The Association of International Staging System (ISS) Stage with Disease and Symptom Burden in Patients with Newly Diagnosed Multiple Myeloma
Authors: Fiala Mark A , Slade Michael , Keller Jesse , Stockerl-Goldstein Keith , Tomasson Michael , Wildes Tanya M , Vij Ravi 
Published: October 2019

Abstract
Background: The clinical presentation of multiple myeloma (MM) varies greatly but often includes bone pain, anemia, renal dysfunction, hypercalcaemia, and/or constitutional symptoms. There are no signs or symptoms that are disease specific. The earliest staging system for MM, the Durie-Salmon (DS), associated disease and symptom burden with prognosis; however, it has been largely replaced by the International Staging System (ISS), which is easier to compute and better identifies patients with the poorest prognosis. It is unclear if ISS stage, like DS, is associated with disease or symptom burden.
Objective: To compare disease and symptom burden of patients with newly diagnosed MM by ISS Stage.
Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data and patient reported quality of life (EORTC QLQ-C30 and QLQ-MY20), as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years.
All clinical data was reported by trained data analysts at the enrolling center with the exception of flow cytometry which was performed centrally; raw lab values for beta-2 microglobulin and albumin were entered and stage was subsequently calculated by the analysts for this study according to the ISS (Greipp et al, JCO 2005). Twenty-six patients with unknown ISS were excluded from the analysis. Data was analyzed using SPSS 21. Categorical variables were compared using χ2, continuous with one-way ANOVA tests.
Results: 599 patients were eligible for analysis. Sex, race, and heavy and light chain isotypes were all evenly distributed among the ISS stages; however, median age for ISS stage III was 67, 65 for stage II and 62 for stage I (p<0.001). Stage I and II patients were similar in disease burden, but stage III patients had higher serum M-proteins (p<0.001), LDH (p=0.002), bone marrow plasma cells (p<0.001), circulating plasma cells (p<0.001), and creatinine (p<0.001), and lower hemoglobin (p<0.001) and platelets (p=0.001). Further, stage III patients had poorer performance status (p<0.001), global health (p<0.001), physical functioning (p<0.001), social functioning (p<0.001), and role functioning (p<0.001), and increased fatigue (p<0.001) and pain (p=0.016). Results are summarized in Table 1.
Conclusions: Stage III had a higher disease and symptom burden than stage I and II patients. Stage I and II patients were similar in most measures suggesting that ISS may not discriminate between these groups well, this is supported by other studies that have failed to find outcomes differences between stage I and II patients.
Table 1. Stage I n= 204 Stage II n = 210 Stage IIIn = 185 p Demographics Age in years 62 65 67 <0.001 Male 64% 57% 62% NS Race NS White 80% 83% 74% Black 19% 13% 23% Other 2% 3% 3% Heavy Chain NS IgG 80% 80% 75% IgA 20% 20% 25% Light Chain NS Kappa 65% 61% 60% Lambda 34% 38% 38% Biclonal 1% 2% 2% Disease Burden Serum M-Protein g/dL 1.9 2.0 3.2 <0.001 LDH μkat/L 2.7 2.8 3.0 0.002 Bone Marrow Plasma Cells* 7% 9% 13% <0.001 Circulating Plasma Cells* 0% 0% 0.1% <0.001 Calcium mmol/L 2.4 2.3 2.4 <0.001 Creatinine μmol/L 82 88 149 <0.001 Hgb mmol/L 7.4 6.4 5.8 <0.001 Platelets x109/L 222 212 199 .001 Bone Lesions 61% 52% 53% NS Symptom Burden/Quality of Life Measures ECOG Performance Status <0.001 0 47% 42% 22% 1 49% 42% 54% 2 5% 8% 15% 3-4 0% 8% 9% Global Health Scale 66 66 50 <0.001 Physical Functioning Scale 86 80 63 <0.001 Cognitive Functioning Scale 83 83 83 NS Emotional Functioning Scale 75 75 75 NS Social Functioning Scale 83 83 66 <0.001 Role Functioning Scale 66 66 50 <0.001 Disease Symptom Scale 27 22 27 NS Fatigue Scale 33 33 44 <0.001 Pain Scale 33 33 42 0.016 Note-Median presented unless specified. *- CD38+/CD138+ by flow cytometry

Disclosures
Vij: Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.