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.
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.
In this report we describe a patient suffering from chronic myeloid leukemia (CML), who was treated for 4.5 years with imatinib and developed pneumonia caused by two Candida species, i.e., C. krusei and C. glabrata. The patient was in complete hematologic remission and molecular analyses did not display the presence of TLR2-R752Q, TLR4-D299G and TLR4-T399I polymorphisms that may predispose individuals to fungal infections. This case report indicates that in some patients, as previously observed, the long-term administration of targeted therapy might affect immunity and predispose patients to opportunistic and life-threatening fungal infections.
We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.
Hypercalcemia is a defining feature of symptomatic multiple myeloma (MM). Its presence has been associated with lytic bone disease and complications such as renal impairment. The definition of hypercalcemia for symptomatic myeloma requires a corrected serum calcium >11 mg/dl or 1 mg/dl above the upper limit of normal. However, the prognostic significance of hypercalcemia has not been studied extensively, especially in the era of novel anti-myeloma therapies. To address this issue, we analyzed 2129 patients with symptomatic MM who were treated within the centers of the Greek Myeloma Study Group. Using the definition of IMWG, 19.5% of the patients with symptomatic MM had hypercalcemia (i.e. corrected serum calcium ≥ 11 mg/dl). The incidence of hypercalcemia decreased over time (23% before 2000, 18.7% during period 2000-2006 and 16.3% after 2007; p=0.004). The presence of hypercalcemia was strongly associated with severe anemia (Hb <10 g/dl), low platelet counts < 130x109/l, advanced ISS stage, moderate or severe renal dysfunction, elevated LDH, poor performance status (PS) and extensive bone disease (p<0.001 for all comparisons). Regarding bone disease, only 4 patients had hypercalcemia without lytic bone lesions in plain X-rays. In the subgroup of patients, treated in a single center (Alexandra Hospital), with available cytogenetics (N=418), hypercalcemia was associated with the presence of del13q (by FISH) (p=0.003) and of amp1q21 (p=0.022), marginally with the presence of del17p (p=0.081), but not with t(4;14) (p=0.392) or t(11;14) (p=0.66). In multivariate analysis hypercalcemia (>11 mg/dl) was independently associated with poor prognosis (HR: 1.248, 95% CI 1.082-1.439, p=0.002), along with ISS stage, age, poor PS, elevated LDH, Hb <10 g/dl, platelet counts <130x109/L. The prognostic importance of hypercalcemia was independent of the presence of osteolytic bone disease and identified groups with poor prognosis within each ISS-stage (Figure). This effect was more pronounced in patients with ISS-1 (median OS 73 vs 41 months in the presence of hypercalcemia, p<0.001) or ISS-2 (median overall survival (OS) 43 vs 22 months in the presence of hypercalcemia, p=0.001), while in patients with ISS-3, hypercalcemia was associated with very poor outcome (11 vs 27 months of patients without hypercalcemia, p<0.018). Hypercalcemia was also associated with a two-fold increase in the risk of early death (within <2 months): 9.4% vs 4.6% (p<0.001). The presence of hypercalcemia remains a significant prognostic factor even after the introduction of novel therapies, after 2000. We compared the OS of patients with hypercalcemia before and after 2000: the median OS of patients who presented with hypercalcemia improved from 17 months before 2000 to 36 months after 2000 (p<0.001). When the effect of different treatments (conventional chemotherapy, thalidomide, lenalidomide, bortezomib) was evaluated then the use of novel agents was associated with a major improvement in survival of patients with hypercalcemia (median OS: 44, 45 and 46.5 months for those treated with thalidomide, lenalidomide or bortezomib, respectively vs 19 months for those treated with conventional regimens in the absence of novel agents, p<0.001). However, the prognostic importance of hypercalcemia was independent of the type of primary therapy. A prognostic score which includes ISS stage (1, 2 and 3 points for ISS-1, -2 and -3, respectively), presence of hypercalcemia (1 point, 0 for no hypercalcemia) and age (1, 2, 3 and 4 points for ages <55, 55-65, 65-75 and >75 years, respectively), could identify 7 groups of patients with very distinct outcomes and median OS of >10 years (score 2), 84 months (score 3), 55 months (score 4), 42 months (score 5), 31 months (score 6), 19 months (score 7) and 14 months (score 8; p<0.001). In conclusion, hypercalcemia is present in about 19.5% of patients with newly diagnosed symptomatic MM and is associated with poor outcome and specific cytogenetic abnormalities (del 13q by FISH, amp1q21). Its prognostic significance is independent of age, ISS stage and treatment type. The use of new drugs has improved the survival of patients with hypercalcemia, however, the prognostic implications of the presence of hypercalcemia indicates that this factor should be taken into account for the prognostic assessment of patients with MM together with other established factors such as ISS and age. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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