Recent therapeutic advances have made the treatment of multiple myeloma both more complex and more costly. In particular, the median survival of patients with multiple myeloma has been markedly prolonged through the use of targeted drugs such as proteasome inhibitors and immune modulators.

Carfilzomib-based treatment is efficient in advanced multiple myeloma. In our 'real-life' patients, we found considerable cardiotoxic effects in some cases, indicating a need for careful patient selection and close monitoring of the at-risk population.

Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable.Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. The Oncologist 2020;25:112-118 KEY POINTS• BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAF V600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. • Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma.• The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. • CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. • CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition. PATIENT HISTORYAn 81-year-old patient with κ light chain multiple myeloma (MM) was referred to our center after having a seizure and increasing M-proteins. MM had been diagnosed 2 years before and the patient had undergone nine cycles of bortezomibbased combination therapy (VMP) resulting in an initial good disease control. Magnetic resonance imaging of the brain and Correspondence: K.

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Extramedullary disease (EMD) in multiple myeloma (MM) is characterised by an aggressive biology and an adverse prognosis especially when occurring at relapse. Due to the high proliferation found in EMD lesions, we analysed outcome data of patients treated with a lymphoma-type therapy not based on novel compounds, the Dexa-BEAM protocol. Retrospective analysis of MM patients having received Dexa-BEAM (including dexamethasone, carmustine, cytarabine, etoposide and melphalan) at our institution from January 2007 to November 2012. In all, 18 patients were identified, 11 of whom had EMD. Objective response (≥PR) to Dexa-BEAM was achieved in more than half of the patients with EMD (6/11); consecutive high-dose consolidation strategy with autologous or allogeneic stem cell transplantation improved upon the depth of remission in two thirds of EMD patients (4/6) with ongoing remissions in three patients. In contrast, all patients without consolidation relapsed. Progression-free survival after Dexa-BEAM was short in both patient groups with intramedullary or extramedullary myeloma with a median of 3 and 4 months, respectively. Toxicity was relevant with one treatment-related death and grades 3 and 4 toxicities in all 18 patients. Dexa-BEAM is an effective induction regimen in medically fit patients with extramedullary manifestations to regain disease control prior to an intended autologous or allogeneic transplantation.