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Objectives To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma ( MM), especially after the incorporation of new agents. Methods we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/ dL) at diagnosis. Results Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate ( eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. Conclusion Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium. [ABSTRACT FROM AUTHOR]

In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenstr öm macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6mg/m2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixedduration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www. ClinicalTrials.gov #NCT00981708). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this phase 2 multicenter trial, we evaluated the activity of bortezomib, dexamethasone, and rituximab (BDR) combination in previously untreated symptomatic patients with Waldenstrom macroglobulinemia (WM). To prevent immunoglobulin M (IgM) "flare," single agent bortezomib (1.3 mg/m2 IV days 1,4,8, and 11; 21-day cycle), was followed by weekly IV bortezomib (1.6 mg/m2 days 1,8,15, and 22) every 35 days for 4 additional cycles, followed by IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) in cycles 2 and 5. Fifty-nine patients were treated; 45.5% and 40% were high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response [PR]). In 11 % of patients, an increase of IgM ⩾25% was observed after rituximab; no patient required plasmapheresis. After a minimum follow-up of 32 months, median progression-free survival was 42 months, 3-year duration of response for patients with aPR was 70%, and 3-year survival was 81%. Peripheral neuropathy occurred in 46% (grade ⩾3 in 7%); only 8% discontinued bortezomib due to neuropathy. BDR is rapidly acting, well tolerated, and nonmyelotoxtc, inducing durable responses in previously untreated WM. [ABSTRACT FROM AUTHOR]

Objectives The estimation of glomerular filtration rate (e GFR) in multiple myeloma ( MM) is based on equations that use serum creatinine (s Cr), such as the Modification of Diet in Renal Disease ( MDRD) equation. However, the Chronic Kidney Disease Epidemiology Collaboration ( CKD- EPI) group has suggested that e GFR based on both s Cr and cystatin C ( CKD- EPI-s Cr- Cys C) is more accurate than other formulae for the estimation of kidney dysfunction. The aim of this study was to prospectively evaluate, for the first time in the literature, the CKD- EPI-s CR- Cys C formula in newly diagnosed patients with symptomatic MM. Methods We studied 220 newly diagnosed, previously untreated, patients with symptomatic myeloma and calculated e GFR using the MDRD, the CKD- EPI-s CR, the CKD- EPI- Cys C, and the CKD- EPI-s Cr- Cys C equations. Results CKD- EPI-s Cr- Cys C equation detected more myeloma patients with stage 3-5 renal impairment than the MDRD, CKD- EPI, or CKD- EPI- Cys C equations: 45% vs. 39.5%, 42.2%, and 43.1%, respectively ( P < 0.01). This was also observed in the elderly patients (>70 yrs), while in patients ≤70 yrs, the CKD- EPI- Cys C equation managed to identify higher number of patients with stage 3-5 renal impairment ( RI) than the other equations. Furthermore, 63 (28.6%) patients with e GFR values by the MDRD formula were reclassified to higher CKD stages according to CKD- EPI- Cys C equation. The median overall survival for all patients was 52 months. In the multivariate analysis, that included International Staging System stage, lactate dehydrogenase ( LDH) ≥300 U/L and e GFR for each different equation (as a continuous variable), only e GFR that included Cys C, but not s Cr had independent prognostic value ( P = 0.013) along with high LDH ( P = 0.029). Conclusions Our results suggest that equations based on Cys C reveal higher number of MM patients with RI compared with equations based only in s Cr. Furthermore, the CKD- EPI- Cys C formula independently predicted for survival. Based on these data, we suggest that CKD- EPI equations based on Cys C should substitute MDRD, as it has been suggested for patients with several other renal disorders. [ABSTRACT FROM AUTHOR]

Background Multiple myeloma ( MM) affects mainly elderly persons and because the population of octogenarians increases, it is common to treat patients ≥80 years of age. These patients are often not included in clinical trials; thus, there is limited data on their characteristics and treatment outcome. Patients and methods We retrospectively analyzed 682 consecutive, unselected patients with newly diagnosed symptomatic myeloma who started treatment between January 1, 2003 and December 31, 2010. Results We identified 155 (23%) patients ≥ 80 years of age. Compared to patients <80 years, octogenarians had poorer performance status ( P < 0.001), anemia ( P = 0.006), low serum albumin ( P = 0.001), and advanced ISS ( P < 0.001). The median survival of patients ≥80 years was 22 months, and 14% died within 2 months from therapy initiation. The median survival of patients ≥80 years who received upfront novel agents was 26 vs. 17 months for those who did not. ECOG performance status ≤1 and frontline use of novel agents were independently associated with better survival. Response to first-line therapy was associated with improved survival (29 vs. 16 months, P = 0.017). Conclusions Patients ≥80 years of age present with features of advanced myeloma and impaired performance status. The addition of novel agents may improve their outcome, but careful assessment and prospective clinical trials targeting the population of elderly patients are needed. [ABSTRACT FROM AUTHOR]

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespeci-fied cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. [ABSTRACT FROM AUTHOR]

Objectives: High serum lactate dehydrogenase (LDH) is associated with features of advanced disease and inferior survival in multiple myeloma. It is however unclear whether LDH adds to the prognostic value of International Staging System (ISS) and whether it retains its prognostic significance in patients who are exposed to novel agent-based therapies. Patients/Methods: To address these issues we analyzed 996 consecutive symptomatic patients who were included in the database of the Greek Myeloma Study Group and received frontline treatment between January 1, 1995 and December 31, 2008. Results: The median overall survival (OS) of all patients was 40 months with a clear improvement in those who started treatment after January 1, 2000 (49 vs . 31 months; P < 0.01). A multivariate model showed that LDH, ISS, performance status, age and platelet counts had an independent prognostic value for OS ( P < 0.001 for all parameters). The median OS of patients with high (11% of patients) and normal LDH was 15 vs . 44 months ( P < 0.001). High LDH was associated with inferior OS within all ISS groups: 22 vs . 76 months for high and normal LDH groups, respectively, in ISS-1 ( P < 0.01); 11 vs . 40 months in ISS-2 ( P < 0.001) and 17 vs . 27 months in ISS-3 ( P < 0.01). The median OS of high and normal LDH groups among patients who received novel agents was 21 vs . 51 months, respectively ( P < 0.001). Conclusions: Lactate dehydrogenase is a readily available and inexpensive variable, which has a major impact on the survival of myeloma patients even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapies. [ABSTRACT FROM AUTHOR]

The "POWERFUL" multicenter, retrospective, and prospective study investigated the effectiveness of pomalidomide plus low-dose dexamethasone (POM/LoDex) therapy in relapsed/refractory multiple myeloma in routine care in Greece. Ninety-nine eligible adult patients treated with POM/LoDex according to the approved label after having received ≥2 prior therapies, including lenalidomide and bortezomib, were consecutively enrolled between 16 November 2017 and 21 February 2019 in 18 hematology departments. Fifty patients (50.5%) started POM/LoDex as third-line treatment. During the treatment period (median: 8.3 months; range: 0.3–47.6 months), the median POM dose was 4 mg/day, and 31.3% of the patients received additional antimyeloma agents. The overall response rate was 32.3%. During a median follow-up period of 13.8 months (Kaplan–Meier estimate), the median progression-free survival (PFS) was 10.5 months (95% CI: 7.4–14.4). The PFS was not significantly different between patients receiving POM/LoDex in the third versus later line of therapy, nor between patients receiving concomitant antimyeloma therapy versus POM/LoDEx doublet. During the prospective safety data collection period (median: 7.6 months) among patients with prospective follow-up (N = 75), POM-related adverse event incidence rate was 42.7% (serious: 18.7%; grade  ≥  3 hematological POM-related adverse events: 8.0%). Only neutropenia (13.3%) was reported at a frequency ≥10%. In conclusion, in this real-world study, POM/LoDex displayed a long PFS with no new safety signals emerging. [ABSTRACT FROM AUTHOR]