Early Mortality Following Diagnosis of Multiple Myeloma; Analysis of Patients Entered into the UK Medical Research Council Trials 1980–2002.
Authors: Augustson Bradley M. , Begum Gulnaz , Barth Nicola J. , Dunn Janet A. , Morgan Gareth J. , Child J. Anthony , Drayson Mark T. 
Published: October 2019

Abstract
Introduction: Early mortality in newly dignosed patients with multiple myeloma (MM) is attributed to active disease and co-morbid factors, however there is little information regarding the exact mode of these deaths in the literature. The aim of this study is to analyse presentation features and clinical management of early mortality patients to identify strategies to avoid these deaths.
Methods: 3107 patients entered into the UK MRC trials from 1980–2002 had newly diagnosed (MM) with evidence of MM related organ or tissue impairment. These patients were randomised to melphalan based therapy (n=848 patients), ABCM (n= 1967), intensive therapy (n=231) or cyclophosphamide (n=61). Presentation laboratory and clinical information was collected from the centrally stored patient files. Early death was defined as occurring within 60 days of diagnosis. The main and contributory causes of death were ascertained from the final clinical summary and post-mortem reports. Whether the final illness developed at home or hospital, delay in presentation, pre-morbid illness, bone pain and medications were specifically assessed.
Results: 299 MM patients (10%) who entered MRC trials died within 60 days of diagnosis. The incidence of early mortality in ABCM treated patients aged over 65 years did not change for the periods 1982–87 to 1988–1992, and 1993–2002 (p=0.19). Patients who died early were older, had significantly worse skeletal disease, higher β2-microglobulin, lower platelet counts and more renal dysfunction, than the remaining MRC trial patients (P<0.0001 all parameters). However some early deaths occurred in patients with overall good prognostic features and 11% of patients dying within 60 days had a serum β2-microglobulin <4mg/l. The most common cause of early death was bacterial infection (45%). This was often associated with bone pain and delay in presentation to hospital. Renal failure (14% of early deaths) was associated with light chain disease, hypercalcaemia or a precipitating event such as dehydration or medications and infection. Vascular disease (13%) was associated with older age, and pre-existing vascular risk factors. Sudden death (10%), bleeding (5%), pulmonary embolus (3%) and orthopaedic complication (3%) accounted for the remaining deaths with no cause determined for 8% of cases.
Conclusions: With intensive treatment and emerging therapies the long-term outlook for MM patients is improving. However we find in patients over 65 yrs receiving conventional therapy, the incidence of early death has remained constant since 1982 despite advances in supportive care. It is most commonly due to bacterial infection, renal failure and vascular complications in patients with poor prognostic indicators. Effective analgesia, avoidance of dehydration and nephrotoxic agents, attention to vascular risk factors, patient education and prompt presentation may contribute to reducing such deaths. One small trial has shown a survival benefit from prophylactic antibiotics; this requires further study given that 50% of early deaths were attributable to infection as a major or the main cause of death. Renal failure was a major or the main cause of death in 28% of patients highlighting the need for renal care and outcome of the current UK MERIT trial that is assessing the role of plasma exchange.