Improved risk stratification in myeloma using a microRNA‐based classifier

Multiple myeloma (MM) is a heterogeneous disease. International Staging System/fluorescence hybridization (ISS/FISH)‐based model and gene expression profiles (GEP) are effective approaches to define clinical outcome, although yet to be improved. The discovery of a class of small non‐coding RNAs (micro RNAs, miRNAs) has revealed a new level of biological complexity underlying the regulation of gene expression. In this work, 163 presenting samples from MM patients were analysed by global miRNA profiling, and distinct miRNA expression characteristics in molecular subgroups with prognostic relevance (4p16, MAF and 11q13 translocations) were identified. Furthermore we developed an “outcome classifier”, based on the expression of two miRNAs (MIR17 and MIR886‐5p), which is able to stratify patients into three risk groups (median OS 19·4, 40·6 and 65·3 months, P = 0·001). The miRNA‐based classifier significantly improved the predictive power of the ISS/FISH approach (P = 0·0004), and was independent of GEP‐derived prognostic signatures (P < 0·002). Through integrative genomics analysis, we outlined the potential biological relevance of the miRNAs included in the classifier and their putative roles in regulating a large number of genes involved in MM biology. This is the first report showing that miRNAs can be built into molecular diagnostic strategies for risk stratification in MM.     

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (r_s = 0·604, P = 0·017) and IL‐10 (r_s = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.     

Telomere length is a critical determinant for survival in multiple myeloma

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high‐resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk‐stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS.     

Thalassaemia major and infectious risk: High Mobility Group Box‐1 represents a novel diagnostic and prognostic biomarker

High mobility group box ‐1 (HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in β‐thalassemia major (TM) by evaluating its diagnostic and prognostic role. Fifty‐one TM patients and 30 healthy subjects (HS) were enrolled. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1 to determine the best cut‐off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14·6 ± 8·7 vs. 2·08 ± 0·9 ng/ml, P < 0·0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10·2 ± 8 vs. 19·1 ± 7 ng/ml, P = 0·004). ROC analyses revealed an AUC for serum HMGB1 of 0·801, with a sensitivity and specificity of 92·3% and 68·2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events (HR: 0·81; P = 0·006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events.     

Characteristics and outcomes of patients with multiple myeloma aged 21–40 years versus 41–60 years: a multi‐institutional case‐control study

We compared the outcomes of multiple myeloma (MM) patients aged 21–40 and 41–60 years in the novel agent era. This case‐control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high‐risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five‐ and 10‐year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21–40 years, treated in the era of novel agents have a better OS than their counterparts aged 41–60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM.     

sVE‐cadherin and sCD146 serum levels in patients with multiple myeloma

The role of angiogenesis in multiple myeloma (MM) pathogenesis is well established. Angiogenesis is linked to the functional state of endothelial junctions that are modulated by the growth and activation of endothelial cells. CD146 and vascular endothelial‐cadherin (VE‐cadherin) are cell adhesion molecules localized at the endothelial junction. The aim of the study was to assess sVE‐cadherin and sCD146 serum levels in MM patients. Forty‐six untreated patients with MM were included in this study. In addition, 23 of 46 patients were analyzed again in partial remission after initial chemotherapy. Twenty‐two samples from healthy volunteers were evaluated as the control. There was no significant difference in sCD146 level between MM patients and the control (511 ± 177.2 vs. 460.9 ± 156.9 ng/ml respectively). In untreated MM patients, sVE‐cadherin level was significantly higher than in the control (1.36 ± 0.55 vs. 0.63 ± 0.56 ng/ml respectively; P < 0.05). In untreated MM patients, sVE‐cadherin level was significantly higher than in MM patients in partial remission (1.36 ± 0.55 vs. 0.5 ± 0.33 respectively; P < 0.05). sVE‐cadherin but not sCD146 serum level was increased in untreated MM patients and decreases after chemotherapy in patients in partial remission. VE‐cadherin may reflect intensity of angiogenesis in MM and may be useful in prognosis of response to treatment.     

Circulating plasma cells in newly diagnosed symptomatic multiple myeloma as a possible prognostic marker for patients with standard‐risk cytogenetics

Detection of circulating plasma cells (PCs) in multiple myeloma (MM) patients is a well‐known prognostic factor. We evaluated circulating PCs by flow cytometry (FC) in 104 patients with active MM at diagnosis by gating on CD38⁺ CD45^‐cells and examined their relationship with cytogenetic risk. Patients had an average follow‐up of 36 months. By using a receiver operating characteristics analysis, we estimated the optimal cut‐off of circulating PCs for defining poor prognosis to be 41. Patients with high‐risk cytogenetics (n = 24) had poor prognosis, independently of circulating PC levels [PC < 41 vs. PC ≥ 41: overall survival (OS) = 0% vs. OS = 17%, P = not significant (n.s.); progression‐free survival (PFS) = 0% vs. 17%, P = n.s.]. Patients with standard‐risk cytogenetics (n = 65) showed a better prognosis when associated with a lower number of circulating PCs (PC < 41 vs. PC ≥ 41: OS = 62% vs. 24%, P = 0·008; PFS = 48% vs. 21%, P = 0·001). Multivariate analysis on the subgroup with standard‐risk cytogenetics confirmed that the co‐presence of circulating PCs ≥ 41, older age, Durie‐Salmon stage >I and lack of maintenance adversely affected PFS, while OS was adversely affected only by lactate dehydrogenase, older age and lack of maintenance. Our results indicate that the quantification of circulating PCs by a simple two‐colour FC analysis can provide useful prognostic information in newly diagnosed MM patients with standard‐risk cytogenetics.     

Magnetic resonance imaging pattern of bone marrow involvement as a new predictive parameter of disease progression in newly diagnosed patients with multiple myeloma eligible for autologous stem cell transplantation

We investigated the prognostic value of the magnetic resonance imaging (MRI) pattern of bone marrow involvement in patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). 126 patients with untreated MM indicated for ASCT underwent spine MRI and cytogenetic analysis at diagnosis. All patients received ASCT after induction therapy of VAD (vincristine, doxorubicin, dexamethasone; n = 55) or a thalidomide‐based regimen (TCD; n = 71). Thalidomide maintenance therapy was performed in 68 patients. The MRI pattern was normal in 27, focal in 47, and diffuse/variegated in 52 patients. Patients with the diffuse/variegated pattern showed significantly higher stage (P = 0·038), higher β‐2 microglobulin level (P = 0·001) and severe anaemia (P = 0·015). However, the cytogenetics were not different among the MRI patterns (P = 0·890). Progression‐free survival (PFS) was lower in the diffuse/variegated pattern (P = 0·002) than other patterns, but not overall survival (OS) (P = 0·058). Thalidomide maintenance therapy was correlated only with PFS (P = 0·001). High‐risk cytogenetics were associated with both poorer PFS (P < 0·001) and OS (P = 0·003). In a multivariate analysis, the diffuse/variegated MRI pattern was an independent predictor of disease progression (Hazard Ratio, 1·922; 95% confidence interval, 1·185–3·118; P = 0·008). The diffuse/variegated MRI pattern is a novel prognostic factor for disease progression in MM patients eligible for ASCT.     

Phase 2 study of tabalumab,a human anti‐B‐cell activating factor antibody,with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N  = 72), tabalumab 100 mg (N  = 74), or tabalumab 300 mg (N  = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m² on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS ]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR ) [95% confidence interval (CI )] = 1·13 [0·80–1·59], P  =  0·480; tabalumab 300 mg vs. placebo HR [95% CI ] = 1·03 [0·72–1·45], P  =  0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF 13B) expression (n  = 162) had significantly longer mPFS than those with high BAFF expression (n  = 55), using the 75th percentile cut‐off point (mPFS [95% CI ] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI ] = 1·59 [1·11–2·29], P  =  0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.     

Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution

Autologous stem‐cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant‐related mortality rates are high, and a recent randomized trial suggested that non‐transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant‐related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain‐type natriuretic peptide (BNP) >300 pg/ml (17·5 months vs. not‐reached) (P = 0·0004), troponin‐I >0·07 ng/ml (13·5 months vs. not‐reached) (P = 0·00001) and those not achieving a complete haematological response (88 months vs. not‐reached) (P = 0·0345); high BNP and troponin‐I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin‐I should be considered transplant candidates.     

Clinical utility of C‐terminal telopeptide of type 1 collagen in multiple myeloma

Myeloma bone disease (MBD) is a major cause of morbidity in multiple myeloma (MM). We investigated bone turnover markers (BTM) as relapse predictors and biomarkers for monitoring MBD. We measured C‐terminal telopeptide of type I collagen (CTX‐1), and Procollagen type 1 N Propeptide (P1NP) in 86 MM patients and 26 controls. CTX‐1 was higher in newly diagnosed patients compared to control, remission and relapse (P < 0·05), and decreased following treatment. In the setting of relapse, a CTX‐1 rise greater than the calculated least significant change (LSC) was observed in 26% of patients 3–6 months prior to relapse (P = 0·007), and in 60·8% up to 3 months before relapse (P = 0·015). Statistically significant changes in CTX‐1 levels were also observed in patients who were with and without bisphosphonate therapy at the time of relapse. In patients with normal renal function, mean CTX‐1 level was highest in the newly diagnosed group (0·771 ± 0·400 μg/l), and lowest in the remission group (0·099 ± 0·070 μg/l) (P < 0·0001). P1NP levels were not statistically different across the patient groups. We conclude that CTX‐1, measured on an automated hospital laboratory platform, has a role in routine treatment monitoring and predicting relapse of MBD, even in patients on bisphosphonates.     

Clinical applicability and prognostic significance of molecular response assessed by fluorescent‐PCR of immunoglobulin genes in multiple myeloma. Results from a GEM/PETHEMA study

Minimal residual disease monitoring is becoming increasingly important in multiple myeloma (MM), but multiparameter flow cytometry (MFC) and allele‐specific oligonucleotide polymerase chain reaction (ASO‐PCR) techniques are not routinely available. This study investigated the prognostic influence of achieving molecular response assessed by fluorescent‐PCR (F‐PCR) in 130 newly diagnosed MM patients from Grupo Español Multidisciplinar de Melanoma (GEM)2000/GEM05 trials (NCT00560053, NCT00443235, NCT00464217) who achieved almost very good partial response after induction therapy. As a reference, we used the results observed with simultaneous MFC. F‐PCR at diagnosis was performed on DNA using three different multiplex PCRs: IGH D‐J, IGK V‐J and KDE rearrangements. The applicability of F‐PCR was 91·5%. After induction therapy, 64 patients achieved molecular response and 66 non‐molecular response; median progression‐free survival (PFS) was 61 versus 36 months, respectively (P = 0·001). Median overall survival (OS) was not reached (NR) in molecular response patients (5‐year survival: 75%) versus 66 months in the non‐molecular response group (P = 0·03). The corresponding PFS and OS values for patients with immunophenotypic versus non‐immunophenotypic response were 67 versus 42 months (P = 0·005) and NR (5‐year survival: 95%) versus 69 months (P = 0·004), respectively. F‐PCR analysis is a rapid, affordable, and easily performable technique that, in some circumstances, may be a valid approach for minimal residual disease investigations in MM.     

Single versus tandem high‐dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long‐term results from the phase III GMMG‐HD2 trial

The prospective, randomized phase III trial GMMG‐HD2 aimed at demonstrating non‐inferiority of single (Arm A) versus tandem (Arm B) high‐dose melphalan followed by autologous transplantation (HDM/ASCT) with regard to 2‐year event‐free survival (EFS) in newly‐diagnosed multiple myeloma (MM) and included 358 evaluable patients [Intention‐to‐treat population, (ITT), single/tandem HDM/ASCT: n = 177/181]. After a median follow‐up of more than 11 years, non‐inferiority of single versus tandem HDM/ASCT was demonstrated using the planned non‐inferiority threshold of 15% of the 2‐year EFS rate. Neither EFS (P = 0·53) nor overall survival (OS) (P = 0·33) differences were observed in the ITT population. In the tandem arm, 26% (n = 47/181) of patients refused a second HDM/ASCT due to non‐medical reasons. A per‐protocol (PP) analysis, including patients who received the intervention (single/tandem HDM/ASCT: n = 156/93) and patients who did not receive a second HDM/ASCT due to medical reasons (12%, n = 22/181), did not yield differences in EFS (P = 0·61) or OS (P = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM/ASCT (both P = 0·04). Ten‐year OS for the entire ITT was 34% (95% confidence interval: 29–40%). OS after first relapse was significantly shortened in the tandem arm (P = 0·04). In this study single HDM/ASCT was non‐inferior to tandem HDM/ASCT in MM.     

Presenting D‐dimer and early symptom severity are independent predictors for post‐thrombotic syndrome following a first deep vein thrombosis

Post‐thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Current preventative strategies are limited to the daily wear of graduated compression stockings (GCS). The aim of this study was to evaluate early predictors of PTS. One hundred and twenty‐two consecutive patients with a first DVT were prospectively recruited from diagnosis and followed for up to 6 months post‐end of anticoagulation. D‐dimer was measured in 107 participants at presentation and Villalta scale was evaluated in 70 participants at a median of 2 weeks following diagnosis. PTS developed in 51·6% of participants. GCS were obtained by 78·1% of participants, with 33·7% reporting daily wear at the end of follow‐up. Mean early Villalta scale was significantly higher in those with PTS (8·1 ± 3·7) compared to those without (2·6 ± 2·7, P < 0·001). Median D‐dimer was significantly higher in those with PTS [3260 ng/ml, interquartile range (IQR) 820–8000 ng/ml] compared to those without (1540 ng/ml, IQR 810–2520 ng/ml, P < 0·001). The adjusted odds ratio for every one point increase in early Villalta scale was 1·78 [95% confidence interval (CI), 1·19–2·64; P = 0·005] and for D‐dimer >1910 ng/ml it was 2·71 (95% CI, 1·05–7·03; P = 0·04). These markers could enable targeted counselling regarding GCS for those at high risk of PTS.     

Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two‐centre prospective study

Paroxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventy‐four patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0·60% in granulocytes and 0·15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH‐ patients, both after first‐ and second‐line IST: 68% vs. 45%, P = 0·0164 and 53% vs. 13%, P = 0·0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH‐ patients (P = 0·0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2·56, P = 0·0180) and baseline absolute reticulocyte count (ARC) ≥30 × 10⁹/l (odds ratio 5·19, P = 0·0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 × 10⁹/l showed significant distinctions for cumulative incidence of response, overall and failure‐free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.     

Delayed Haematological recovery after autologous stem cell transplantation is associated with favourable outcome in acute myeloid leukaemia

Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 10⁹/l] and platelets (platelet count >20·0 × 10⁹/l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3‐internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.     

Substratification of patients with newly diagnosed standard-risk multiple myeloma

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0–1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24–0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41–0·72, P < 0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67–1·24, P = 0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.     

Endothelial stress products and coagulation markers in patients with multiple myeloma treated with lenalidomide plus dexamethasone: an observational study

In this prospective study of patients with relapsed or relapsed and refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone, relationships between markers of endothelial stress and drug administration and incidence of venous thromboembolism (VTE) were assessed. Of 33 enrolled patients, laboratory and treatment data were available for 32 patients. Of these, 23 received pulsed dexamethasone (40 mg/day on days 1–4, 9–12 and 17–21 of each 28‐day cycle) and 9 received weekly dexamethasone (40 mg/day on days 1, 8, 15 and 21 of each cycle). The overall incidence of VTE was 9%. A decreasing trend in markers values was observed with intercellular adhesion molecule (P = 0·05), fibrinogen (P = 0·008), plasminogen activator inhibitor‐1 (P < 0·001), homocysteine (P = 0·002) and P–selectin (P < 0·001) during therapy. Compared with weekly dexamethasone, pulsed dexamethasone was associated with significantly greater variation in mean adjusted relative values of fibrinogen, P‐selectin and vascular endothelial growth factor (P < 0·001 for all comparisons), although there was no apparent association with VTE incidence. Lenalidomide plus dexamethasone affects endothelial stress marker levels in patients with advanced MM. The higher variation seen with pulsed dexamethasone suggests greater endothelial stress with this approach.     

Phase I,multicentre, dose‐escalation trial of monotherapy with milatuzumab (humanized anti‐CD74 monoclonal antibody) in relapsed or refractory multiple myeloma

CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti‐CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 1·5 (N = 8), 4·0 (N = 9), 8·0 (N = 4) or 16·0 mg/kg (N = 4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post ≥1 stem cell transplantation) and were refractory (N = 7) or relapsed (N = 18) with generally short‐lived responses to last treatment (median 4·0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute‐Common Terminology Criteria v3 toxicity Grades 1–2) with no dose‐limiting toxicity at higher doses. Only one patient developed borderline positive human anti‐milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B‐cell levels were moderately decreased with treatment (median decrease, 34%). There were no objective responses by European Group for Blood and Marrow Transplantation criteria, but 5 of 19 patients (26%) who completed treatment in this heavily pretreated and generally refractory group had stable disease for ≥3 months post‐treatment (one continuing for 17 months). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate. ( Clinicaltrials.gov identifier: NCT00421525)     

Rituximab maintenance improves survival in male patients with diffuse large B‐cell lymphoma. Results of the HD2002 prospective multicentre randomized phase III trial

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m² every 3 months for 2 years) versus observation was evaluated for CD20⁺ B‐cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5‐year relapse‐free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B‐cell lymphoma (DLBCL) subgroup (n = 152), 5‐year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5‐year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00–1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05–0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.