Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.

BACKGROUND: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. METHODS: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. FINDINGS: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. INTERPRETATIONS: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. FUNDING: Janssen Research & Development.

Efficacy and safety of frontline rituximab, cyclophosphamide, doxorubicin and prednisone plus bortezomib (VR-CAP) or vincristine (R-CHOP) in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized, phase 3 LYM-3002 study.

This post-hoc subanalysis of the LYM-3002 phase 3 study assessed the efficacy and safety of substituting vincristine in rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHOP; n = 42) for bortezomib (VR-CAP; n = 38) in a subgroup of 80 mantle cell lymphoma (MCL) patients aged <60 years who did not receive stem cell transplantation (SCT) despite medical eligibility. Complete response (CR)/unconfirmed CR (CRu) rates were 67 vs. 39% (odds ratio 3.69 [95% CI(confidence interval): 1.31, 10.41]; p = .012). After 40 months median follow-up, median progression-free survival by independent radiology committee with VR-CAP vs. R-CHOP was 32.6 vs. 12.0 months (hazard ratio (HR) 0.59 [95% CI: 0.31, 1.13]; p = .108); median overall survival was not reached vs. 47.3 months (HR 0.81 [95% CI: 0.33, 1.96]; p = .634). Adverse events included neutropenia (92/76%), thrombocytopenia (70/10%) and leukopenia (65/50%). VR-CAP represents a potential alternative to R-CHOP in combined and/or alternating regimens for younger, SCT-eligible MCL patients.

Gender-Specific Aspects in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A Single-Center Experience.

OBJECTIVE: Limited data exist on gender-specific aspects in hematologic malignancies and have been obtained mostly in non-Hodgkin lymphomas. The objective of this study was to investigate gender-specific aspects in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). METHODS: A retrospective data analysis of 191 patients with MM who underwent ASCT was performed. Data collected from clinical records included age, sex, stage, induction therapy, outcome of induction, kind of stem cell mobilization, response to induction therapy and ASCT, cytogenetic aberrations, progression-free survival, and overall survival. RESULTS: Eighty-one patients (42%) were female, whereas 110 patients were male (58%). No differences between female and male patients could be observed according to the international staging system (ISS) (e.g. , ISS III: 14.8 vs. 17.3%), type of paraprotein, and cytogenetic aberrations (e.g., Del(13q): 32.7 vs. 28.9%). Five-year overall survival rates, when calculated from time to ASCT until death, were 27.2 and 36.4% and, when calculated from time to diagnosis until death, were 34.6 and 44.5%, respectively, and did not differ between groups according to ISS subgroups. CONCLUSION: Prognosis and baseline characteristics were identical and no differences could be observed between female and male patients with MM undergoing ASCT.

Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post-bortezomib). The purpose of this report is to provide longer follow-up on the MCL-001 study (follow-ups were 6.8 [NHL-002], 7.6 [NHL-003], and 52.2 [MCL-001] months). The 206 relapsed MCL patients treated with single-agent lenalidomide (25 mg/day PO, days 1 to 21 every 28-days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow-up of X, the combined best overall response rate (ORR) was 33% (including 11% with complete remission [CR]/CR unconfirmed CRu). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response (DOR) of 16.6 months (95% CI: 11.1%-29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event (AE). Overall, single-agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP versus R-CHOP in the phase 3 LYM-3002 study.

In the phase 3 LYM-3002 study comparing intravenous VR-CAP with R-CHOP in patients with newly-diagnosed, measurable stage II-IV mantle cell lymphoma, not considered or ineligible for transplant, the median progression-free survival was significantly improved with VR-CAP (24.7 versus 14.4 months with R-CHOP; P<0.001). This post-hoc analysis evaluated the association between the improved outcomes and quality of responses achieved with VR-CAP versus R-CHOP in LYM-3002. Patients were randomized to six to eight 21-day cycles of VR-CAP or R-CHOP. Outcomes included progression-free survival, duration of response (both assessed by an independent review committee), and time to next anti-lymphoma treatment, evaluated by response (complete response/unconfirmed complete response and partial response), MIPI risk status, and maximum reduction of lymph-node measurements expressed as the sum of the product of the diameters. Within each response category, the median progression-free survival was longer for patients given VR-CAP than for those given R-CHOP (complete response/unconfirmed complete response: 40.9 versus 19.8 months; partial response: 17.1 versus 11.7 months, respectively); similarly, the median time to next anti-lymphoma treatment was longer among the patients given VR-CAP than among those treated with R-CHOP (complete response/unconfirmed complete response: not evaluable versus 26.6 months; partial response: 35.3 versus 24.3 months). Within the complete/unconfirmed complete and partial response categories, improvements in progression-free survival, duration of response and time to next anti-lymphoma treatment were more pronounced in patients with low-and intermediate-risk MIPI treated with VR-CAP than with R-CHOP. In each response category, more VR-CAP than R-CHOP patients had a sum of the product of the diameters nadir of 0 during serial radiological assessments. Results of this post-hoc analysis suggest a greater duration and quality of response in patients treated with VR-CAP in comparison with those treated with R-CHOP, with the improvements being more evident in patients with low- and intermediate-risk MIPI. LYM-3002 ClinicalTrials.gov: NCT00722137.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Outcome in Multiple Myeloma Patients Eligible for Stem Cell Transplantation: A Single-Center Experience.

Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for selected patients with multiple myeloma (MM). Many data exist on ASCT in the era of novel agents. We retrospectively analyzed 189 patients (108 males and 81 females) with biopsy-proven MM, who had received ASCT after induction therapy with either conventional chemotherapy alone or in combination with novel agents at our department. The outcomes of both groups and the risk factors for shorter survival were investigated. The most commonly used induction chemotherapy prior to ASCT was VAD (vincristine, doxorubicin and dexamethasone, 42%), followed by PAD (bortezomib, doxorubicin and dexamethasone, 21%). One-hundred and twenty-nine patients (68%) received cyclophosphamide-recombinant human granulocyte colony-stimulating factor for stem cell mobilization. No differences were observed for progression-free survival in terms of the number of transplanted CD34+ cells (p = 0.261). A trend in improved overall survival (OS) was seen for the use of novel agents when compared to conventional chemotherapy (164.3 vs. 82.0 months; p = 0.046). The International Staging System stages had a significant (p = 0.036) impact on OS. The novel agents improved OS in our patients with MM undergoing ASCT when compared to conventional chemotherapy regimens. The number of transplanted CD34+ cells had no significant impact on hematopoietic reconstitution.

Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial.

Patients with mantle cell lymphoma (MCL) generally respond to first-line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL-001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long-term efficacy follow-up of the prospective phase II MCL-001 study (N = 134), including new exploratory analyses with baseline Ki-67 (MIB1), a biological marker of tumour proliferation. With longer follow-up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression-free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki-67. Ki-67 data in 81/134 MCL-001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki-67-expressing groups, yet lower Ki-67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post-bortezomib.

Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.

BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. RESULTS: After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

Novel agents have a significant impact on survival of patients with multiple myeloma.

BACKGROUND: In addition to conventional chemotherapeutic regimens and autologous transplantation, novel agents are now part of the treatment armamentarium against multiple myeloma (MM). To evaluate the presumed benefit of novel agents, we performed an analysis of patients with MM at our institution before and after the availability of novel agents. DESIGN AND METHODS: In all, 200 consecutive patients with newly diagnosed MM (male = 119; female = 81; median age: 61.5 years) treated at our institution between June 1993 and December 2008 were included in this retrospective analysis. Patient cohorts were defined according to date of diagnosis (before and after 01-Jan-2000, respectively), treatment received (chemotherapy only vs. therapy including novel agents), risk profile (International Staging System (ISS)-stage), and cytogenetic features. Primary focus of the analysis was overall survival (OS). RESULTS: Median OS for MM patients who received conventional chemotherapy was 45.2 months and for patients who received novel agents 74.6 months (P < 0.01). OS for those patients who relapsed after autotransplantation before 2000 was 35.2 months, but 72.7 months (P < 0.01) for those patients with a later relapse. Prolongation of survival for patients receiving novel agents was most evident for patients with ISS stage III (median OS 68.4 vs. 11.2 months for patients with chemotherapy only; P < 0.01). MM patients with an intermediate risk had a longer median OS when receiving novel agents (47.2 vs. 32.8 months). CONCLUSION: Treatment with novel agents in MM resulted in a significant prolongation of OS. Benefit of therapy with novel agents was particularly evident for transplant-eligible patients and MM patients with unfavorable prognosis.

Extracellular matrix remodeling by bone marrow fibroblast-like cells correlates with disease progression in multiple myeloma.

The pathogenesis of multiple myeloma (MM) is regarded as a multistep process, in which an asymptomatic stage of monoclonal gammopathy of undetermined significance (MGUS) precedes virtually all cases of MM. Molecular events characteristic for the transition from MGUS to MM are still poorly defined. We hypothesized that fibroblast-like cells in the tumor microenvironment are critically involved in the pathogenesis of MM. Therefore, we performed a comparative proteome profiling study, analyzing primary human fibroblast-like cells isolated from the bone marrow of MM, of MGUS, as well as of non-neoplastic control patients. Thereby, a group of extracellular matrix (ECM) proteins, ECM receptors, and ECM-modulating enzymes turned out to be progressively up-regulated in MGUS and MM. These proteins include laminin α4, lysyl-hydroxylase 2, prolyl 4-hydroxylase 1, nidogen-2, integrin α5ß5, c-type mannose receptor 2, PAI-1, basigin, and MMP-2, in addition to PDGF-receptor ß and the growth factor periostin, which are likewise involved in ECM activities. Our results indicate that ECM remodeling by fibroblast-like cells may take place already at the level of MGUS and may become even more pronounced in MM. The identified proteins which indicate the stepwise progression from MGUS to MM may offer new tools for therapeutic strategies.

Screening for adenoviruses in haematological neoplasia: High prevalence in mantle cell lymphoma.

Human adenoviruses possess oncogenic capacity which is well documented in mammalian animal models, but their possible implication in human malignancy has remained enigmatic. Following primary infection, adenoviruses can persist in a latent state in lymphocytes where the virus is apparently able to evade immune surveillance. In the present study, we have employed a broad-spectrum adenovirus polymerase chain reaction (PCR) assay to systematically screen more than 200 diagnostic specimens of different lymphoid malignancies including acute lymphocytic leukaemia (n=50), chronic lymphocytic leukaemia (n=50), various types of malignant lymphoma (n=100) and multiple myeloma (n=11) for the presence of adenoviral sequences. While most entities analysed revealed negative findings in virtually all specimens tested, adenoviral DNA was detected in 15/36 (42%) mantle cell lymphomas investigated. The most prevalent adenoviral species detected was C, and less commonly B. Adenovirus-positive findings in patients with mantle cell lymphoma were made at different sites including bone marrow (n=7), intestine (n=5), lymph nodes (n=2) and tonsillar tissue (n=1). The presence of adenoviral sequences identified by PCR was confirmed in individual cells by fluorescence in-situ hybridisation (FISH). The frequent observation of adenoviruses in mantle cell lymphoma is intriguings, and raises questions about their possible involvement in the pathogenesis of this lymphoid malignancy.

Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.

PURPOSE: Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib. PATIENTS AND METHODS: Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease progression or intolerance. Primary end points were overall response rate (ORR) and duration of response (DOR); secondary end points included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: In all, 134 patients were enrolled with a median age of 67 years and a median of four prior therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% CI, 7.7 to 26.7 months). Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months), and median OS was 19.0 months (95% CI, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). CONCLUSION: The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were refractory to bortezomib.

Rituximab, Ara-C, dexamethasone and oxaliplatin (R-ADOx) is effective for treatment of elderly patients with relapsed mantle cell lymphoma.

PURPOSE: The management of patients with mantle cell lymphoma (MCL) not eligible for stem cell transplantation in relapse after receiving standard approaches remains challenging, and the search for active and tolerable regimens is still warranted. PATIENTS AND METHODS: We have retrospectively analyzed activity of rituximab (375 mg/m(2) i.v. day 1), Ara-C (1,000 mg i.v. total twice daily on day 2) and oxaliplatin (130 mg/m(2) i.v. day 3) (R-ADOx) in 12 patients (median age 69 years) with relapsed MCL. RESULTS: Patients had been heavily pretreated (median 3 prior therapies, range 1-9) and had stage III/IV disease. Nine out of 12 patients responded (75 %, 4 CR, 5 PR). Median progression-free survival was 9.3 months, and overall survival has not been reached. Adverse events greater than grade II included anemia (17 %) and thrombocytopenia (33 %). CONCLUSION: R-ADOx is active and well tolerated in heavily pretreated MCL patients.

A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma.

Multiple myeloma (MM) typically follows a relapsing course with many patients requiring multiple therapies. This single-arm phase 2 study prospectively evaluated the efficacy and safety of bortezomib retreatment in MM patients who had relapsed after achieving at least a partial response (≥ PR) to prior bortezomib-based therapy. Patients aged ≥ 18 years, with measurable, secretory MM, who relapsed ≥ 6 months after prior bortezomib treatment were eligible. Patients received up to eight cycles of bortezomib (± dexamethasone). The primary endpoint was best confirmed response at retreatment; secondary endpoints included duration of response (DOR), time to progression (TTP), and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. A total of 130 patients (median of two prior lines of therapy) were enrolled and received retreatment. At retreatment, 28% and 72% of patients received bortezomib and bortezomib-dexamethasone, respectively. Overall response rate was 40%. In patients who achieved ≥ PR, median DOR and TTP were 6.5 and 8.4 months, respectively. Thrombocytopenia was the most common grade ≥ 3 AE (35%). Forty percent of patients experienced neuropathy events, which improved and resolved in a median of 1.5 and 8.9 months, respectively. In conclusion, bortezomib retreatment was effective and tolerable in relapsed MM patients, with no evidence of cumulative toxicities.

Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma.

BACKGROUND: G protein-coupled receptor 5D (GPRC5D) is a novel surface receptor. As this new subtype of G protein-coupled receptors was discovered, little is known about the role of this gene. MATERIALS AND METHODS: In this retrospective study, we investigated GPRC5D mRNA expression by real-time polymerase chain reaction (RT-PCR) in bone marrow (BM) of 48 patients with multiple myeloma (MM). RESULTS: Highly variable levels of GPRC5D (median, 288; quartiles, 17-928) were detected in patients with MM, whereas only low expression was detected in normal tissues (median, 1; quartiles, 1-23). High mRNA expression of GPRC5D correlated positively with high plasma cell count in bone marrow (r = 0·64, P < 0·001), high ß(2) -microglobulin (r = 0·42, P = 0·003) and poor-risk cytogenetics: deletion 13q14 (rb-1), P = 0·003; and 14q32 translocation t(4;14)(p16;q32), P = 0·029. GPRC5D mRNA expression showed a significant correlation with overall survival (P = 0·031). The estimated overall survival of patients expressing GPRC5D above or below the median of 288 was 43·9% vs. 70·2% at 48 months. Here, we report, for the first time, the association of GPRC5D expression and cancer. CONCLUSIONS: Overexpression in poor-risk myeloma, low expression in normal tissues and cell surface expression identify GPRC5D as a potential novel cancer antigen. Our data demonstrate that GPRC5D is a prognostic factor in MM correlating with other major risk factors.

European perspective on multiple myeloma treatment strategies: update following recent congresses.

The management of multiple myeloma has undergone profound changes over the recent past as a result of advances in our understanding of the disease biology as well as improvements in treatment and supportive care strategies. Notably, recent years have seen a surge in studies incorporating the novel agents thalidomide, bortezomib, and lenalidomide into treatment for different disease stages and across different patient groups. This article presents an update to a previous review of European treatment practices and is based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.

Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response.

BACKGROUND: Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. DESIGN AND METHODS: Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients. RESULTS: Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). CONCLUSIONS: The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).