scholarly journals Clinical and Biological Implications of BRAF V600E Mutation in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5685-5685
Author(s):  
Even Holth Rustad ◽  
Hong Yan Dai ◽  
Haakon Hov ◽  
Eivind Coward ◽  
Vidar Beisvag ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Cancer Cell ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Detection Methods ◽  
Clone Size ◽  
Symptomatic Disease ◽  
Extramedullary Disease ◽  
High Fraction

Abstract In a retrospective cohort, seven patients with multiple myeloma carrying the BRAF V600E mutation had significantly shorter overall survival and higher prevalence of extramedullary disease than 251 BRAF wild type (wt) controls (Andrulis et al Cancer Discov 2013). Three case reports are in concordance with this view (Bohn et al and Sharman et al, Clin Lymphoma Myeloma Leuk, 2014). We conducted this study to further investigate the clinical and biological implications of this mutation in multiple myeloma. We used mutation-specific quantitative real-time PCR (qPCR) to screen biopsies from 209 myeloma patients, of which 185 were taken prior to first relapse. The BRAF V600E mutation was detected in 13 (6.2 %) of the patients. 10 of them also expressed the corresponding protein as evaluated by immunohistochemistry (IHC) using the BRAF V600E specific VE1 antibody, and 2 patients had simultaneous mutations in BRAF and NRAS/KRAS. RAS mutations are of particular interest because in vitro studies indicate that their presence may imply a paradoxical effect of BRAF inhibitors (Lohr et al Cancer Cell 2014). Whole exome sequencing (WES) was carried out in three BRAF V600E positive patients from whom we had stored purified myeloma cells. Among the top 11 recurrently mutated genes listed in Lohr et al (Cancer Cell 2014), we found mutations only in BRAF, NRAS, and KRAS. Clonal fraction of BRAF V600E mutated plasma cells as evaluated by IHC and WES varied from 4 to 100 %. There was agreement between detection methods in the patient with a dominating V600E mutated clone, but less so in the patients with small clones. Estimates of BRAF V600E clone size and RAS mutation analysis in 13 patients positive for BRAF V600E by qPCR Table 1 IHC (clone size, %) WES (clone size, %) Sanger sequencing NRAS / KRAS mutation 75-100 86 + negative 75-100 negative negative 75-100 + negative 50-75 + negative 50-75 + negative 25-50 negative negative 25-50 negative negative <25 0 negative KRAS p.G12A (ex2) and p.Q61H (ex3) <25 + negative <25 + negative negative negative negative negative 4 negative NRAS p.Q61K (ex3) negative negative negative BRAF V600E positive patients presented a variety of clinical phenotypes and no characteristic genotype-phenotype relation could be identified. Progression free and overall survival, and all clinical parameters including the presence of extramedullary disease, were similar in patients with BRAF V600E and BRAF wt. Three patients carried the mutation in > 75 % of tumour cells, and all had indolent disease. One of them died after seven years, whereas the remaining two responded with long lasting CR to broad acting therapy (MP, MPT) and are still in remission after five and seven years. The Regional Ethics Committee approved the study (REK 2165-2012). Figure 1 Overall Survival from symptomatic disease Figure 1. Overall Survival from symptomatic disease In conclusion, we found no evidence supporting a prognostic role or association with a particular clinical phenotype for the BRAF V600E mutation in early multiple myeloma, which is in contrast to earlier reports. Furthermore, the three patients with a high fraction of mutated cells had a relatively benign disease responsive to conventional treatment. This study demonstrates that the role of mutation V600E is more diverse than previously assumed. Presence, and particularly high fraction of BRAF V600E mutated cells as well as translation to protein, are prerequisites for specific inhibitory treatment. However, these characteristics are alone not sufficient to predict outcome or to choose the right treatment. Disclosures Hovig: PubGene Inc.: Equity Ownership; GeneSeque AS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vodák:PubGene AS: Research Funding.

scholarly journals Lack of BRAF V600E mutation in human myeloma cell lines established from myeloma patients with extramedullary disease

2013 ◽  
Vol 3 (11) ◽  
pp. e163-e163 ◽  
Author(s):  
L Lodé ◽  
P Moreau ◽  
A Ménard ◽  
C Godon ◽  
C Touzeau ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloma Cell ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Extramedullary Disease ◽  
Human Myeloma Cell

Meat consumption and BRAF mutation status in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15135-e15135
Author(s):  
Rosa L. Frias ◽  
Michael Lam ◽  
Michael J. Overman ◽  
Van K. Morris ◽  
David R. Fogelman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Logistic Regression ◽  
Meat Consumption ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
P Value ◽  
Mutation Status ◽  
Molecular Features ◽  
Total Meat

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value < .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.

Increased Incidence of Extramedullary Plasmacytomas In Patients with Multiple Myeloma In the Era of Novel Therapy and Effect of Pomalidomide on Extramedullary Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3047-3047
Author(s):  
Kristen Detweiler Short ◽  
S. Vincent Rajkumar ◽  
Francis Buadi ◽  
Dirk Larson ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Soft Tissue ◽  
Research Funding ◽  
Low Dose ◽  
Novel Agents ◽  
Temporal Area ◽  
Immunomodulatory Agents ◽  
Extramedullary Disease ◽  
Extramedullary Plasmacytomas

Abstract Abstract 3047 Background: There is concern about the increased incidence of extramedullary plasmacytomas among patients with multiple myeloma (MM) in recent years (Varettoni et al Annals of Oncology 21: 325–330, 2010). There is controversy about whether novel agents increase the risk of extramedullary disease (EMD). EMD may be associated with decreased overall survival in MM. The purpose of this study was to determine the incidence of true, treatment-emergent EMD in MM among a cohort of patients who have been previously exposed to novel agent (thalidomide, lenalidomide, or bortezomib) therapy, and to evaluate the activity of pomalidomide in patients with EMD. Methods: We examined 174 consecutive patients with relapsed refractory multiple myeloma that were enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone. The study cohort was chosen since all patients had previously been exposed to novel agents, and were followed systematically. We adopted a strict definition of EMD which required that in order to be considered extramedullary, plasmacytomas must not have risen from any bone. Thus, masses arising from the bone with a soft tissue component were not considered extramedullary. Results: Of 174 patients studied, 16 patients (9.2%) had EMD prior to enrollment. In 3 of the 16 patients, EMD was present at time of diagnosis and was therefore not considered as treatment-emergent disease for this analysis. In 13 of 174 patients (7.5%) EMD developed during the course of MM, after starting therapy. All 13 patients by inclusion criteria were exposed to novel agents prior to the onset of EMD, including 100% to immunomodulatory agents (thalidomide or lenalidomide); and 78% (10 patients) were exposed to bortezomib prior to developing EMD. The median number of lines of prior therapy in these patients was 6, range 1–12). EMD occurred a median of 48 months following diagnosis (range, 16–183 months); the rate of EMD in the first 3 years following diagnosis of MM was 3%. Since all patients had prior exposure to immunomodulatory agents in this cohort, we were able to calculate the median length of time from initiation of immunomodulatory agents to onset of EMD as 24 months (range 7–119 months). The EMD sites involved included the temporal area soft tissue (3), muscle (3 [1 pt with 10 different areas of involvement, 1 pt with 5 muscles involved]), chest wall not attached to bone (3), abdominal/pelvic masses (3), kidney (2), scrotum (2), sinus (1), paraspinal (1), hilar/pleural based (1), paraesophageal (1), subcutaneous tissue (1), pancreas (1), spleen (1), mediastinum (1), pleural fluid (1), liver (1). Per protocol, all patients received pomalidomide (2-4 mg per day) and low dose dexamethasone (40 mg once a week). Of the 13 patients, there were 2 CR (with complete disappearance of EMD), 2 PR, 2 stable disease, 3 with progressive disease, and 4 patients who did not have their EMD re-evaluated. Thirty percent (n=4) of patients had a 50% or greater reduction in size of the EMD including one patient who received concomitant radiation. Overall survival from measured from trial entry was significantly shorter for patients who presented with EMD compared to those who did not have EMD, median 16 months versus not reached, p=0.002 (log-rank). Conclusion: We found that 7.5% of patients with relapsed refractory myeloma in the era of novel agents develop EMD during the course of their myeloma, including 3% within 3 years of diagnosis. The underlying reasons for the possible increased incidence of EMD may include better radiographic detection (the role of PET/CT scans and MRI), improved overall survival of patients in recent years, and the possibility that novel agents may increase the risk for strictly defined, true EMD among patients who did not have EMD at time of initial MM diagnosis. These need further study. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

The Role of PET/TC in the Full Range of Monoclonal Gammopathies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3365-3365
Author(s):  
Rafael Ríos Tamayo ◽  
Juan Sáinz Pérez ◽  
Jose Manuel Puerta Puerta ◽  
Rosario Leyva Ferrer ◽  
Youssef Moatassim de la Torre ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Monoclonal Gammopathy ◽  
Focal Lesion ◽  
Consecutive Series ◽  
Monoclonal Gammopathies ◽  
Extramedullary Disease ◽  
Pet Ct ◽  
Uncertain Significance

Abstract Positron emission tomography (PET) with 18fluorine-fluoro-deoxyglucose (FDG) integrated with computed tomography (PET/CT) is a functional imaging technique helping us to assess bone marrow infiltration as well as unsuspected disease sites involving the bones and/or extramedullary sites. PET/TC has proved to be an independent prognostic factor for overall survival (OS) in symptomatic multiple myeloma (MM)(Zamagni,2011). However, its role in other monoclonal gammopathies (MG) is still a matter of debate. We have prospectively analyzed the contribution of baseline PET/TC in a unselected consecutive series of 158 patients with MG, including 88 MM, 7 MM smoldering (MMS), 11 Waldenstršm's macroglobulinemia (WM), 3 WM smoldering (WMS), 3 solitary bone plasmacytoma (SBP) and 46 monoclonal gammopathy of uncertain significance (MGUS). Patients with only palliative care were excluded. The pattern of bone marrow uptake on PET/TC was described as negative (NEG), diffuse involvement (DI) or focal lesions (FLs). Patients with more than 3 FLs as well as the presence of extramedullary disease (EMD) were analyzed separately. Overall survival (OS) was estimated by the Kaplan-Meier method. The main characteristics of PET/TC findings according to the type of MG are shown in Table 1. PET/TC was positive in 70 (79,5 %) of MM and 8 (72,7%) of WM. PET/TC was NEG in 100 % of MMS, WMS and SBP (except for the primary lesion). In MGUS, the findings reflect the clinical heterogeneity of this group: 19,6 % had bone disease (all but one case of probable inflammatory etiology), 17,4 % positive lymphadenopathy, 15,2 % lung disease (infection, fibrosis, pulmonary nodules), 6,5 % splenomegaly, 6,5 % liver disease, 6,5 % positive uptake in adrenal gland and other organs such as thyroid, stomach, colon or skin were affected less frequently. Median age of MM patients was 62 years (12-91), 51 men and 37 women (42%), the distribution according ISS was I (36,5 %), II (28,2 %) and III (35,3%). Among PET-positive MM, 39 (55,7 %) had >3 FLs, 17 (24,3 %) 3 or less FLs and 14 (24,3 %) DI. Median OS was 40 months, not reached (NR) and 85,7 months, respectively (p=ns). Mean bone marrow plasma cells in the >3 FLs group vs 3 or less FLs was 25 vs 12 (p=0,028). EMD was present in 13 (18,6 %) of PET-positive MM. Response with PET/CT was available in 32 patients: 18 achieved CR, 8 PR and 8 progressed. OS was NR for CR and PR vs 40 months (p <0,0001). In WM, patients with NEG or FL had NR OS vs 26 months in those with DI (p=0,16). PET/CT is positive in the majority of MM and WM patients, helping to separate patients with true indolent disease. At baseline, PET/TC is a useful tool to improve prognostic assessment in patients with MG. MM with >3 FLs or EMD at baseline had a trend towards lower OS. Negative serial PET/CT in MM is associated with favorable prognosis. Table SEQ Tabla \* ARABIC 1. Characteristics of main PET/TC findings according to the type of MG Type MM MMS WM WMS SBP MGUS n 88 7 11 3 3 46 Positive n /% 70/79,5 0 8/72,7 0 0 9/19,6 ->3 FLs 39/55,7 0 0 0 0 0 -3 or < FLs 17/24,3 0 1/12,5 0 0 1/2,2 -DI 14/20 0 5/62,5 0 0 1/2,2 -EMD 13/18,6 0 0 0 0 0 -Adenopathy 2/2,9 2/28,6 2/25 0 0 8/17,4 -Spleen 3/4,3 0 1/12,5 0 0 3/6,5 MG: Monoclonal gammopathy; MM: Multiple myeloma symptomatic; MMS: Smoldering myeloma; WM: Waldenstršm's macroglobulinemia; WMS: Smoldering Waldenstršm's macroglobulinemia; SBP: Solitary bone plasmocytoma; MGUS: Monoclonal gammopathy of uncertain significance; FL: Focal lesion; DI: Diffuse involvement; EMD: Extramedullary disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals BRAF V600E mutation in papillary thyroid carcinoma: it’s relation to clinical features and oncologic outcomes in a single cancer centre experience

2021 ◽  
Author(s):  
Mahmoud Al-Masri ◽  
Tawfiq Al-Shobaki ◽  
Hani Al-Najjar ◽  
Rafal Iskanderian ◽  
Enas Younis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Disease Free Survival ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Cancer Center ◽  
Papillary Thyroid ◽  
Free Survival ◽  
Disease Free

Purpose: This study focuses on the oncologic influence of BRAF V600E mutations in a cohort of Middle Eastern PTC patients treated at a single centre. We test the association of BRAFV600E mutation with papillary thyroid carcinoma at King Hussein Cancer Center. Methods: Patients with histologically confirmed PTC who underwent surgical treatment between 2006 and 2015 were included in this study. Oncological outcomes, both short and long termed were collected. Results: A total of 128 patients (68% females) were included in this study with a mean age of 38 years (±13.8). The median follow-up period was 50 months. The BRAF V600E mutation was found in 71% of patients. The tumor size for patients with a negative BRAF V600E mutation were significantly larger in comparison to patients who tested positive for the mutation (3.47 cm versus 2.31 cm, respectively, P = 0.009). The two groups showed similar disease-free survival (DFS) rates; positive = 75% (median 43 months (0-168)) compared to 78% for the negative BRAF V600E mutation (median 38 months (3-142)) (P= 0.162, HR=0.731) Furthermore, both groups showed similar overall survival rates: positive = 94.5% (median 56 months (0-228)) compared to 94.6% for the negative BRAF V600E mutation (median 43 months (3-157)) (P = 0.941, HR= 0.940). Conclusion: BRAF V600E mutation had no effect on loco-regional recurrence, distant metastasis, overall survival or disease-free survival. These findings may be attributed to geographic variations or reflect that BRAF V600E may only serve as an indicator of poor prognosis in high risk groups.

scholarly journals BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation

2021 ◽  
Author(s):  
Toshi Ghosh ◽  
Patricia T. Greipp ◽  
Darlene Knutson; ◽  
Sara Kloft-Nelson; ◽  
Sarah Jenkins ◽  
...  
Keyword(s):  
Overall Survival ◽  
In Situ Hybridization ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Genomic Profiling ◽  
Clinicopathologic Features ◽  
Comprehensive Genomic Profiling

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15547-e15547
Author(s):  
Jianwei Zhang ◽  
Cailu Shen ◽  
Jianxia Li ◽  
Zehua Wu ◽  
Huabin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Systemic Treatment ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinicopathologic Features ◽  
Significant Difference ◽  
The Impact ◽  
Braf Mutant

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P < 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P < 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.

BRAF V600E Mutations in Multiple Myeloma: Clinical and Therapeutic Implications

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4040-4040
Author(s):  
Nicola Lehners ◽  
Mindaugas Andrulis ◽  
David Capper ◽  
Andreas von Deimling ◽  
Anthony D Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Soft Tissue ◽  
Soft Tissues ◽  
Autologous Transplantation ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Abstract Abstract 4040 Background: Activating mutations of the serine/threonine kinase BRAF are observed in various solid and hematologic malignancies with the point mutation V600E being the most common. However, both frequency and relevance of the mutation differ greatly between entities. This year, a small molecule inhibitor specifically targeting V600E-mutated BRAF has been approved for metastatic melanoma. Recently, BRAF mutations in multiple myeloma (MM) have been reported by several groups in the context of next generation sequencing projects. However, the clinical relevance of these mutations remains unclear. Objective: We report on frequency and clinical characteristics of MM patients harboring the BRAF V600E mutation. Furthermore, first clinical data on treatment with vemurafenib in MM with BRAF V600E mutation is presented. Methods: A V600E-mutation specific monoclonal antibody was recently developed at our institution. We screened 338 tissue samples by immunohistochemistry (315 bone marrow, 23 soft tissue plasmocytoma) from 310 patients with monoclonal gammopathy collected at out center between April 1999 and May 2011. Positive results were verified by direct sequencing. Of 310 analyzed patients, 205 had symptomatic MM, 12 symptomatic light chain amyloidosis, 45 smoldering MM and 48 MGUS. MM subtypes comprised 174 IgG, 60 IgA, 55 Bence Jones, 14 IgM, 4 IgD, 1 biclonal, 4 asecretory. From 25 patients serial bone marrow samples or tissue from different compartments were available. Median age at biopsy was 61.4 years (range 29–87) and 244 samples were obtained at from newly diagnosed patients. Results: Six patients (2%) were positive for BRAF V600E mutation both by immunohistochemistry and by confirmatory sequencing. A brief overview of patient characteristics is shown in Table 1. Five patients received bortezomib-based first line treatment whereas one received conventional chemotherapy. Four patients underwent autologous transplantation. Interestingly, PFS after start of first-line treatment was relatively short with a median PFS of 10.5 months. Remarkably, four of these six patients developed extramedullary myeloma in their disease course (soft tissues in 2, CNS in 1, both soft tissues and CNS in 1). In two of these patients a re-biopsy after two and three lines of therapy, respectively, was available. In both cases the mutation remained present in all cells without signs of clonal evolution in regard to BRAF V600E. One of the BRAF V600E positive patients had relapsed with multiple soft tissue plasmocytomas after autologous transplantation followed by multiple treatment lines containing bortezomib, lenalidomide and bendamustine. After informed consent we started the patient on vemurafenib 480mg BID and increased the dosage to 720mg BID after one week. Vemurafenib was well tolerated and no grade III/IV adverse events were noted. Already after the first cycle (four weeks), a partial response was achieved according to IMWG and RECIST criteria for serological and radiological assessment, respectively. As assessed by immunohistochemistry, a dramatic decrease in proliferative activity (MIB-1) accompanied by a sharp increase in apoptosis, as well as loss of MAP kinase signaling (p-ERK) could be observed in tumor samples under treatment with vemurafenib. Conclusions: Immunhistochemistry is a rapid and reliable method for the detection of BRAF V600E and provides a useful tool especially if applied to entities with low mutation frequency, such as MM. In our cohort, however small, patients harboring the mutation show a conspicuous course of disease with a comparably short PFS and an unusually high frequency of extramedullary myeloma. Individualized treatment with vemurafenib seems feasible and rapid response was observed. A detailed follow-up of the clinical course will be presented at the meeting. Disclosures: Off Label Use: Vemurafenib is a BRAF inhibitor FDA approved for treatment of metastatic melanoma.

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