Hypercalcemia Remains an Adverse Prognostic Factor for Newly Diagnosed Patients with Symptomatic Multiple Myeloma in the Era of Novel Anti-Myeloma Therapies, Independently of Age, ISS Stage and Treatment Type: An Analysis of 2129 Patients
Authors: Zomas Athanasios , Terpos Evangelos , Katodritou Eirini , Symeonidis Argiris , Delimpasi Sosana , Pouli Anastasia , Vassilakopoulos Theodoros P. , Michalis Eurydiki , Giannouli Stavroula , Kartasis Zafiris , Christoforidou Anna , Kokoviadou Kiriaki , Hatzimichael Eleftheria , Gika Dimitra , Megalakaki Catherine , Papaioannou Maria , Kyrtsonis Marie-Christine , Konstantopoulos Kostas , Dimopoulos Meletios A. , Kastritis Efstathios 
Published: October 2019

Abstract
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.