Frequency and Prognostic Significance of Hypercalcemia in Patients with Multiple Myeloma: An Analysis of the Database of the Greek Myeloma Study Group
Authors: Kastritis Efstathios , Katodritou Eirini , Pouli Anastasia , Hatzimichael Eleftheria , Delimpasi Sosana , Michalis Eurydiki , Zomas Athanasios , Kartasis Zafiris , Parcharidou Agapi , Gika Dimitra , Repousis Panagiotis , Stefanoudaki Ekaterini , Symeonidis Argiris , Panayiotidis Panayiotis , Konstantopoulos Konstantinos , Terpos Evangelos , Dimopoulos Meletios Athanasios 
Published: October 2019

Abstract
Abstract 5083
Hypercalcemia is a common presenting feature of symptomatic myeloma. In the Durie-Salmon staging system elevated calcium was used to define advanced stage myeloma, indicating the adverse prognostic significance of hypercalcemia. The ISS staging system includes serum albumin and beta-2-microglobulin; however, in the analysis that led to the formation of the prognostic model, hypercalcemia (>10 mg/dl) was associated with inferior survival, but was not included in the final model. Development of ISS was based on data from patients who had been treated with conventional chemotherapy (CC). In order to identify the frequency of hypercalcemia in unselected newly diagnosed patients with symptomatic myeloma and the prognostic significance of elevated calcium in the era of novel agents and modern supportive care, we performed a retrospective analysis of the database of the Greek Myeloma Study Group.
Among 1692 patients with available data, 347 (21%) presented with corrected serum calcium (csCa) ≥11 mg/dl, 270 (16%) with csCa ≥11.5 mg/dl (as per the IMWG criteria for the diagnosis of symptomatic myeloma), 162 (9.5%) with csCa ≥12.5 mg/dl and 68 (4%) with csCa ≥14 mg/dl. The frequency of csCa ≥11.5 mg/dl at initial diagnosis was 17% for patients diagnosed before 1/1/1995, 19.4% for those diagnosed between 1/1/1995 and 31/12/1999 and 13.5% for those diagnosed after 1/1/2000 (p=0.018). The frequency for csCa ≥11 mg/dl during the same calendar periods was 22%, 24% and 18%, respectively (p=0.031). There were no differences in the incidence of hypercalcemia with a cut-off value of csCA ≥12.5 mg/dl and ≥14 mg/dl among patients who were diagnosed in the aforementioned periods (p=0.272 and 0.197, respectively).
There was no difference in the frequency of hypercalcemia (csCa ≥11.5 mg/dl) between genders and among patients of > or ≤70 years of age. However, hypercalcemia was strongly associated with poor performance status (ECOG PS>1), anemia (Hb <10 gr/dl), low platelet counts (<130×109/L), low serum albumin, elevated beta2-microglobulin, advanced ISS stage, elevated creatinine (≥2 mg/dl), elevated serum LDH (≥300 IU/L) and high levels of Bence Jones proteinuria (p<0.001 for all comparisons). Importantly, only 7 patients (1%) presented at diagnosis with csCa ≥11.5 mg/dl as the only feature of symptomatic myeloma (thus, without anemia <10 gr/dl, osteloytic bone disease or elevated serum creatinine >2 mg/dl).
The survival of patients who presented with hypercalcemia was significantly shorter than patients who presented with lower/normal serum calcium for every different cut-off of csCa (log-rank p-value<0.001 for all comparisons). The presence of csCa ≥11 mg/dl was associated with the strongest discriminating ability (chi-square: 55 vs. 41 for csCa ≥11.5 mg/dl vs. 29 for csCa ≥12.5 mg/dl vs. 12.7 for csCa ≥14 mg/dl). We then performed a multivariate analysis that included multiple prognostic factors. Age >70 years, PS ≥2, csCa ≥11 mg/dl (HR: 1.23, 95% CI: 1.005–1.5, p=0.044), low platelet counts (<130×109/L), elevated serum LDH (≥300 IU/L), ISS-3 and type of treatment (CC vs. novel agent-based therapy) were independently associated with poor survival. The survival of patients with csCa ≥11 mg/dl was significantly shorter only in patients treated upfront with CC (19 vs. 43.5 months, p<0.001), but in patients treated upfront with novel agents there was no significant difference in survival (54 vs. 46.5 months, p=0.288). Hypercalcemia (csCa ≥11 mg/dl) could discriminate different prognostic groups within ISS stages: patients with ISS-1 and csCa ≥11 mg/dl had a median survival of 39 vs. 76 months (p<0.001) for all others, for ISS-2 it was 27.5 vs. 47 months (p=0.018) and for ISS-3 it was 16 vs. 31 months (p=0.012).
In conclusion, hypercalcemia is a presenting feature in 21% of patients with newly diagnosed symptomatic myeloma and is associated with features of advanced disease but only rarely (∼1%) is the only presenting feature of symptomatic disease. It appears that the frequency of hypercalcemia has decreased in the recent decade. CsCa ≥11 mg/dl can identify patients with poor prognosis within ISS subgroups and is associated with poor prognosis in patients who are treated with conventional agents; thus, these patients should be treated upfront with novel agents, which seem to overcome the deleterious effect of hypercalcemia.

Disclosures:
No relevant conflicts of interest to declare.