Incorporation of the Bone Marker Carboxy-Terminal Telopeptide of Type-1 Collagen (ICTP) into a Combined ISS-ICTP Score Improves the Prognostic Significance of the ISS in Newly Diagnosed Symptomatic Multiple Myeloma and Identifies a Very Low Risk Group Which Has No Benefit from High-Dose Therapy
Authors: Jakob Christian , Liebisch Peter , Heider Ulrike , Kaiser Martin , Sterz Jan , Rademacher Jessica , Fleissner Claudia , Müller Christian , Sezer Orhan 
Published: April 2020

Abstract
The prognosis of patients with newly diagnosed symptomatic multiple myeloma (MM) has been improved, but the outcome is still highly variable. Several prognostic markers, including parameters of tumor burden and cytogenetics were adopted to identify high-risk patients. Recently the International Staging System (ISS), including the parameters β2-microglobulin (β2M) and albumin, was introduced for patients with symptomatic MM. In previous studies the bone resorption marker carboxy-terminal telopeptide of type-1 collagen (ICTP) was identified as a sensitive and specific marker of increased bone resorption and as a strong prognostic factor for overall survival (OS) in MM. Since bone disease is a hallmark of MM, we investigated the prognostic impact of the bone resorption marker ICTP in combination with ISS, β2M, albumin and deletion of chromosome 13 (del(13q14)) and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. β2M alone, albumin alone, ISS, del(13q14) and ICTP were significant prognostic factors for overall survival. In contrast to ICTP, lytic bone lesions were not an independent prognostic factor for OS (P=0.289). In a multivariate analysis, ICTP was the most powerful prognostic factor (log rank P&lt;0.001, hazard-ratio: 9-fold increase). Furthermore ICTP clearly separated two subgroups with a good and a worse prognosis within each of the three ISS stages (ISS I: P=0.027, ISS II: P=0.022, ISS III: P=0.013). A combined ISS-ICTP score, including β2M (cut off: 3.5 mg/l), albumin (cut off: &lt; 3.5 g/dl) and ICTP (cut off: reference limit) significantly (P&lt;0.001) separated four risk groups with a 5-year overall survival rate of 94% in the very low risk group, 65% in the low risk group, 46% in the intermediate risk group and 22% in the high risk group, respectively. In the very low risk group, there was no significant survival benefit with highdose therapy (P=0.24), while HDT was a favorable prognostic factor in ISS-ICTP risk groups 1–3 (P=0.037, P=0.011 and P=0.012) and in ISS stages I–III (P=0.026, P=0.001 and P=0.052). These data demonstrate that the inclusion of the bone resorption marker ICTP adds to the prognostic value of ISS and may have clinical implications for selection of HDT in frontline treatment strategies in newly diagnosed MM.
Table: Comparison between ISS and combined ISS-ICTP score in newly diagnosed symptomatic MM.
Combined ISS-ICTP Score ISS Risk factors† (group) Patients (%) 5-yr OS (%) Stage* Patients (%) 5-yr OS (%) 0 (very low) 21 94 1 (low) 38 64 I 38 72 2 (intermediate) 26 46 II 35 62 3 (high) 15 22 III 27 35 † risk factors: β2M ≥3.5 mg/l&#x2028; Albumin &lt;3.5 g/dl&#x2028; ICTP &gt;reference limit * ISS I:&#x2028; ISS II:&#x2028; ISS III: β2M &lt;3.5 mg/l,&#x2028; Albumin ≥3.5 g/dl&#x2028; not stage I or III&#x2028; β2M ≥5.5 mg/l