Extramedullary myeloma (EMM) is defined by the presence of plasma cells (PCs) outside the bone marrow in a patient with multiple myeloma (MM). Using sensitive imaging techniques including magnetic ...resonance imaging and positron emission tomography/computed tomography, EMM may be found in up to 30% of MM patients across the overall disease course. The molecular mechanisms underlying the hematogenous spread of PCs outside the bone marrow are only partially known and involve hypoxia and an altered expression of adhesion molecules. Extramedullary disease is associated with adverse prognostic factors (ie, high lactate dehydrogenase level, 17p deletion, and high-risk gene expression profile). The prognosis of EMM is poor, and the median overall survival of patients who experience an extramedullary relapse is <6 months. The adverse prognosis is less pronounced in patients with bone-related plasmacytomas than in those with hematogenous EMM. EMM patients should be considered as having high-risk myeloma and treated accordingly. However, EMM clinical situations are extraordinarily heterogeneous, and their management is particularly challenging. In the present review, a case-and-comment format is used to describe our approach to the management of EMM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite advances in the treatment of multiple myeloma, the disease still remains incurable for the majority of patients. The overexpression of anti-apoptotic proteins (i.e., Bcl-2, Bcl-X
or Mcl-1) is ...a hallmark of cancer and favors tumor cell survival and resistance to therapy. The oral drug venetoclax is the first-in-class Bcl-2-specific BH3 mimetic. In myeloma, in vitro sensitivity to venetoclax is mainly observed in plasma cells harboring the t(11;14) translocation, a molecular subgroup associated with high Bcl-2 and low Mcl-1/Bcl-XL expression. In addition with Bcl-2 members expression profile, functional tests as BH3 profiling or in vitro BH3 mimetic drug testing also predict sensitivity to the drug. Phase 1 clinical trials recently confirmed the efficacy of venetoclax monotherapy in heavily pretreated myeloma patients, mostly in patients with t(11;14). In combination with the proteasome inhibitor bortezomib, venetoclax therapy was found to be feasible and allowed promising response rate in relapsed myeloma patients, independent of t(11;14) status. The present review summarizes the current knowledge, "from bench to bedside", about venetoclax for the treatment of multiple myeloma.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 ...inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea 46%, constipation 41%, and nausea 38%) and grade 3/4 cytopenias (thrombocytopenia 29% and anemia 15%). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% 17/18) than patients with low BCL2 expression (59% 16/27). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.
•In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious.•This is a novel therapeutic approach for MM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone ...D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone Rd, n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone VMP, n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).
•In patients with transplant-ineligible NDMM, durable MRD negativity is associated with improved PFS.•Daratumumab-based therapies are associated with higher rates and durability of MRD negativity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. ...Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n = 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163
M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells, leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n = 8) highlighted a rapid decrease of CSF1, IL-10, and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is included in the International Myeloma Working Group (IMWG) imaging guidelines for the work-up at diagnosis ...and the follow-up of multiple myeloma (MM) notably because it is a reliable tool as a predictor of prognosis. Nevertheless, none of the published studies focusing on the prognostic value of PET-derived features at baseline consider tumor heterogeneity, which could be of high importance in MM. The aim of this study was to evaluate the prognostic value of baseline PET-derived features in transplant-eligible newly diagnosed (TEND) MM patients enrolled in two prospective independent European randomized phase III trials using an innovative statistical random survival forest (RSF) approach.
Methods
Imaging ancillary studies of IFM/DFCI2009 and EMN02/HO95 trials formed part of the present analysis (IMAJEM and EMN02/HO95, respectively). Among all patients initially enrolled in these studies, those with a positive baseline FDG-PET/CT imaging and focal bone lesions (FLs) and/or extramedullary disease (EMD) were included in the present analysis. A total of 17 image features (visual and quantitative, reflecting whole imaging characteristics) and 5 clinical/histopathological parameters were collected. The statistical analysis was conducted using two RSF approaches (train/validation + test and additional nested cross-validation) to predict progression-free survival (PFS).
Results
One hundred thirty-nine patients were considered for this study. The final model based on the first RSF (train/validation + test) approach selected 3 features (treatment arm, hemoglobin, and SUV
max
Bone Marrow (BM)) among the 22 involved initially, and two risk groups of patients (good and poor prognosis) could be defined with a mean hazard ratio of 4.3 ± 1.5 and a mean log-rank
p
value of 0.01 ± 0.01. The additional RSF (nested cross-validation) analysis highlighted the robustness of the proposed model across different splits of the dataset. Indeed, the first features selected using the train/validation + test approach remained the first ones over the folds with the nested approach.
Conclusion
We proposed a new prognosis model for TEND MM patients at diagnosis based on two RSF approaches.
Trial registration
IMAJEM: NCT01309334 and EMN02/HO95: NCT01134484
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Monoclonal antibodies (mAbs) targeting antigens expressed by plasma cells demonstrated major clinical activity in multiple myeloma patients and therefore became a new major class of drug for these ...patients. Elotuzumab is a humanized mAb targeting the cell surface signaling lymphocytic activation molecule family member 7, a glycoprotein highly expressed on plasma cells, that is the second mAb approved for the treatment of myeloma patients. The mechanism of action of elotuzumab includes natural killer cell (NK) mediated antibody-dependent cellular cytotoxicity and direct activation of NK-cells. Elotuzumab has been approved in combination with lenalidomide and dexamethasone (Elo-Rd) and pomalidomide and dexamethasone (Elo-Pd) for the treatment of relapsed myeloma patients. The present review will focus on elotuzumab, providing a summary of the mechanism of action, efficacy and safety and taking into consideration patients' selection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The development of proteasome inhibitors contributed to the dramatic life expectancy improvement observed in myeloma patients over the past decades. Ixazomib is a boron-containing selective and ...reversible proteasome inhibitor that demonstrated antimyeloma activity with excellent safety profile. Ixazomib is the first orally available proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of myeloma patients who received at least one prior therapy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patients.
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