Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation.

Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%-20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.

Is it possible to cure myeloma without allogeneic transplantation?

During the last decades, a better understanding of the biology of multiple myeloma (MM) has led to the application of novel treatment strategies for MM patients. The new anti-myeloma regimens produce higher incidence of durable and of better quality responses and they improve overall survival, challenging the dogma of incurable disease, outside the context of allogeneic transplantation. This review presents all these strategies that aim to cure MM, including continuous treatment i.e. induction, consolidation and maintenance, treatment of asymptomatic MM and monitoring minimal residual disease using modern techniques, such as multi-parameter flow cytometry, molecular assays and advanced imaging.

Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek Myeloma Study Group experience.

Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS-MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS-MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly.

Clinical features, outcome, and prognostic factors for survival and evolution to multiple myeloma of solitary plasmacytomas: a report of the Greek myeloma study group in 97 patients.

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T.