Cyrille Touzeau

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BACKGROUND Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma

The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma

BH3-profiling identifies heterogeneous dependency on Bcl-2 family members in Multiple Myeloma and predicts sensitivity to BH3 mimetics

BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics

Efficacy of lenalidomide plus dexamethasone in patients older than 75 years with relapsed multiple myeloma

Abstract Few data are available on the efficacy of the combination of lenalidomide plus dexamethasone (Len/Dex) in very elderly patients above 75 years of age with relapsed multiple myeloma (MM). We report here a single-center series of 45 consecutive patients aged 75 years or older with relapsed MM treated with this combination. The overall response rate was 62% and the median progression-free survival was 14 months, which compares favorably to that described in the two pivotal prospective studies that formed the basis for the approval of Len/Dex in the relapse setting. Our study confirms that Len/Dex is an effective combination in very elderly patients with relapsed MM.

Investigation of the impact of HLA-DPB1 matching status in 10/10 HLA matched unrelated hematopoietic stem cell transplantation: Results of a French single center study

The impact of HLA-DPB1 mismatches after unrelated hematopoietic stem cell transplantation (HSCT) remains controversial. We retrospectively analyzed the impact of permissive/non-permissive HLA-DPB1 mismatches on the outcome of 141 patients who underwent 10/10 HLA allelic-matched unrelated HSCT. Each pair was classified according to the 3 (TCE3) and 4-group (TCE4) algorithm based on DPB1 alleles immunogenicity. Outcome analysis revealed that TCE3 and TCE4 non-permissive HLA-DPB1 disparities were not associated with worsened overall survival, relapse risk neither risk of acute GvHD. Overall, this single center retrospective study does not confirm the adverse prognostic of non-permissive HLA-DPB1 mismatches.

Lack of BRAF V600E mutation in human myeloma cell lines established from myeloma patients with extramedullary disease.

After whole genome sequencing of samples from 38 patients with multiple myeloma (MM) had identified one patient with an activating mutation of BRAF (G469A), BRAF mutations have been intensively screened in MM patients.1 Among 161 samples, 3 K601N and 4 V600E (the most common in melanoma) mutations were found in 4% of the patients.1 This low incidence is still consistent with a recent study involving 32 MM samples that reported no BRAF mutation.2 In the more specific field of extramedullary disease (EMD) in MM, Andrulis et al.3 recently reported a significant association with BRAF exon 15 mutations. Notably, the V600E mutation was found in 8.5% of patients with EMD (4 out of 47) versus 1.5% of patients without EMD (3 out of 204). The EMD of the four patients harbouring BRAF V600E mutation (all soft tissue plasmacytomas) was primitive for one patient and secondary after one or several lines of treatments for the three others. This recent work contrasts with an older one in which no BRAF mutation was found in 65 fresh bone marrow samples from 18 patients with PCL and 47 patients with MM at diagnosis.4 The incidence of EMD in MM is rare at diagnosis but extramedullary involvement increases with disease evolution. Spreading of MM cells out of the bone marrow is commonly associated with a poor outcome and resistance to salvage therapies.5 In this context, the recent findings of Andrulis et al. raise the interest of identifying patients with EMD carrying the BRAF V600E mutation, who could benefit from the V600E-mutated BRAF protein targeted therapy, that is, vemurafenib.

Second-degree relative donors for T-replete haploidentical allogeneic stem cell transplantation with high-dose post-transplant cyclophosphamide: toward crossing the major HLA barrier.

Second-degree relative donors for T-replete haploidentical allogeneic stem cell transplantation with high-dose post-transplant cyclophosphamide: toward crossing the major HLA barrier

Combination of lenalidomide with vitamin D3 induces apoptosis in mantle cell lymphoma via demethylation of BIK.

Mantle cell lymphoma (MCL) is a currently incurable B-cell malignancy. Lenalidomide (Len) has been demonstrated to be one of the most efficient new treatment options. Because Len and 1α,25-dihydroxyvitamin (VD3) synergize to kill breast cancer cells, we investigated whether VD3 could increase the ability of Len to induce MCL cell death. While MCL cells were weakly sensitive to Len (1 μM), the addition of VD3 at physiological dose (100 nM) strongly increased cell death, accompanied by slowdown in cell cycle progression in MCL cell lines (n=4 out of 6) and primary samples (n=5 out of 7). The Len/VD3 treatment markedly increased the expression of the BH3-only BCL2-interacting killer (Bik) without affecting the expression of other Bcl-2 molecules. Immunoprecipitation assays demonstrated that Bik was free from anti-apoptotic partners, Bcl-2 and Bcl-xL, in treated cells. Moreover, silencing of BIK prevented apoptosis induced by Len/VD3, confirming the direct involvement of Bik in cell death. Bik accumulation induced by Len/VD3 was related to an increase in BIK mRNA levels, which resulted from a demethylation of BIK CpG islands. The sensitivity of MCL cells to Len/VD3 was similar to the response to 5-azacytidine, which also induced demethylation of BIK CpG islands. These preclinical data provide the rationale to investigate the role of VD3 in vivo in the response to Len.

Added prognostic value of FDG-PET/CT in relapsing multiple myeloma patients

Bastien Jamet , Cl ement Bailly, Thomas Carlier, Lucie Planche, Cyrille Touzeau, Françoise Kraeber-Bod er e, Philippe Moreau and Caroline Bodet-Milin Nuclear Medicine Unit, University Hospital, Nantes, France; INSERM U892, CRCNA, Nantes, France; Statistics Unit, University Hospital, Nantes, France; Department of Haematology, University Hospital, Nantes, France; Nuclear Medicine Unit, ICO-Gauducheau, Nantes-Saint-Herblain, France

Abstract C48: Dual targeting of myeloma cells by 2-deoxy-D-glucose and ABT-199 combination respectively through the down-regulation of Mcl-1 and binding to Bcl-2.

Multiple myeloma (MM) is a heterogeneous but incurable plasma cell malignancy which still requires new therapeutic approaches. Several molecular subsets of MM have been defined based on genetic and chromosomal aberrations. Briefly, t(4;14) or t(14;16) translocations and TP53 deletion are most frequent poor-risk genetic features of MM, while t(11;14) confers a neutral prognostic value. Because cancer cells have a high glycolytic metabolism, we investigated the efficiency of 2-deoxy-d-glucose (2-DG), a competitive inhibitor of hexokinase, to kill myeloma cells. For this purpose we used 28 human myeloma cell lines (HMCL) representative of these different molecular subsets. Cell death induced by 2-DG was assessed by Apo-2.7 staining. Investigation of the underlying apoptotic mechanisms was evaluated by analyzing, by western blotting, modulation of the UPR response and implication of the Bcl-2 protein family. Finally, the possibly synergistic effect of the combination of 2-DG and ABT-199 was investigated. Cell death induced by 2DG was very heterogeneous among HMCLs, ranging from 5% to 96%. Of note, HMCLs carrying t(4;14) showed a trend to be more sensitive to 2DG (p=0.06) while HMCLs carrying t(11;14) appeared to be more resistant (p=0.08). Interestingly, 2-DG not only strongly inhibited the glycolytic activity of HMCLs but also interfered with N-glycosylation. Indeed, addition of D-mannose, an N-linked glycosylation precursor, partly reversed 2-DG-induced cell death. However, the D-mannose efficiency was also heterogeneous among HMCLs, suggesting that the inhibition of N-glycosylation was not the only mechanism of 2-DG-induced cell death. An up-regulation of GRP78, CHOP and ATF-4 expression was induced by 2-DG in both sensitive and resistant HMCLs, suggesting that 2DG-induced cell death was independent from the UPR response. Finally, 2-DG uniformly induced Mcl-1 down-regulation in HMCLs, but only those dependent on Mcl-1 for survival were killed by 2-DG. Preliminary results indicate that proteosomal degradation could be involved as part of a more complex mechanism. Of note, most of t(11;14) HMCLs were resistant to Mcl-1 down-regulation but highly sensitive to ABT-199, which targets Bcl-2 and efficiently kills t(11;14) HCMLs depending on this pathway for survival. Because 2-DG uniformly down-regulated Mcl-1, we combined it with ABT-199 in ABT-199-resistant HMCLs i.e., in HMCLs expressing a Bcl-2/Mcl-1 gene expression ratio lower to the threshold required for ABT-199 response. The combination of 2-DG and suboptimal ABT-199 dosage indeed strongly synergized in both t(4;14) and t(14;16) HMCLs. This study highlights the fact that dual targeting of Mcl-1 by 2-DG and Bcl-2 by ABT-199, in MM cell lines or primary samples, is highly efficient to induce apoptosis whatever the molecular subtype, including those with the poorest prognostic value. ABT-199 is presently under evaluation in a phase I clinical trial in relapsed MM patients and the present study provides a biological rationale for evaluating 2-DG in combination with ABT-199 in MM patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C48. Citation Format: Maxime Halliez, Sophie Maiga, Cyrille Touzeau, Patricia Gomez-Bougie, Steven Le Gouill, Catherine Pellat-Deceunynck, Martine Amiot. Dual targeting of myeloma cells by 2-deoxy-D-glucose and ABT-199 combination respectively through the down-regulation of Mcl-1 and binding to Bcl-2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C48.