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Background: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.Methods: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.Results: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).Conclusions: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .). [ABSTRACT FROM AUTHOR]

BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. [ABSTRACT FROM AUTHOR]

Background: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.Methods: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.Results: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.Conclusions: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .). [ABSTRACT FROM AUTHOR]

Waldenström's macroglobulinemia (WM) is a rare, low-grade malignancy with no established standard of care. Rituximab regimens are most commonly used, supported by their efficacy in hematologic malignancies, including WM. A growing number of investigational regimens for WM have been evaluated in phase II clinical trials, including single-agent and combination strategies that include newer-generation monoclonal antibodies (ofatumumab and alemtuzumab), proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide and lenalidomide), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), a Bruton's tyrosine kinase inhibitor (ibrutinib), and a histone deacetylase inhibitor (panobinostat). Other novel agents are in early-stage development for WM. International treatment guidelines for WM suggest suitable regimens in the newly diagnosed and relapsed/refractory settings, in accordance with patient age, disease presentation, and efficacy and safety profiles of particular drugs. These factors must be considered when choosing appropriate therapy for individual patients with WM, to maximize response and prolong survival, while minimizing the risk of adverse events. This review article provides a clinical perspective of the modern management of patients with WM, in the context of available trial data for novel regimens and recently updated treatment guidelines. [ABSTRACT FROM AUTHOR]

While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario. [ABSTRACT FROM AUTHOR]

In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed. [ABSTRACT FROM AUTHOR]

The incidence and severity of renal impairment at the time of diagnosis of myeloma remains unchanged during the past 20 years due to increasing numbers of elderly patients who are diagnosed and treated for myeloma. Novel therapies have improved significantly the survival of patients with severe renal dysfunction and may also decrease the risk of early death which is high in patients with severe renal impairment, especially among older patients.Background Renal impairment (RI) is a common presenting complication of multiple myeloma (MM); the availability of new treatments has improved the outcomes of patients with MM; however, their impact on the survival of patients who present with RI has not been extensively studied. Patients and methods We analyzed the characteristics and outcomes of 1773 consecutive unselected patients who were treated for symptomatic myeloma since January 1990. Results Although there was a significant increase in the proportion of patients of advanced age in the more recent periods, the frequency of RI as well as the proportion of patients who presented with severe RI (eGFR < 30 ml/min/1.73 m2) remained unchanged around 18%. Thus, after adjustment for age, there was a decrease in the risk of severe RI at presentation after 2000. Myeloma response rates (≥PR) to frontline therapy have substantially increased, and this was translated in a significant increase in the median survival. Specifically for patients with severe RI, the median OS has improved from 18 and 19.5 months in the 1990–1994 and 1995–1999 to 29 and 32 months for the periods 2000–2004 and after 2005 (P = 0.005). Severe RI was associated with a high risk of early death (12% versus 7% for patients with moderate RI versus 3% for patients with mild or no RI (P < 0.001), especially among older patients, and has remained unchanged over time. Conclusions There has been a major improvement in the survival of patients with severe RI in the past decade, despite the increasing numbers of patients of advanced age. However, the risk of early death remains high in patients with severe RI, especially in the elderly. [ABSTRACT FROM AUTHOR]

The role of thalidomide, bortezomib and lenalidomide in multiple myeloma patients presenting with renal impairment was evaluated in 133 consecutive newly diagnosed patients who were treated with a novel agent-based regimen. A significant improvement of renal function (renalPR (renal partial response)) was observed in 77% of patients treated with bortezomib, in 55% with thalidomide and in 43% with lenalidomide (P=0.011). In multivariate analysis, bortezomib-based therapy was independently associated with a higher probability of renal response compared with thalidomide- or lenalidomide-based therapy. Other important variables included eGFR (estimated glomerular filtration rate) 30 ml/min, age 65 years and myeloma response. Patients treated with bortezomib achieved at least renalPR in a median of 1.34 months vs 2.7 months for thalidomide and >6 months for lenalidomide-treated patients (P=0.028). In multivariate analysis bortezomib-based therapy, higher doses of dexamethasone (160 mg during the first month of treatment), an eGFR 30 ml/min and age 65 years were independently associated with shorter time to renal response. In conclusion, bortezomib-based therapies may be more appropriate for the initial management of patients with myeloma-related renal failure; however, thalidomide and lenalidomide are also associated with significant probability of improvement of their renal function. [ABSTRACT FROM AUTHOR]

Background: The International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum β2-microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include ‘up-staged’ MM patients in whom elevated β2-microglobulin reflects the degree of renal dysfunction rather than tumor load. Patients and methods: In order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria. Results: Forty-eight percent patients had stages 3–5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day. Conclusions: ISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction. [ABSTRACT FROM PUBLISHER]

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions ≥12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions ≥12 months had a significantly longer median PFS than those who had reductions before 12 months (P=0.007) or no dose reductions (P=0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction ≥12 months was an independent predictor of improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for ≥12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy; prospective studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. [ABSTRACT FROM AUTHOR]

Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future. [ABSTRACT FROM AUTHOR]

We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were associated with lower response rates in RD (P=0.01), but not in VRD (P=0.219). The median progression-free survival (PFS) was similar for RD (9 months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor risk cytogenetics, especially del17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del17p remains extremely poor even with VRD combination. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in the response of the article "Diffuse MRI marrow pattern correlates with increased angiogenesis, advanced disease features and poor prognosis in newly diagnosed myeloma treated with novel agents," in April 29, 2010 issue.

The article examines the role of molecular markings on the development of epithelial ovarian cancer. It presents an analysis on the potential usefulness and function of molecular markers, which include the ras proteins, endothelin, and metalloproteinase, in ovarian cancer. It also suggests the need for accurate and efficient prognosis of cancer and the awareness of the physicians in molecular biology to make them capable treating every patient according to their risk factors and tumour markers.

In this study a test method based on wavelet energy of the supply current measurements is presented. The method has been utilised by a microcontroller-based versatile test system which is used for the production line testing of emergency luminaire products. The presented method is simple, offers a single–point test measurement solution and may easily be adapted to test various other analogue and mixed-signal systems. Fault detectability comparative experimental results between the wavelet energy and the root mean square (RMS) plus spectrum component values of the supply current measurements are presented showing the effectiveness of the proposed test method. [ABSTRACT FROM AUTHOR]

We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low β2-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone. [ABSTRACT FROM AUTHOR]

Several imaging technologies are used for the diagnosis and management of patients with multiple myeloma (MM). Conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging are all used in an attempt to better clarify the extent of bone disease and soft tissue disease in MM. This review summarizes all available data in the literature and provides recommendations for the use of each of the technologies. Conventional radiography still remains the ‘gold standard’ of the staging procedure of newly diagnosed and relapsed myeloma patients. MRI gives information complementary to skeletal survey and is recommended in MM patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. Urgent MRI or CT (if MRI is not available) is the diagnostic procedure of choice to assess suspected cord compression. Bone scintigraphy has no place in the routine staging of myeloma, whereas sequential dual-energy X-ray absorptiometry scans are not recommended. Positron emission tomography/CT or MIBI imaging are also not recommended for routine use in the management of myeloma patients, although both techniques may be useful in selected cases that warrant clarification of previous imaging findings, but such an approach should ideally be made within the context of a clinical trial. [ABSTRACT FROM AUTHOR]

Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.Leukemia (2008) 22, 1485–1493; doi:10.1038/leu.2008.131; published online 5 June 2008 [ABSTRACT FROM AUTHOR]

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders. Leukemia (2008) 22, 1343–1353; doi:10.1038/leu.2008.123; published online 29 May 2008 [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.Leukemia (2007) 21, 1875–1884; doi:10.1038/sj.leu.2404843; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

Abstract: Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m-2 , vincristine 2 mg, E 70 mg m-2 on day 1 and prednisone 60 mg on days 1–7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m-2 . Randomization was stratified according to stages I–IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P = 0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P = 0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival... [ABSTRACT FROM AUTHOR]

Preliminary evidence suggests that high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation may be effective in some patients with resistant Waldenstrom's macroglobulinemia. During the last 10 years, seven patients with Waldenstrom's macroglobulinemia have received transplants at the MD Anderson Cancer Center, four with autologous and three with allogeneic stem cells. Four patients achieved partial remission, and three patients have remained alive for at least 2 years. Our data confirm the feasibility of high-dose therapy in patients with macroglobulinemia and support the need for prospective studies of this modality in patients with chemosensitive disease. Bone Marrow Transplantation (2001) 27, 1027–1029. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common hematological malignancy, with an incidence of 6/100 000 in Europe. Interactions between myeloma cells and the microenvironment are essential for MM cell survival. Better knowledge of disease biology has led to the introduction of novel agents for the management of myeloma patients. Patients with asymptomatic MM may remain stable for a long time without any therapy, and treatment is needed only in symptomatic disease. Patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT) are usually treated with bortezomib- or immunomodulatory drug (IMiD)-based regimens as induction therapy pre-ASCT. In elderly patients, the combination of melphalan and prednisone with either thalidomide (MPT) or bortezomib (MPV) is considered as the standard of care in this setting. Novel agent-based therapies are used for the management of relapsed/refractory disease. However, previous therapies, age, comorbidities and drug safety have to be taken into consideration before deciding the appropriate therapy for patients with relapsed/refractory myeloma. Patients with renal impairment or with extended bone disease may be treated with bortezomib-based regimens, while patients with pre-existing peripheral neuropathy may be treated with lenalidomide-based combinations. Maintenance therapy with thalidomide can be administered post-ASCT; however, caution is needed due to thalidomide toxicity. [ABSTRACT FROM AUTHOR]

Background: We undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix. Patients and methods: One hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m2, daily, on days 1–3 and cisplatin 70 mg/m2 on day 2) or the same combination with the addition of paclitaxel 175 mg/m2 on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis. Results: A modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet. Conclusion: The ITP combination merits further investigation in randomized phase III studies. [ABSTRACT FROM AUTHOR]

The article examines new agents and their combinations and their role in the treatment of multiple myeloma. It states that oral thalidomide-based regimens are the most common treatment for relapsed or refractory myeloma and the most widely used are the oral combinations of cyclophosphamide, thalidomide and dexamethasone (CTD). It notes that lenalidomide combined with chemotherapy has proven to be effective in relapsed or refractory patients.

Discusses the novel treatment of multiple myeloma. Addition of dexamethasone to thalimodide; Combination of Imid lenalidomide with dexamethasone; Development of genomics and proteomics.

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. Results: Median age was 64.57 years (SD: 9.72; range 39.2–87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42–14.67)) and 34.69 months (95% CI: 23.26–46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). Conclusion: NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS. Research highlights: Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed: • Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy. • NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer. • Elevated NLR was associated with worse prognosis. • No association between NLR and response to chemotherapy was noted. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on the increased expression of macrophage inflammatory protein-1α on trephine biopsies, which correlates with extensive bone disease that was published in the July 9, 2009 issue.

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT–PCR). The overall concordance between kRT–PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT–PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.British Journal of Cancer (2008) 99, 1775–1785. doi:10.1038/sj.bjc.6604769 www.bjcancer.com Published online 4 November 2008 [ABSTRACT FROM AUTHOR]

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2–3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.Leukemia (2008) 22, 414–423; doi:10.1038/sj.leu.2405062; published online 20 December 2007 [ABSTRACT FROM AUTHOR]

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin’s lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age ≥15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I–II and 54.6% had stages III–IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Determinations of the cadmium content of a wide variety of foodstuffs from the Greek market were carried out. The values detected ranged from <0.1 ng g[sup -1] in alcoholic beverages to 1595.8 ng g[sup -1] in large snails. The highest values were observed in molluscs and crustaceans (117.4 ng g[sup -1]), followed by leafy vegetables (28.3 ng g[sup -1]), potatoes (22.3 ng g[sup -1]) and organs and offal (20.7 ng g[sup -1]), whereas the other food categories had a lower cadmium content. The results are comparable with those from the rest of Europe. Preliminary analytical data on the cadmium content of food samples of organic cultivation showed significantly lower values compared with those of samples of conventional produce. [ABSTRACT FROM AUTHOR]

Background: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib.Methods: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs.Results: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment.Conclusions: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. [ABSTRACT FROM AUTHOR]

Background: In the open-label randomized phase III AURELIA trial, adding bevacizumab to chemotherapy for platinumresistant ovarian cancer (PROC) significantly improved progression-free survival and response rate versus chemotherapy alone, but not overall survival (OS). We explored the effect of bevacizumab use after disease progression (PD) in patients randomized to chemotherapy alone. Patients and methods: In AURELIA, 361 women with PROC were randomized to chemotherapy alone or with bevacizumab. Patients initially randomized to chemotherapy were offered bevacizumab after PD. Post hoc analyses assessed efficacy and safety in three subgroups: chemotherapy alone, chemotherapy followed by bevacizumab after PD, and chemotherapy plus bevacizumab at randomization. Results: Of the 182 patients randomized to chemotherapy alone, 72 (40%) received bevacizumab after PD and 110 (60%) never received bevacizumab. There were no significant differences in patient and disease characteristics between these subgroups at baseline or the time of PD. Compared with patients never receiving bevacizumab, the risk of death was significantly reduced in patients receiving bevacizumab either upfront with chemotherapy [hazard ratio (HR)=0.68, 95% confidence interval (CI) 0.52-0.90] or after PD (HR=0.60, 95% CI 0.43-0.86). The tolerability of bevacizumab was similar with administration upfront or after PD. Conclusions: Post-PD bevacizumab use may have confounded OS results in AURELIA. In these exploratory analyses of nonrandomized subgroups, bevacizumab use, either with chemotherapy or after PD on chemotherapy alone, improved OS compared with no bevacizumab. Combining bevacizumab with chemotherapy at first appearance of platinum resistance maximises the likelihood of patients receiving this active treatment for PROC. ClinicalTrials.gov: NCT00976911. [ABSTRACT FROM AUTHOR]

A 52-year-old dentist with kappa light chain multiple myeloma relapsed 6 months after 180 mg/m2 melphalan and an autograft. A partial remission had been attained after the autograft. Relapse occurred while he was on dexamethasone maintenance therapy. Chemotherapy was not an option due to low blood counts. Thalidomide was administered at relatively high doses (escalated up to 700 mg daily and continued for 4 months). There was a prompt decline in urine protein from 6067 mg/day to 2177 mg/day within a month. The response continued to improve with achievement of near-complete remission within 6 months and a decline in urine protein to 413 mg/day. Subsequently, grade 3 neutropenia and peripheral neuropathy required dose reduction to 200 mg/day. Disease activity parameters continued to improve on the lower dose of thalidomide. Nine months after starting thalidomide, the patient is in near-complete remission, enjoys an excellent quality of life, and has returned to work. We conclude that thalidomide can effectively control myeloma relapsing after high-dose chemotherapy, and may be especially useful in resistant cases or those unable to tolerate further chemotherapy. Bone Marrow Transplantation (2000) 25, 1319–1320. [ABSTRACT FROM AUTHOR]

Background:Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown.Methods:Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study.Results:In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001).Conclusions:Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy. [ABSTRACT FROM AUTHOR]

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs. [ABSTRACT FROM AUTHOR]

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs. [ABSTRACT FROM AUTHOR]

We prospectively evaluated the effect of bortezomib, thalidomide and dexamethasone (VTD) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation (ASCT). VTD started on day 100 post ASCT; patients received four cycles of VTD (first block), were followed without treatment for 100 days and then received another four VTD cycles (second block). During this 12-month period, bisphosphonates were not administered. Best response included stringent complete remission (sCR) in 15 (35.7%) patients, complete response (CR) in 13 (30.9%), vgPR in 7 (16.6%), PR in 4 (9.5%), while 3 (7.1%) patients developed a progressive disease (PD). Importantly, 33.3% and 47.6% of patients improved their status of response after the first and second VTD block, respectively. VTD consolidation resulted in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I (CTX), soluble receptor activator of the nuclear factor-kappa B ligand (sRANKL) and osteocalcin (OC), whereas bone-specific alkaline phosphatase (bALP) remained stable compared with pre-VTD values. During the study period, only one patient with a PD developed a skeletal-related event (that is, radiation to bone). The median time to progression (TTP) after ASCT was 34 months and the median time of next treatment was 40 months. We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events (SREs) despite the absence of bisphosphonates; the later do not appear to be necessary in this context. [ABSTRACT FROM AUTHOR]