The Association of International Staging System (ISS) Stage with Disease and Symptom Burden in Patients with Newly Diagnosed Multiple Myeloma

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 III n = 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