The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.
BACKGROUND: Despite remarkable therapeutic advances in the last 2 decades and a major improvement in survival, a number of multiple myeloma (MM) patients (pts) present a short-term outcome. AIMS: Our aim was to identify the main factors (baseline characteristics, response to therapy, relapse features) determining early mortality (EM) among a cohort of newly diagnosed symptomatic MM pts treated with novel agents. METHODS: We conducted a national multicenter retrospective study, including a cohort of symptomatic MM pts diagnosed between January/2010 and June/2017, treated with novel agents (bortezomib, thalidomide or lenalidomide) with the maximum age of 75 years-old and living <3 years (y) after diagnosis. We considered EM as pts living <12 months (m). All pts were dead at the time of the analysis. Data were collected from medical registries and databases. Response to treatment was evaluated according to the International Myeloma Working Group (IMWG) consensus criteria (2016). Statistical analysis was performed using STATA v.14.2 and significant levels were set at p<0.05. All risk factors with p<0.15 in the univariate model were further entered into the multivariate analysis. RESULTS: A total of 142 pts were included in the study, 58% male and the median age at diagnosis was 65 y (27-75). IgG was the most frequent subtype (41%), followed by IgA (32%) and light-chain κ (14%) and λ (9%). At diagnosis, renal impairment (RI) was present in 32%, extramedullary disease (EMD) in 18% and bone disease in 69% of the pts; 58.3% were in stage III and 30.6% in stage II (ISS). Fluorescent in situ hybridization analysis was performed in 76 pts, 45% presenting high-risk cytogenetic abnormalities (HRC) [del(17p) and/or t(4;14) and/or t(14;16)]. Hypertension was present at diagnosis in 32% and diabetes in 18% pts. First-line therapy (1stL) included novel agents in 97% of the pts (64% bortezomib-based (Bor), 23% thalidomide-based (Thal) and 10% bortezomib plus IMID-based (BorIM). Response evaluation showed an overall response rate (ORR) of 73% (12% CR; 25% VGPR; 36% PR); 27% were refractory. Median time to response was 3.2m. Median number of therapy lines was 2 (1-3); 65% of the pts were refractory or progressed after 1stL therapy, 18% developed extramedullary disease (EMD) and 5 pts progressed to plasma cell leukemia. In pts receiving a 2ndL therapy, treatment-free interval was 9.2m and the most used regimens were lenalidomide (33%), Thal (25%), Bor (14%) and BorIM (11%) -based. ORR to 2ndL was 19.5% (3.4% VGPR and 16.1% PR). Six-month, 1-year and 2-years mortality was 7%, 27% and 65%, respectively. Median time until death was 18.2m; 55% of the pts died directly from disease progression (DP) and 45% from other causes [infection in 68% (only 17% of whom in DP), and cardiovascular complications in 13%]. In our study, prior hypertension (HR 1.53; 95% CI 1.01-2.32; p=0.046) and relapse with EMD (HR 2.0; 95% CI 1.23-3.26; p=0.005) were associated with increased risk of death. Pts≥70y also showed an increased risk of death, although not statistically significant (HR 1.42; 95% CI 0.96-2.12; p=0.081). In our cohort, refractoriness to 1stL treatment was not related to a significant increased risk of death (HR 1.48; 95% CI 0.91-2.40; p=0.11). Moreover, age, HRC, ISS stage, RI, bone disease and lactate dehydrogenase levels didn´t show a mortality predictive value. When comparing pts living <1y (EM) with pts living 1-3y, we identified the lack of at least PR (42.1% vs 21.2%, respectively; p=0.013) and a shorter time to 2ndL treatment (1.2 vs 10.0m; p=0.033) as predictors of death within the first 12m. Finally, in a multivariate analysis only the age at diagnosis >70y (HR 2.11; 95% CI 1.22-3.65; p=0.008) and EMD at relapse/progression (HR 2.55; 95% CI 1.45-4.50; p=0.001) predicted higher risk of mortality. CONCLUSIONS: ORR to 1stL therapy was similar to the generally expected response rate, showing that IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. The same was observed with classical baseline risk stratification features, raising the importance of defining a more accurate strategy to predict survival in MM pts. Refractory disease after 2ndL (higher than generally reported) and infections were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM. Disclosures No relevant conflicts of interest to declare.
Introduction MM is a B cell malignancy characterized by the presence of a monoclonal immunoglobulin (Ig) in the serum and/or urine produced by clonal plasma cells. MM has a variable outcome depending on age, stage and cytogenetic abnormalities. FLCr is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities, helping to clarify International Staging System (ISS), namely the heterogeneous stage II. In the era of new therapeutic agents trending to personalized therapy, its prognostic value needs to be proved. Purpose To evaluate the prognostic value of baseline serum FLCr on outcome of patients with newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from January 2005 to December 2012. We analyzed the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera drew at diagnosis before treatment, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of <0,03 or >32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a bortezomib based regimen (64,7%), with doxorubicin and dexamethasone (PAD) in 55 patients (53,9%), with cyclophosphamide and dexamethasone (Cy-Bor-D) in 11 patients (10,8%) or thalidomide, doxorubicin and dexamethasone (TAD) in 36 patients (35,3%). Median follow-up from diagnosis was 30 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 102 patients treated with thalidomide or bortezomib based-regimens eligible for HDM. Fifty one percent of patients were male and median age was 52 years (22-70y). The Ig type was IgG in 62,7%, IgA in 14,7%, IgD in 3,9%, light chains MM in 17,7% and non-secretory MM in 1,0% of patients. The median Hb level was 9,8 g/dL (5,3-16,7mg/L) and median serum albumin was 31,5 g/L (22,3-48,3g/L). Creatinine clearance <30ml/mn occurred in 18,6% of patients, 34,3% had elevated LDH and median β2-microglobulin was 6,61 mg/L (1,06-45,77mg/L). According to ISS, 39,2%% of patients were on stage I, 25,5%% on stage II and 35,3% on stage III. Clonal k light chain present in 58,8% of patients: 64,7% had abnormal FLCr (<0,03 or >32,00). Cytogenetic FISH analysis was performed in 86,3% of patients: 32,4% presented high-risk features. We observed a significant difference on overall survival (OS) and progression free survival (PFS) according to Mayo Clinic risk-factors: 0, not reached (NR), 1, NR, 2, 49 months and 3, 71 months for OS (P=0,000) and 0, 68 months, 1, 55 months, 2, 16 months and 3, 24 months for PFS (P=0,000). According the FLCr there was a significant advantage on OS for standard FLCr: NR vs 71 months (P=0,035). A trend to a better OS (P=0,061) was observed in stage II patients with standard FLCr but no significant difference at any stage. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib-based therapies. We fail to fully demonstrate FLCr prognostic value on ISS stage II patients, only a trend for better outcome with standard FLCr. Disclosures: Esteves: Janssen-Cylag and Celgene. Consultancy on the area of multiple myeloma and acute myeloid leukaemia: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.
Introduction MM is characterized by the presence of a monoclonal immunoglobulin in the serum and/or urine, produced by malignant plasma cells. MM has a highly uncertain evolution and prognostic depending on age, stage and cytogenetic abnormalities. FLC is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities helping to clarify International Staging System (ISS). Its value in the era of new therapeutic drugs is to be proved. Purpose To determine the prognostic value of baseline serum FLCr in patients with newly diagnosed MM, consecutively treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from July 2004 to December 2012. We studied the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera at initial diagnosis, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of < 0,03 or > 32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a thalidomide based regimen, 91 patients (38,9%): thalidomide, doxorubicin, dexamethasone (TAD), 37 patients (15,8%) and melphalan/cyclophosphamide, thalidomide, prednisone (M/CTP), 54 patients (23,0%) or bortezomib based regimens, 143 patients (61,1%): bortezomib, doxorubicin and dexamethasone (PAD), 53 patients (22,6%), bortezomib, cyclophosphamide and dexamethasone (Cy-Bor-D), 7 patients (2,9%) and melphalan/cyclophosphamide, bortezomib, prednisone (M/CVP), 83 patients (35,6%). Median follow-up from diagnosis was 25 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 234 patients consecutively treated. Male gender was 46,6% and median age was 67 years (22-84y). The Ig type was IgG in 59,4%, IgA in 22,2%, IgD in 1,7%, light chains MM in 15,4% and non-secretory MM in 1,3%. The median Hb level was 10,7g/dL (4,9-16,7g/dL) and serum albumin was 27,4 g/L (9,0-50-0g/L). Twenty five percent of patients had a creatinine clearance <30ml/mn, 30,1% elevated LDH and median β2-microglobulin was 4,08 mg/L (0,97-100,8mg/L). According to ISS, 35,0% of patients were on stage I, 28,2% on stage II and 36,8% on stage III. Mayo Clinic stratification revealed 21,4% with 0, 31,2% with 1, 28,2% with 2 and 19,2% 3 risk-factors. Sixty percent of patients had k light chain clonality: 50,9% had abnormal FLCr (< 0,03 or > 32,00) and 49,1% had standard FLCr 0,03-32,00. FISH was performed in 74,4% patients: 26,0% presented high-risk features. Overall survival (OS) and progression free survival (PFS) were significantly different according the patients presented 0, 1, 2 or 3 Mayo Clinic risk factors, with median survival times of 83, not reached (NR), 39 and 36 months, for OS, p=0,000, and 41, 41, 17 and 17 months for PFS, p=0,000. Patients with abnormal FLCr had similar outcome of standard FLCr. Patients in ISS II had significant different OS according the FLCr: 77 and 39 months for standard and abnormal FLCr, respectively, P=0,015. There was no such correlation on stages I and III. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM treated with thalidomide or bortezomib-based therapies. FLCr helps to clarify the outcome of ISS stage II patients identifying a subgroup with clearly inferior outcome. Disclosures: Esteves: Yassen: Consultancy; Celgene: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.
Myeloid sarcomas (MS) are rare extramedullary (EM) hematological tumors that generally arise during the natural course of acute myeloid leukemia (AML), occurring concomitantly with the onset of systemic leukemia; it can also occur following onset but rarely before. Common sites of EM involvement include the lymph nodes, skin, soft tissue, bone and peritoneum. Herein, we report the case of a 63-year-old man who presented EM AML upon initial diagnosis involving the bone marrow, lymph nodes and skin (leukemia cutis). A diagnosis was made based on immunohistochemistry (IHC). This case presents a diagnostic dilemma due to its atypical presentation and the sites involved. It also highlights the importance of IHC in the diagnosis of EM AML. The potential role of hypomethylating agents and Venetoclax in cases not eligible for hematopoietic stem cell transplant are also discussed.
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