Dataset Information

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma.

ABSTRACT: Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M-protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed 'HLC-matched pair'. We investigated the impact of the suppression of the HLC-matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the host's attempt to control the myeloma clone. Severe (>50%) HLC-matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC-matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC-matched pair suppression retained its prognostic impact also during follow-up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC-matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC-matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma.

SUBMITTER: Ludwig H

PROVIDER: S-EPMC4832268 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Immunotherapy is changing the paradigm of multiple myeloma (MM) management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved for the treatment of this malignancy. Daratumumab exerts anti-myeloma activity by different mechanisms of action as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulation. After GEN501 and SIRIUS trials showed efficacy of daratumumab monotherapy in heavily pretreated relapsed-refractory multiple myeloma (RRMM), in patients with at least two previous line of therapy, two phase III trials demonstrated superior overall response rate (ORR) and progression free survival (PFS) using triplets daratumumab-bortezomib-dexamethasone (DVd) vs Vd (CASTOR) or daratumumab-lenalidomide-dexamethasone (DRd) vs Rd (POLLUX) in relapsed-refractory MM patients; so these combinations have been approved and introduced in clinical practice. The ongoing phase III CANDOR is evaluating the triplet daratumumab-carfilzomib-dexamethasone (DKd) vs Kd whereas phase III APOLLO trial is exploring daratumumab-pomalidomide-dexamethasone (DPd) vs PD. Many other trials exploring daratumumab combinations in relapsed-refractory MM are ongoing, and they will provide other interesting results. In newly diagnosed transplant-eligible patients, phase III CASSIOPEIA trial found the combination daratumumab-bortezomib-thalidomide-dexamethasone (Dara-VTd) significantly improves stringent Complete Response (sCR) rate and PFS compared with VTD, whereas in the phase II GRIFFIN study, comparing daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) vs VRD, sCR rate was significantly higher using quadruplet combination. Many studies are evaluating daratumumab in consolidation and maintenance therapy after autologous stem cell transplantation (ASCT). As regard patients ineligible for ASCT, a great efficacy of daratumumab-containing combinations was reported by the phase III trials ALCYONE and MAIA, exploring daratumumab-bortezomib-melphalan-prednisone (DVMP) vs VMP and daratumumab-lenalidomide-dexamethasone (DRd) vs Rd, respectively. These studies provided results never seen before in this setting. The aim of this paper is to critically review the results obtained with regimens containing daratumumab both in relapsed-refractory and in newly diagnosed MM.

Project description:BackgroundDiagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible.Methods and patientsFifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC).ResultsAfter a median follow-up of 11.5 (range 6.1-22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2-20.5) months, 5.0 (0.8-24.3) months and 4.0 (1.5-22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10-22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 - 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9-4.9) months versus 10.4 (0.8-24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89-22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5-24.3) months versus 5.0 (0.8-22.1) months, respectively, (HR 0.53, 95% CI 0.23 - 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 - 436.2, p < 0.05). The most common adverse events were hematological, with grade 3 and 4 neutropenia and thrombocytopenia reported in 44.6% and 14.5% of patients, respectively.ConclusionDetailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.

Dataset Information

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets