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ABSTRACT: Novel agents are increasingly used during induction therapy for multiple myeloma (MM), but there is concern about their potential impact on stem cell mobilization. Regimens containing either thalidomide or cyclophosphamide have little or no impact on stem cell collection. In this retrospective review of 136 patients with newly diagnosed MM, we show that the combination of thalidomide and oral CY with dexamethasone (CTD) during induction therapy impaired stem cell mobilization substantially. Compared with VAD (vincristine, doxorubicin, dexamethasone) and a VAD-like induction regimen, the stem cell collection yield after CTD was decreased by 49% (median 5.0 vs 9.8 × 10(6) CD34+cells/kg, P<0.001). Following CTD, more patients failed to mobilize enough stem cells for one (25.4 vs 5.8%, P=0.002) or two (39.4 vs 15.9%, P=0.002) transplants. These results demonstrate that the combination of thalidomide and oral CY impairs stem cell mobilization and indicate that drugs with no previously reported relevant effect on stem cell mobilization can have a substantial impact when given in combination.
Bone marrow transplantation 03/2011; 46(3):364-7. · 3.00 Impact Factor
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ABSTRACT: Antigen expression of multiple myeloma (MM) cells is heterogeneous. We have investigated the clinical impact of expression of some of the commonly used immunohistochemical markers in the diagnostic work-up of bone marrow trephine biopsy (BMTB) samples in MM.
BMTB samples from 107 MM patients who had received an autologous stem cell transplant (ASCT) following chemotherapy were evaluated. In 75 cases, the immunophenotype had been evaluated on two or more occasions on further follow-up.
In the cases evaluated, 32%, 79%, 73%, 39% and 60% of cases had been scored positive for CD20, CD79a, CD56, cyclin D1 and epithelial membrane antigen (EMA) respectively. Absence of CD79a was predictive of poor overall survival (OS) from the time of transplant (p = 0.029) and poor event-free survival (EFS) from the time of transplant (p = 0.003). Absence of EMA (p = 0.02) was predictive of poor EFS from the time of diagnosis. Presence of CD56 was predictive of poor EFS from the time of diagnosis (p = 0.026). On multivariate analysis, only CD79a expression (OS and EFS from the time of transplant) and EMA expression (EFS from the time of diagnosis) maintained their significance. 13 of 75 patients showed an immunophenotypic drift during the disease course. Loss of CD20 (four cases) during the disease course in cases that were previously scored positive correlated with significant worsening both, of OS (p = 0.02) and EFS (p = 0.009) from the time of diagnosis.
Immunophenotype impacts on clinical outcome in MM.
Journal of clinical pathology 11/2009; 62(11):1009-15. · 2.43 Impact Factor
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ABSTRACT: AL amyloidosis (ALA) is a form of plasma cell (PC) dyscrasia characterised by deposition of insoluble fibrillar deposits in various organs causing organ damage. This is believed to be the first study to evaluate the expression of CD79a, CD20, CD56, cyclin D1 and epithelial membrane antigen (EMA) in neoplastic PCs of ALA. Methods and
The study included 36 well-documented cases of ALA. In all cases presence of amyloid deposits had been documented by Congo Red stain in the bone marrow trephine biopsy (BMTB) and/or in other tissues. BMTBs showed varying degrees of PC infiltration (median 12%). In eight of the 36 cases with associated myeloma, the mean (2 x SE) percentage of PCs (PC%) was 34 (18)%, while in the remaining, PC% was 15 (4)%. Expression of CD20, CD79a, CD56, cyclin D1 and EMA was noted in 42%, 86%, 50%, 53% and 83% of cases, respectively. Aberrant antigen expression in the form of CD56 and/or cyclin D1 expression was seen in 79% of cases. Nine of 10 cases with small lymphoid-like PCs were positive for CD20 and all the 10 cases were positive for cyclin D1. On the other hand, among cases without small lymphoid-like morphology, CD20 and cyclin D1 expression was seen in only 6 of 26 and 8 of 26 cases respectively (p = 0.001 and 0.002 respectively). CD20 expression correlated with cyclin D1 expression (p = 0.045). Cytological atypia/pleomorphism was predictive of associated myeloma (p = <0.001).
Marrow involvement by neoplastic PCs in ALA can be identified by their aberrant antigen expression apart from light chain restriction, and rituximab as a possible treatment option may be explored in CD20-positive ALA.
Journal of clinical pathology 08/2009; 62(8):724-30. · 2.43 Impact Factor
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ABSTRACT: Multiple myeloma (MM) guidelines in the UK do not advocate performing bone marrow trephine biopsy (BMTB) during follow-up. In a recent study, it was found that the plasma cell per cent (PC%) in BMTB performed at the time of autologous stem cell transplant strongly correlated with survival. The current study addresses whether BMTB is superior to bone marrow aspiration (BMA) in documenting presence of disease and its volume at follow-up.
The study involved 106 samples. A conventional 500-cell differential count was performed on the BMAs to document the PC%. The PC% on BMTBs had been estimated on CD138 immunostain. Furthermore, BMTBs had also been immunostained for CD56, cyclin D1 and light chains.
The mean (2SEM) PC% values in BMAs and BMTBs were 13.1 (2.6)% and 31.8 (5.8)% respectively. Based on BMA, BMTB and serum/urine paraprotein or light chain estimation, on 92 occasions (89%) there was detectable disease. The positive predictive value of both BMA and BMTB was 100%, and the negative predictive values for BMTB and BMA were 57% and 22% respectively. Among 98 secretory MM cases, the BMTB-PC% showed significant correlation with paraprotein levels, whereas BMA-PC% did not.
It is strongly recommended that BMTB is performed and adequately investigated with immunohistochemistry during follow-up of MM.
Journal of clinical pathology 03/2008; 61(2):213-6. · 2.43 Impact Factor
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Journal of Clinical Pathology 10/2007; 60(9):1064-5. · 2.31 Impact Factor
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M P Simula,
S Marktel,
C Fozza,
J Kaeda,
R M Szydlo,
E Nadal,
M Bua, A Rahemtulla,
E Kanfer,
D Marin,
E Olavarria,
J M Goldman,
J F Apperley,
F Dazzi
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ABSTRACT: Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.
Leukemia 05/2007; 21(5):943-8. · 9.56 Impact Factor
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J B Perz,
C Giles,
R Szydlo,
D O'Shea,
J Sanz,
A Chaidos,
S Wagner,
J Davis,
S Loaiza,
D Marin,
J Apperley,
E Olavarria, A Rahemtulla,
I Lampert,
K Naresh,
D Samson,
D MacDonald,
E J Kanfer
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ABSTRACT: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit.
Bone Marrow Transplantation 02/2007; 39(1):41-7. · 3.75 Impact Factor
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ABSTRACT: Light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which amyloidogenic monoclonal light chains deposit in various tissues resulting in organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. Several phase II studies report haematological and clinical remission in up to 50% of patients after high-dose melphalan and autologous stem cell transplantation. We analysed retrospectively the long-term outcome of 19 patients treated in this way between August/1996 and December/2001. We observed a relatively high treatment-related mortality of 26%, but 12 patients (63%) were high-risk candidates. Eight patients (42%) surviving longer than 100 days achieved haematological remission and long-term survival, whereas 6 (32%) obtained no clear benefit from high-dose therapy. However, 62% of patients survived beyond 2 years and the median survival from transplant was 48 months (range 0-104 months).
Bone Marrow Transplantation 06/2006; 37(10):937-43. · 3.75 Impact Factor
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D O'Shea,
C Giles,
E Terpos,
J Perz,
M Politou,
V Sana,
K Naresh,
I Lampert,
D Samson,
S Narat,
E Kanfer,
E Olavarria,
J F Apperley, A Rahemtulla
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ABSTRACT: High-dose therapy with autologous stem cell therapy (ASCT) has become the treatment of choice for eligible patients with myeloma. We analysed retrospectively the prognostic influence of pre-transplant characteristics and transplant modalities on response and survival in 211 myeloma patients who were transplanted in our centre between 1994 and 2004. All patients received peripheral blood stem cell support after conditioning with melphalan alone (183 patients), or melphalan and total blood irradiation (28 patients). We evaluated the influence of age, type of multiple myeloma, status prior and post ASCT, previous treatment regimens, time of ASCT from diagnosis, year of autograft, dose of re-infused CD34(+) cells, plasma cell infiltration and beta2-microglobulin at diagnosis on overall survival (OS) and event-free survival (EFS) to define patients with better prognosis. Median OS and EFS from transplantation were 50.9 and 20.1 months, respectively. Median OS from diagnosis was 68.8 months. Transplant-related mortality was 1.4%. Lower beta2-microglobulin levels, achievement of complete remission (CR) post transplant and lower plasma cell infiltration at diagnosis and transplant correlated with longer EFS and OS, whereas CR at transplant and low international prognostic index at transplant correlated with better EFS. Higher CD34(+) cell dose correlated with improved OS. We conclude that ASCT is safe and effective and the outcome is independent of age, time from diagnosis, previous treatment and conditioning regimen.
Bone Marrow Transplantation 05/2006; 37(8):731-7. · 3.75 Impact Factor
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ABSTRACT: The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
Leukemia 12/2005; 19(11):1969-76. · 9.56 Impact Factor
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D Marin,
J Kaeda,
R Szydlo,
S Saunders,
A Fleming,
J Howard,
C Andreasson,
M Bua,
E Olavarria, A Rahemtulla,
F Dazzi,
E Kanfer,
J M Goldman,
J F Apperley
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ABSTRACT: We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of 'residual' disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.
Leukemia 05/2005; 19(4):507-12. · 9.56 Impact Factor
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ABSTRACT: The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
Leukemia 09/2004; 18(8):1420-6. · 9.56 Impact Factor
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ABSTRACT: A case of disseminated Aspergillus terreus infection in a patient with prolonged neutropenia after stem cell transplant for myeloma is reported. The isolate was resistant to amphotericin B in vitro, and the patient was successfully managed with surgical debridement and the recently licensed antifungal agent caspofungin. There are many challenges associated with treating invasive aspergillosis, particularly that due to A. terreus, and the early use of caspofungin should be considered.
Clinical Microbiology and Infection 01/2004; 9(12):1238-41. · 4.54 Impact Factor
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ABSTRACT: Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m(2)), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.
Bone Marrow Transplantation 11/2003; 32(7):653-6. · 3.75 Impact Factor
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ABSTRACT: High-dose therapy with autologous stem cell transplantation (ASCT) has become the treatment of choice for symptomatic eligible patients with multiple myeloma (MM). We report our centre experience and analyse retrospectively the prognostic influence of pretransplant characteristics and transplant modalities on response and survival. A total of 127 MM patients (median age: 55.2 years) were transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients were in complete remission (CR), 73% in partial remission (PR), 12% showed minor response to previous treatment and 9% had stable or refractory disease. Prior to autograft, 79% of cases had received only one line of chemotherapy and 21% two or more lines. All patients received PBSC support after conditioning with 200 mg/m(2) melphalan alone (100 patients) or melphalan and TBI (27 patients). We evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65 years), type of MM, status pre- and post-ASCT, number of lines of previous regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+ cells, plasma cell infiltration and beta(2)-microglobulin at diagnosis on overall (OS) and progression-free survivals (PFS) to define patients with better prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only two patients progressed. Median OS and PFS from transplantation were 50.4 and 23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant-related mortality was 2.3%. Low levels of beta(2)-microglobulin and the achievement of CR post-transplant correlated with longer PFS (P<0.03 and P<0.01, respectively). The median PFS was 36.1, 23.9, 21.1 and 16.4 months for nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an important prognostic factor at a cutoff value of 55 or 60 years. We conclude that ASCT is a safe and effective procedure even in resistant cases. The outcome was independent of age, time from diagnosis, previous treatment and conditioning regimen, but there was a tendency for better survival in the nonsecretory patients.
Bone Marrow Transplantation 02/2003; 31(3):163-70. · 3.75 Impact Factor
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ABSTRACT: Interaction between receptor activator of nuclear factor kB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodelling markers in121 newly diagnosed MM patients to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The ratio sRANKL/OPG was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The ratio sRANKL/OPG, CRP and b2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We have generated a prognostic index based on these factors, which divides our patients into three risk groups. The low-risk group had a 96% probability of survival at five years while the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0% respectively. Not only do these results confirm for the first time in humans the importance of the sRANKL/OPG in the development of bone disease but they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
The Hematology Journal 01/2003; 4:256. · 1.86 Impact Factor
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ABSTRACT: Bone disease is a major cause of morbidity in multiple myeloma (MM). Through the interactions between myeloma and stromal cells, osteoclasts are activated resulting in an increased resorptive activity, which is illustrated by the elevated levels of N-telopeptide of type-I collagen (NTX), and of tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), an enzyme which is produced only by activated osteoclasts. The receptor activator of nuclear factor-kB ligand (RANKL) and osteoprotegerin (OPG) pathway has been found to be the dominant mediator of osteoclastogenesis and possibly promotes growth of myeloma cells. The aim of this study was to evaluate the role of soluble RANKL (sRANKL), OPG and markers of bone remodelling [NTX, TRACP-5b, bone-alkaline phosphatase (bALP), and osteocalcin (OC)] in bone disease and survival in MM. A total of 121 newly diagnosed patients (61M/60F; median age: 68 years) with MM were studied. Ten patients had no lytic lesions or osteoporosis only; 28 patients had 1-3 osteolytic lesions, while 83 patients had >3 osteolytic lesions and/or a pathological fracture. The above markers were also measured in 46, age and sex matched, healthy controls. Patients with MM had elevated mean sRANKL, TRACP-5b and NTX values and decreased levels of OPG, OC and bALP compared with controls. The ratio of sRANKL/OPG was also significantly higher in MM patients. There was a strong correlation between the ratio sRANKL/OPG and the extent of bone disease (p<0.001), stage of MM (p<0.0001), levels of TRACP-5b (p<0.0001), NTX (p<0.0001), IL-6 (p<0.0001), and beta2-microglobulin (p<0.0001). The median overall survival for the 121 patients was 56.9 months. Eighty-two patients had received only conventional chemotherapy, while 39 patients had undergone autologous stem cell transplantation. The multivariate analysis revealed that only the ratio of sRANKL/OPG, and the levels of beta2-microglobulin and CRP were independent prognostic factors for survival. Based on these 3 factors, we created a risk score (Hammersmith Prognostic Index): sRANKL/OPG ratio of <1 and beta2-microglobulin levels of 3 mg/l was given a score of 1 point; sRANKL/OPG ratio of between 1-3 and CRP levels of 10 mg/l had 2 points; 3 points were given for CRP levels of >10 mg/l and beta2-microglobulin of >3 mg/l, and 4 points for sRANKL/OPG ratio of >3. This system has subdivided our patients into three groups. The low-risk group included 26 patients (score <6), the intermediate group 55 patients (score 6-8), and the high-risk group 40 patients (score >8). The 5-year probability of survival for each group is illustrated in the Figure. We compared this scoring system with that proposed by Bataille et al using beta2-microglobulin and CRP as prognostic values. Our risk score appears to be more discriminating in identifying a very good risk group, and a superior intermediate risk group. Not only do these results confirm for the first time in humans the importance of the RANKL/OPG system in the development of bone disease but they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
Hematology J. 4 (suppl 1), S161, 2003. 01/2003; 4:S161.
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ABSTRACT: Tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a new marker reflecting osteoclast activity, and osteoprotegerin were measured in 121 patients with multiple myeloma (MM) at diagnosis and in 63 of them during pamidronate administration. Levels of TRACP-5b were increased, while osteoprotegerin was decreased in MM patients compared with controls (p<.0001) TRACP-5b levels were associated with the radiographically assessed extent of bone disease (p<.001) as well as with levels of N-terminal cross-linking telopeptide of type-I collagen (NTX), interleukin-6 and beta2-microglobulin. The combination of pamidronate with VAD-chemotherapy produced a reduction in TRACP-5b, NTX, interleukin-6, paraprotein, and beta2-microglobulin levels from the 2nd month of treatment, with no effect on bone formation and osteoprotegerin. A significant correlation was observed between changes of TRACP-5b and changes of NTX, IL-6 and beta2-microglobulin. These findings suggest that TRACP-5b is increased in MM, being a useful new marker for monitoring pamidronate administration, which had no effect on osteoprotegerin levels.
Blood. 01/2002; 100:811a.
