on days 1, 4, 8 and 11 of a 21-day cycle, while lenalidomide was given at a dose of 25 mg, p.o., daily on days 1-14. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VR consolidation. Bone remodeling was studied by the measurement of the following serum indices on the day of stem cell collection prior to ASCT and then before and after VR consolidation (3 measurements for each patient): i) osteoclast regulators [soluble receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin], ii) osteoblast inhibitors dickkopf-1 (Dkk-1) and sclerostin, iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Before HDM, one (1.7%) patient had achieved a stringent complete remission (sCR), one (1.7%) was in CR, 30 (50.8%) were in very good partial remission (vgPR), 22 (37.3%) were in PR, while 5 (8.5%) patients had stable disease. After ASCT, 34 (57.6%) patients improved their status of response; in total, 14 (23.7%) patients achieved a sCR, one (1.7%) CR, 35 (59.3%) vgPR and 9 (15.3%) PR. After VR consolidation, 23/59 (39%) patients further improved their status of response; overall, 30 (50.8%) patients achieved a sCR, one (1.7%) CR, 26 (44.1%) vgPR and two (3.4%) PR. The most important adverse events (>10% of the patients) included neutropenia (68%, grade 3/4 23%), thrombocytopenia (59%, grade 3/4 7%), peripheral neuropathy (56%, grade 3/4 2%), anemia (50%, grade 3/4 4.5%), skin rash (34%, grade 3/4 9%), infections (34%, no grade 3/4), fatigue (20%, no grade 3/4), diarrhea (16%, no grade 3/4) and constipation (14%, 2% grade 3/4). No patient developed deep vein thrombosis. Fifteen patients (34.1%) experienced at least one infectious episode (grade 1 and 2); the majority included viral or bacterial infections of the upper respiratory tract. Post-VR consolidation there was a reduction of sRANKL/OPG ratio and of sclerostin (p<0.001) in all patients. Patients who achieved at least vgPR showed higher reductions of sRANKL/OPG and sclerostin compared to patients who achieved a PR (p<0.01). There was no reduction of markers of bone resorption (CTX and TRACP-5b) during the study period, possibly due to the dramatic reduction of these markers during induction therapy when zoledronic acid was given. Furthermore, there were no alterations in Dkk-1, bALP and OC, despite the use of bortezomib which has bone anabolic effects. This may be due to the enhanced expression of Dkk-1 caused by lenalidomide and the short period of observation. No skeletal-related events (SREs) were observed during the study period. The median follow-up after the ASCT was 31 months (range: 7-49 months) and 14 of 44 (31.8%) patients have progressed. The median TTP and TtNT after the ASCT have not been reached yet. The probability of 4-year without progression was 55%. We conclude that 4 cycles of VR consolidation without dexamethasone is an effective regimen which improves the quality of response in approximately 40% of patients and produces long TTP. In the absence of bisphosphonates, VR consolidation has beneficial effects on bone metabolism and is related with no SREs. Disclosures No relevant conflicts of interest to declare.

The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Treatment for Relapsed/Refractory Myeloma: Results of a Phase II Clinical Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 363-363 ◽  
Author(s):  
Evangelos Terpos ◽  
Athanasios Anagnostopoulos ◽  
Efstathios Kastritis ◽  
Athanasios Zomas ◽  
Christos Poziopoulos ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Median Time ◽  
Phase Ii ◽  
Objective Response ◽  
Serum Levels ◽  
Significant Activity ◽  
Bone Formation Markers ◽  
Tracp 5B ◽  
Grade 3 ◽  
Angiopoietin 2

Abstract Interactions between myeloma (MM) cells and marrow microenvironment are crucial for myeloma growth and resistance to anti-myeloma therapy. Bortezomib (VELCADE®; V) and thalidomide (T) have proven anti-MM effect and exert their action partly through perturbation of the MM microenvironment. Furthermore, bortezomib enhances the cytotoxic potential of other agents, such as melphalan (M), and dexamethasone (D) in resistant cell lines. We hypothesize that combining VT (to target both MM cells and microenvironment) with M and D may help overcome resistance and increase clinical efficacy of these agents in relapsed/refractory disease. The aim of this phase II study was to determine the efficacy and safety of the VMDT regimen and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 1–4, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Responders and patients with SD continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as VEGF, angiogenin, angiopoietin-2, and bFGF at baseline and after cycles 4 and 8. Bone remodeling was studied by the measurement of a series of serum indices: i) osteoclast stimulating factors [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α ], ii) bone resorption markers (CTX, TRACP-5b), and iii) bone formation markers [bALP, osteocalcin (OC), and CICP]. Thirty-one pretreated pts (median age: 66 y; range: 45–83 y) have been enrolled in this study, including 20 pts treated during refractory relapse. Median time from 1st treatment to VMDT was 40 months. Many pts had features of advanced disease including ISS stage 3 (32%), high LDH (23%), and creatinine &gt;2mg% (10%). The median number of previous treatments was 2 (range: 1–6), including M (48% of pts), T (65%), D (100%), V (3%) and ASCT (39%). Among 25 pts evaluable for response so far, 14 (56%) achieved an objective response (CR 8% and PR 48%). Furthermore, 2 pts (8%) achieved a MR and 5 (20%) SD. Median time to response was 30 days. Adverse events included fatigue (56%), thrombocytopenia (12% grade 3/4), neutropenia (8% grade 3/4), anemia (8% grade 3), neuropathy (48% grade 1/2, no grade 3/4 observed), infections (36%, including 2 HZ cases), and hyponatremia (12%). No pt experienced DVT, while 2 pts died due to sepsis. At baseline, MM pts had increased serum levels of sRANKL, sRANKL/OPG ratio, MIP-1α , VEGF, angiogenin, angiopoietin-2, and bFGF (p&lt;0.01) compared with controls, while serum levels of CTX, TRACP-5b, bALP, OC were decreased (p&lt;0.03) since all pts have been on zoledronic acid treatment. Our preliminary analysis showed that sRANKL and MIP-1α levels reduced after 4 cycles of VMDT. In conclusion the VMDT combination with intermittent T is associated with significant activity in pts with heavily pretreated MM. The toxicities are manageable; due to intermittent T administration there was no severe neurotoxicity and no DVT. Our study will also provide further data regarding post-treatment changes of cytokines involved in interactions between MM and stromal cells.

Increased Osteoprotegerin Levels in Response to Increased Bone Resorption in AL Amyloidosis: Comparisons with Bone Remodeling of Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3528-3528
Author(s):  
E. Kastritis ◽  
Meletios Athanasios Dimopoulos ◽  
M. Mihail ◽  
E. Mihali ◽  
M.C. Kyrtsonis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Remodeling ◽  
Plasma Cell ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Bone Resorption Markers ◽  
Bone Formation Markers ◽  
Lytic Bone Lesions ◽  
Tracp 5B

Abstract Primary systemic amyloidosis (AL) and multiple myeloma (MM) are both clonal plasma cell disorders with distinct clinical characteristics. Bone disease is a hallmark of symptomatic MM in contrast to AL where lytic bone lesions are not found. Myeloma bone disease is characterized by an imbalance between osteoblastic and osteolytic activity induced by plasma cell-stroma interaction resulting in deregulation of numerous cytokines involved in bone remodeling. There are no data about bone metabolism in AL and the similarities or differences with MM. Levels of bone remodeling indices were measured in stored serum samples, collected from 62 previously untreated patients with AL amyloidosis. These included: bone resorption markers [C- and N- telopeptide of type-I collagen (CTX and NTX, respectively), and tartrate resistant acid phosphatase type-5b (TRACP-5b)], bone formation markers [bone-alkaline phosphatase (bALP), and osteocalcin (OC)], and osteoclast regulators [soluble receptor activator of nuclear factor-kB ligand (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1 alpha (MIP-1a), interleukin-6 (IL-6) and osteopontin (OPN)], as previously described. These markers were also measured in serum collected from 35 age-matched healthy controls and 35 newly diagnosed, untreated, symptomatic myeloma patients. Median age of AL patients at diagnosis was 61 years (range 39–80 years); heart was involved in 60% and kidneys in 66% of patients, while in 64% ≥2 organs were involved. In 16% of AL patients creatinine was ≥2 mg/dl. Median b2-microglobulin was 1.8 mg/l (range 0.5–28 mg/l); 64% of patients had >10% bone marrow infiltration by plasma cells. None of AL patients had lytic bone lesions in plain radiography or other features suggestive of myeloma such as hypercalcemia, significant anemia unrelated to renal impairment or predominant Bence-Jones proteinuria. The levels of sRANKL and OPG were both increased in AL patients compared to controls (p=0.07 and p<0.001). OPG was significantly higher in AL than in MM patients (p<0.001), but not sRANKL; thus sRANKL/OPG ratio was not different between AL and controls but it was significantly lower than in MM patients (p=0.009). Other osteoclast stimulators (MIP-1a, OPN, IL-6) were also increased in AL compared to controls (p<0.02). Bone resorption markers (CTX, NTX, TRACP-5b) were elevated in both AL and MM (p=0.008, p<0.001 and p<0.001 for AL vs. controls, respectively, and p=0.006, p<0.001 and p<0.001 for MM vs. controls). On the contrary, bone formation markers were not different between AL patients and controls, while in MM both bALP and OC had lower values compared to controls. Renal involvement did not affect bone markers but in AL patients with a creatinine level of >2 mg/dl CTX and NTX were higher than in patients with a creatinine level of <2mg/dl (p<0.001 and p=0.016, respectively). Involvement of other organs or the number of involved organs did not appear to influence bone remodeling. This study suggests that bone metabolism in AL is characterized by increased bone resorption with a pattern similar to that found in MM. Increased OPG levels in AL indicate more effective compensation of osteoclast activation compared to MM, probably explaining the lack of lytic disease in AL and possibly reflecting differences in the pathophysiology of plasma cell-stroma interaction between AL and MM.

The Administration of Bortezomib, Dexamethasone and Thalidomide (VTD) after ASCT in Myeloma Patients Who Do Not Receive Bisphosphonates Normalizes sRANKL, Dickkopf-1 and Improves Abnormal Osteoclast Function and Impaired Angiogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1728-1728
Author(s):  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Metabolism ◽  
Serum Levels ◽  
Type I ◽  
Tracp 5B ◽  
Osteoclast Function ◽  
Angiopoietin 2 ◽  
Dickkopf 1 ◽  
Impaired Angiogenesis ◽  
Angiopoietin 1

Abstract Bortezomib (V) monotherapy has been associated with increased osteoblastic activity, reduced osteoclast function and decreased angiogenesis in relapsed/refractory myeloma. The effects of V on bones may be direct or may reflect the reduction of myeloma burden. The co-administration of zoledronic acid, in all reported studies to-date, may also suggest a synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not allowed the independent evaluation of V on bone metabolism. Previous studies have shown that the combination of V with other agents, such as thalidomide (T) and melphalan, although reduced osteoclast activity, did not enhance osteoblast function. We evaluated the effect of VDT consolidation therapy on bone metabolism and angiogenesis in myeloma patients who underwent high dose melphalan (200 mg/m2) followed by autologous stem cell transplantation (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 throughout the period of VDT consolidation. VDT was given on day 100 after ASCT: V was administered at a dose of 1.0 mg/m2 on days 1,4,8,11, while T was given at a dose of 100 mg/day, po, on days 1–21 and D at a dose of 40mg/day on days 1–4 of a 21-day cycle. Patients received 4 VDT cycles (first course) and 4 more VDT cycles (second course) 100 days post-day 21 of the 4th cycle. Bone remodeling was studied by the measurement of a series of serum indices on day 1 of cycles 1 & 5 and on day 21 of cycle 8: i) osteoclast regulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate resistant acid phosphatase isoform 5b (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Effect of VDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as vascular endothelial growth factor (VEGF), angiogenin, angiopoietin-1, angiopoietin-2, and basic fibroblast growth factor (bFGF) on the same dates. The above biochemical markers and cytokines were also measured in 18, gender and age-matched, controls. To-date, 18 patients (7M/11F, median age 60 years) have been entered into this study. On day 100 after ASCT, just before VDT, 5 patients were in CR (2 in sCR), 11 in vgPR and 2 in PR, according to IMWG response criteria. At baseline, although the vast majority of patients were in ≥vgPR, they had increased serum levels of sRANKL (p=0.015), Dkk-1 (p=0.025), CTX (p=0.001), TRACP-5b (p=0.032), VEGF (p&lt;0.0001), bFGF (p&lt;0.0001), angiogenin (p=0.01) and reduced levels of angiopoietin-1/angiopoietin-2 ratio (p&lt;0.0001) compared to controls. Serum levels of sRANKL strongly correlated with CTX (r=0.701, p=0.002) and OPG (r=0.733, p=0.0001), while levels of CTX correlated with TRACP-5b (r=0.619, p=0.0008). The administration of 4 VDT cycles resulted in a significant reduction of sRANKL (p=0.02), TRACP-5b (p=0.016), angiogenin (p=0.03), Dkk-1 (p=0.047), but also of bALP (p=0.003) and OC (p=0.016). A borderline reduction of CTX (p=0.071), and VEGF (p=0.056) was also observed. The levels of sRANKL, Dkk-1, TRACP and angiogenin did not differ from control values, while the reduction of bALP and OC did not produce significant differences compared to controls, after 4 VDT cycles. However, levels of VEGF, angiopoietin-1/angiopoietin-2 ratio and bFGF values continued to be elevated compared to controls’ values, while CTX levels were slightly increased compared to controls (p=0.049). The results of this on going study suggests that VDT consolidation post-ASCT normalizes sRANKL and Dkk-1 serum levels and improves impaired angiogenesis. However, as in other combination regimens (i.e. VMDT in relapsed/refractory patients), bortezomib could not produce an anabolic effect on bones when combined with TD even in these patients with low myeloma burden.

scholarly journals Consolidation with Carfilzomib, Lenalidomide and Dexamethasone (KRd) Following ASCT Results in High Rates of Minimal Residual Disease Negativity and Improves Bone Metabolism, in the Absence of Bisphosphonates, Among Newly Diagnosed Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3118-3118 ◽  
Author(s):  
Maria Gavriatopoulou ◽  
Evangelos Terpos ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Panagiotis Malandrakis ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Metabolism ◽  
Research Funding ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Tracp 5B ◽  
Stage 1 ◽  
Minimal Residual

Consolidation therapy post autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) seems to deepen disease responses. MRD negativity represents a strong prognostic factor for prolonged remission. Carfilzomib is a second-generation proteasome inhibitor, which in combination with lenalidomide has been associated with high rates of deep responses before ASCT in phase 2 studies. In this context, we prospectively evaluated the role of carfilzomib, lenalidomide and dexamethasone (KRd) as consolidation therapy post-ASCT in newly diagnosed MM pts who have not achieved MRD negative complete remission (CR). The primary endpoint was to assess KRd efficacy in terms of improving disease response, whereas secondary endpoints included percentage of minimal residual disease (MRD) (performed by Next Generation Flow Cytometry) negativity post KRd, safety, time to progression (TTP), time to next treatment (TtNT), overall survival (OS) and the effects of KRd on bone metabolism in the absence of bisphosphonate administration. All pts achieving at least partial response and less than MRD negativity post-ASCT were eligible for inclusion in the study. Consolidation consisted of 4 cycles of KRd, starting on day 100 post-ASCT: carfilzomib was given at a dose of 20 mg/m2 iv on day 1 cycle 1 and 56 mg/m2, on days 1, 8, 15 thereafter; lenalidomide was given at 25 mg daily on days 1-21 and dexamethasone at 40mg weekly every 28-days. All pts continued lenalidomide maintenance 10 mg following consolidation until progressive disease. Pts did not receive bisphosphonates during or post-ASCT as well as throughout the period of KRd consolidation. Bone remodeling was evaluated by the following serum indices before and after KRd (2 measurements for each pt): i) osteoclast regulators (soluble receptor activator of nuclear factor kappaB ligand and osteoprotegerin), ii) osteoblast inhibitors (dickkopf-1 and sclerostin) iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Between January 2018 and May 2019, 39 consecutive pts all MRD positive (20M/19F, median age 56 years, range 44-67 years) entered the study. The distribution per revised ISS was 36.1% stage 1, 52.8% stage 2 and 11.1% respectively. After a median follow-up of 16 months (range 1-17) following KRd initiation, 35 (89.7%) pts had received 4 cycles of KRD, whereas two pts continue on treatment and two discontinued treatment due to toxicity. Following ASCT, one (2.6%) pt had achieved stringent CR (sCR), 4 (10.3%) were in CR, 29 (74.4%) were in very good partial remission (VGPR) and 5 pts (12.8%) were in PR. Post KRd consolidation, 30 out of 37 evaluable pts (81%) pts improved their response status with KRd. Overall, 28 (75.7%) pts achieved a sCR, one (2.7%) CR and 8 (21.6%) VGPR, while 25 (67.6%) pts achieved MRD negativity at 10-5. Among the 25 MRD negative pts, 11 (44%) were R-ISS stage 1, 13 (52%) stage 2 and one (4%) stage 3. Positron emission tomography-computed tomography (PET/CT) scans that were performed in 14 MRD (-) pts were negative for all pts except one. The markers of bone metabolism were measured in 22 pts. Only TRACP-5b levels showed a significant reduction (p=0.011) post KRd consolidation, which suggests a beneficial effect on bone resorption that must be further investigated. No new skeletal-related events (SREs) were reported. No patient has progressed whereas 37/39 (95%) are alive. One patient died due to staphylococcal pneumonia and another due to refractory thrombotic thrombocytopenic purpura complicated by brain hemorrhage and in-hospital infection during KRD. 7 (18%) pts experienced ≥grade 3 toxicities (mainly infections, TTP, fatigue, neutropenia, pneumonitis, hypocalcemia and increase of γGT and ALP). There were no new cases of peripheral neuropathy. In conclusion, KRd consolidation with weekly carfilzomib, post ASCT, is highly effective and improves the quality of response by increasing MRD negativity rates. Although it is given for four cycles only, KRD consolidation reduces bone resorption and correlates with no SREs in the absence of bisphosphonates. Infections prophylaxis is strongly encouraged. This triplet combination should be further investigated as a potential consolidation regimen both for standard and high-risk pts. Disclosures Gavriatopoulou: Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Medison: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.

scholarly journals MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia

BMJ Open ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. e046225
Author(s):  
Sarah Brown ◽  
Debbie Sherratt ◽  
Samantha Hinsley ◽  
Louise Flanagan ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cell ◽  
Phase Ii ◽  
Whole Body ◽  
Cell Leukaemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Genetic Changes ◽  
Novel Treatment

IntroductionMultiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and disseminationEthics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN16847817, May 2017; Pre-results.

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