Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Μελέτη των μορίων προσκόλλησης σε ασθενείς με μονοκλωνική γαμμαπάθεια απροσδιόριστης σημασίας, ασυμπτωματικό πολλαπλό μυέλωμα και συμπτωματικό πολλαπλό μυέλωμα.

Plasma cell dyscrasias include a variety of disorders, from “benign” monoclonal gammopathy of undetermined significance, to symptomatic multiple myeloma. They are the result of unregulated proliferation of monoclonal plasma cells in the bone marrow, resulting in the production of monoclonal immuloglobulin. Adhesion molecules includes a variety of cell surface proteins that bind with their receptors either on the surface of nearby cells or on extracellular matrix. In cancer the dysregulation of cell to cell adhesion and cell to extracellular matrix adhesion can result in unregulated proliferation and development of metastasis. In plasma cell dyscrasias, adhesion molecules are expressed on the surface of plasma cells, of epithelial cells and of the bone marrow stromal cells. Adhesion of cells result in the production of cytokines that promote tumor growth and survival of plasma cells. In the present study sVCAM-1, sICAM-1, sE-selectin, sP-selectin, sL-selectin were measured using ELISA in the serum of 47 patients with MGUS, 61 with SMM and 145 with MM. Also these adhesion molecules were measured in the serum of 87 patients at first relapse that received therapy with new agents, 47 lenalidomide and dexamethasone (RD) and 40 bortezomib and dexamethasone (VD). Patients with symptomatic multiple myeloma had low levels of L- and P- selectin in comparison with MGUS and SMM patients, while they had elevated levels of VCAM-1 and ICAM-1. Also VCAM-1 levels showed positive correlation with high ISS stage, elevated β2-microglobulin and creatinine levels, while patients with high levels of VCAM-1 had decreased overall survival. The opposite was observed in patients with high levels of P-selectin, as there was negative correlation with ISS stage, β2-microglobulin and creatinine, and also low levels were related with worst prognosis. In smoldering MM, high levels of VCAM-1 and ICAM-1 correlated with shorter time to progression to symptomatic disease, and shorter overall survival. In patients with symptomatic multiple myeloma at first relapse administration of RD and VD resulted in a decrease in VCAM-1, while ICAM-1 was decreased only after VD. From these results we can conclude that plasma cell dyscrasias express different levels of adhesion molecules, resulting in different biological behavior. High levels of VCAM-1 were associated with more aggressive disease and worst outcome. Regarding SMM, high levels of VCAM-1 and ICAM-1 were associated with shorter time to progression to symptomatic disease and worst outcome. This is the first report of the association between the levels of adhesion molecules and disease outcome. Probably more samples are required in order to reach safe conclusions for the contribution of adhesion molecules to biology of asymptomatic disease. In regard to symptomatic disease at first relapse and treatment with newer agents, they seem to affect and reduce the levels of adhesion molecules as VCAM-1 and ICAM-1.Οι πλασματοκυτταρικές δυσκρασίες προκαλούνται από πολλαπλασιασμό μονοκλωνικών πλασματοκυττάρων τα οποία προκαλούν αναιμία, οστικούς πόνους, υπερασβεστιαιμία, νεφρική ανεπάρκεια. Τα μόρια προσκόλλησης είναι ομάδα επιφανειακών κυτταρικών πρωτεϊνών. Συνδέονται με υποδοχείς, στην επιφάνεια κυττάρων και την εξωκυττάρια θεμέλια ουσία, με αποτέλεσμα τη μετακίνηση κυττάρων στην κυκλοφορία. Στο ΠΜ τα μόρια προσκόλλησης εκφράζονται στην επιφάνεια των πλασματοκυττάρων, επιθηλιακών και στρωματικών κυττάρων. Η πρόσδεση μέσω των μορίων προσκόλλησης επάγει αντιαποπτωτικούς μηχανισμούς και παραγωγή κυτταροκινών, υπεύθυνων για τον πολλαπλασιασμό και την επιβίωση των πλασματοκυττάρων. Στον ορό 47 ασθενών με MGUS, 61 με ασυμπτωματικό ΠΜ και 145 με συμπτωματικό μετρήθηκαν τα sVCAM-1, sICAM-1, sE-, sP-, sL- σελεκτίνη, καθώς και σε 87 ασθενείς με νόσο σε υποτροπή που έλαβαν είτε λεναλιδομίδη- δεξαμεθαζόνη είτε μπορτεζομίβη- δεξαμεθαζόνη. Ασθενείς με συμπτωματική νόσο είχαν μειωμένα επίπεδα L-, P-σελεκτίνης σε σχέση με MGUS και ασυμπτωματική νόσο, ενώ είχαν αυξημένα επίπεδα VCAM-1 και ICAM-1. Επίσης τα επίπεδα VCAM-1 σχετίζονταν με υψηλό ISS, β2-μικροσφαιρίνη, ενώ ασθενείς με υψηλά επίπεδα VCAM-1 είχαν μειωμένη επιβίωση. Στην ασυμπτωματική νόσο τα υψηλά επίπεδα VCAM-1 και ICAM-1 σχετίζονταν με μικρότερο χρόνο μέχρι την πρόοδο. Τέλος στους ασθενείς με νόσο σε υποτροπή τα RD και VD μείωσαν τα επίπεδα VCAM-1. Από τα αποτελέσματα προκύπτει πως MGUS, ΑΠΜ και συμπτωματικό, έχουν διαφορετικό βαθμό έκφρασης των μορίων προσκόλλησης. Σε ότι αφορά την ασυμπτωματική νόσο, τα υψηλά επίπεδα VCAM-1 και ICAM-1 σχετίζονται με δυσμενή πρόγνωση και ταχύτερη πρόοδο σε συμπτωματική. Τέλος σε ότι αφορά την νόσο σε υποτροπή και την αγωγή με νεότερους παράγοντες, αυτοί φαίνεται πως μειώνουν τα επίπεδα VCAM-1 και ICAM-1

Ibrutinib plus rituximab for the treatment of adult patients with Waldenström’s macroglobulinemia: a safety evaluation

Introduction: Waldenstrom's macroglobulinemia (WM), an orphan disease, is a rare low-grade B-cell lymphoplasmacytic lymphoma with unique clinical features and monoclonal IgM production. Rituximab remains to this date the backbone of most commonly used treatment combinations. The FDA/EMA approval of Ibrutinib, the first-in-class BTK inhibitor, either as monotherapy or in combination with rituximab, changed the treatment landscape of the disease. Areas covered: Clinical trial data that demonstrate mode of action, efficacy, and the safety profile of each agent will be covered. A safety analysis of the combination treatment will also be performed to point out its high efficacy and overall favorable toxicity profile. The disadvantages and treatment gaps that still exist in the treatment of WM which relate to the need for long-term ibrutinib administration and the lack of deep remissions and subsequent disease relapse, will also be reviewed. Expert opinion: The ibrutinib-rituximab combination is both effective and safe, in the newly-diagnosed and relapsed-refractory disease setting. The optimal therapeutic approach for WM patients remains however to be established. The question of which combinatory (or synergistic) regimen can allow for a fixed-treatment duration, deep and durable responses with a safe toxicity profile is being addressed in ongoing clinical trials

Ibrutinib plus rituximab for the treatment of adult patients with Waldenstrom's macroglobulinemia: a safety evaluation

Introduction: Waldenstrom's macroglobulinemia (WM), an orphan disease, is a rare low-grade B-cell lymphoplasmacytic lymphoma with unique clinical features and monoclonal IgM production. Rituximab remains to this date the backbone of most commonly used treatment combinations. The FDA/EMA approval of Ibrutinib, the first-in-class BTK inhibitor, either as monotherapy or in combination with rituximab, changed the treatment landscape of the disease. Areas covered: Clinical trial data that demonstrate mode of action, efficacy, and the safety profile of each agent will be covered. A safety analysis of the combination treatment will also be performed to point out its high efficacy and overall favorable toxicity profile. The disadvantages and treatment gaps that still exist in the treatment of WM which relate to the need for long-term ibrutinib administration and the lack of deep remissions and subsequent disease relapse, will also be reviewed. Expert opinion: The ibrutinib-rituximab combination is both effective and safe, in the newly-diagnosed and relapsed-refractory disease setting. The optimal therapeutic approach for WM patients remains however to be established. The question of which combinatory (or synergistic) regimen can allow for a fixed-treatment duration, deep and durable responses with a safe toxicity profile is being addressed in ongoing clinical trials