Clinical and Immunohistochemical Features Associated with a Response to Bortezomib in Patients with Multiple Myeloma

Abstract

Purpose: Multiple myeloma is an incurable disease withheterogeneous clinical behavior.Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains apaucityofdatainpatients treatedwithbortezomibthataccurately delineates and identifies such patients.This information is crucial to guide management. Experimental Design: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. Results: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16INK4A , cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. Conclusions: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

“…Thus, p53 is a major candidate gene that can serve as a molecular marker in combination with other genes to be able to tailor chemotherapy to the individual patient. Recently, mutant p53 (mutp53) has been identified as a good predictor of chemoresistance in some clinical studies [3,4,5,6,7], and drugs targeting mutp53 have been developed. In this review, we provide an update regarding the mechanisms that underlie mutp53 gain of function (GOF) mutations, summarizing the mechanisms by which mutp53 induces chemoresistance and elucidating the role of mutp53 in clinical chemotherapy.…”

Cyclin kinase subunit 1B nuclear expression predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with bortezomib

“…In a group of newly diagnosed patients with MM receiving conventional chemotherapy and rituximab, Cook et al [27] found that patients who were positive for cyclin D1 IHC exhibited longer OS. In addition, the clinical application of IHC has been further expanded to patients treated with novel therapeutic regimens [29][30][31]. In a study of thalidomide-treated patients with MM, Kelley et al [29] found that cyclin D1 and FGFR3 immunopositivity were not of prognostic significance, whereas newly diagnosed patients who were positive for p53 IHC showed reduced survival.…”

Znaczenie bortezomibu w leczeniu szpiczaka plazmocytowego u pacjentów z ryzykiem cytogenetycznym

“…Dawson i wsp. [50] bortezomibem skojarzonym z tandemowym autoSCT może nawet prowadzić do przełamania niekorzystnego wpływu rokowniczego t (4;14). Wymaga to jednak potwierdzenia w dalszych badaniach klinicznych.…”