Originally published as JCO Early Release 10.1200/JCO.2005.03.2086 on November 7 2005

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Early Mortality After Diagnosis of Multiple Myeloma: Analysis of Patients Entered Onto the United Kingdom Medical Research Council Trials Between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party

From The Department of Immunology and Cancer Research United Kingdom Clinical Trials Unit, the University of Birmingham, Birmingham; Section of Haemato-Oncology Institute for Cancer Research, Royal Marsden Hospital, London; the Department of Haematology, St Helier Hospital National Health Service Trust, Carshalton, Surrey; and the Department of Haematology Southampton University National Health Service Trust, Southampton, United Kingdom

Address reprint requests to Mark T. Drayson, PhD, Division of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, United Kingdom, B15 2TT; e-mail: m.t.drayson{at}bham.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency.

PATIENTS AND METHODS: A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed.

RESULTS: Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002.

CONCLUSION: A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Early mortality after diagnosis of multiple myeloma (MM) is often attributed to combined effects of active disease and comorbid factors.^1-5 Symptomatic myeloma causes anemia (40%), thrombocytopenia (14%), and neutropenia (6%) at diagnosis. Skeletal disease (70%) reduces mobility, impairs ventilation, and may result in hypercalcemia.⁴ Renal impairment, present in up to 20% at diagnosis,^6-8 and increased risk of infection are particularly important contributory factors to early mortality.^1,3,9 The median age at presentation is 65 to 70 years¹⁰; consequently, major comorbidities are common. Therapy may further compromise renal and cardiac function and cause immunosuppression by damaging mucosal barriers and impairing both innate and specific cellular immunity. In the first 2 months from diagnosis, these adverse effects of therapy occur before major reduction of tumor load and MM-related organ and tissue impairment is achieved,^8,11 and so this period of induction treatment is associated with a high mortality risk.

The introduction and development of multidisciplinary approaches have impacted and improved the clinical management of patients.^15,16 The overall median survival of MM patients is 2.5 years with conventional-dose chemotherapy, but in younger cohorts of patients, median survival more than 5 years can now be achieved with the introduction of high-dose therapy.^17,18 Further improvement is expected after the introduction of new agents, including bortezomib, thalidomide, and lenalidomide, coupled with a better understanding of basic disease biology.^19-21 Such advances, however, have not yet made an impact on reducing early mortality. Ten percent to 25% of MM deaths occur within 6 months of diagnosis.^1,3,4 Furthermore, the accuracy with which staging systems can predict outcome for an individual patient is rather low, and many unexpected deaths and survivals occur.^12-14

Patients in the United Kingdom Medical Research Council (MRC) trials from 1980 to 2002 who died within 60 days of diagnosis were the subject of this study. The main aim was to analyze the documented direct cause of death and the associated contributing factors. The secondary aim was to analyze the accuracy with which these early deaths can be predicted to allow prevention or rapid therapeutic intervention. Ultimately this should result in a reduction of the proportion of patients who do not survive long enough to reap the benefits of antitumor therapy.

	PATIENTS AND METHODS

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Patient Population
A total of 3,107 consented patients registered onto the MRC multiple myeloma trials between 1980 and 2002 were eligible for this study, which was approved by local ethics committees. Our diagnostic criteria were consistent with the recently agreed criteria for symptomatic myeloma as defined and published by the International Myeloma Working Group.²²

Table 1 lists the characteristics of these trials. Patients were randomly assigned to standard dose melphalan-based chemotherapy (848 patients), melphalan-based-conventional dose combination chemotherapy as exemplified by doxorubicin, carmustine, cyclophosphamide, and melphalan (ABCM; 1,967 patients), conventional dose vincristine doxorubicin dexamethasone-like infusional chemotherapy (cyclophosphamide vincristine doxorubicin methylprednisolone), and high-dose melphalan (231 patients). Sixty-one patients presenting with thrombocytopenia received cyclophosphamide therapy. Early death was defined as occurring within 60 days of entry onto the trial.

Statistical Methods
Early mortality was calculated from date of entry onto the trial to date of death or date last seen, as appropriate, and was defined as death within 60 days. Differences in patient and disease characteristics for early death versus nonearly death patients were investigated using Pearson's ² test. Beta 2-microglobulin, performance status, age, blood urea, platelets, and corrected calcium were considered in a stepwise logistic regression analysis. Analyses were carried out using a 5% significance level to determine independent factors predicting early death. All patients alive for more than 60 days were censored for this analysis. Sensitivity and specificity were calculated and proportion of false positives and negatives and overall percentage of correct predictions are presented. The probability cut point was chosen to balance sensitivity and specificity. Data were analyzed using the statistical software SAS (SAS Institute, Cary, NC).

	RESULTS

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Patient Data
Early mortality before day 60 occurred in 299 (10%) of patients registered onto MRC trials 1980 to 2002. Table 2 shows presentation characteristics for the early death patients compared with those who survived longer than 60 days. Patients who died early were shown to be older (> 65 years; P < .0001), have a poorer performance status (P < .0001), and reduced serum albumin (P < .0001) compared with the remainder of the MRC trial patients. Early mortality was associated with a greater tumor burden and activity (bone marrow plasma cells, beta 2-microglobulin, and C-reactive protein; P < .0001).

It is striking that although across all trials, the average percentage of early deaths is 10%, in the VIIth trial it is only 4% (Table 1). In contrast to the other trials, eligibility criteria for entry to the VIIth trial included age younger than 65 years and predicted ability to tolerate high-dose melphalan; this is reflected in the overall more favorable distribution of prognostic indices in VIIth trial patients. To assess for a change in the early mortality rate over time, we examined patients of similar prognostic characteristics who received similar induction treatment. A total of 1,550 patients 65 years of age and who received ABCM chemotherapy were assessed. They were divided into equal groups for the periods 1982 to 1987, 1988 to 1992, and 1993 to 2002. No reduction in the proportion of early deaths was observed for these time periods (11%, 8%, and 9%, respectively; P = .20).

Early Death Data
Bacterial infection directly caused 135 early deaths (45%) and contributed to death in almost 50% of cases (Fig 1). Specifically pneumonia occurred in 89 (66%) of 135 bacterial infections, generalized sepsis occurred in 31 (23%) of 135 bacterial infections, and other infections occurred in 15 (11%) of 135 (eg, osteomyelitis, peritonitis). Thoracic pain was identified in 22 (25%) of 89 patients with pneumonia. Eleven of the 135 patients dying of infection had a neutrophil count less than 2.0 x 10⁹/L, and 20 patients had a count between 2.0 and 3.0 x 10⁹/L. Positive culture results were available for 10 pneumonia cases (11%) and eight generalized sepsis cases (25%). The most common organisms cultured were Pneumococcus pneumoniae (six cases) Staphylococcus aureus (five cases), and Escherichia coli (three cases). In 45 (33%) of 135 infective deaths, the final illness developed at home (Fig 2), with delay in presentation to hospital in 48% of these cases; no information was available for 19% of patients.

View larger version (21K): [in this window] [in a new window]   Fig 1. Causes of early deaths. The number of deaths within 60 days of trial entry by direct cause of death and the additional number of patients in whom clinical modality contributed to the cause of death are shown.

View larger version (25K): [in this window] [in a new window]   Fig 2. Origin of the final illness. Patients are grouped by the direct cause of death. For each cause, numbers of patients are shown for those in whom the final illness developed at home, in hospital, or for whom information was not available.

Myocardial infarction¹⁴ or cerebrovascular accident¹¹ accounted for 25 cases (8%) of early death (Fig 1). There was no increase in cardiac deaths for ABCM- versus melphalan-treated patients (P = .65). These deaths were associated with vascular risk factors, such as hypertension, renal impairment, or previous vascular events in 33% of cases. Cardiac failure was implicated in the final illness in 38 cases (13%) and was associated with renal impairment (nine of 38), infection (15 of 38), and vascular disease (four of 38). Sudden death without a specific identifiable cause occurred in 32 (11%) of 299 patients, with half of these deaths occurring at home. There were six cases of pulmonary embolus, with postmortem examination confirming four of these. All these patients dying of pulmonary embolus had severe pain and restricted activity or were bed-bound. Bleeding accounted for nine early deaths (3%). Four of these were gastrointestinal bleeds and three were intracranial. Two were iatrogenic, one after the use of fibrinolytic therapy for myocardial infarction and the other after renal biopsy. Thrombocytopenia was definitely implicated in three of these deaths, and two patients had abnormal coagulation profiles. Five patients died of complications directly related to skeletal events (four with rib fracture and respiratory failure). Treatment was withdrawn in nine cases (3%) with no further follow-up information, and the final death form had not been returned in 19 cases (6%).

The final logistic regression model was derived using 2,374 patients with complete data; 239 of these were early death patients. The analysis identified older patients with increased beta 2-microglobulin and poor performance status as having increased odds of an early death. The final model was able to correctly predict 61% of early death patients and 74% of patients surviving longer than 60 days. Overall, the model correctly predicts 1,735 (73%) of 2,374 patients. Ninety-three patients were incorrectly predicted to be nonearly deaths (6% false-negative rate), and 546 patients were incorrectly predicted to be early deaths (79% false-positive rate). Comparing cause of early death between the IVth and Vth trials (1980 to 1986), the VIth trial (1986 to 1991), and the VIIIth trial (1993 to 2002), there was no significant difference in the proportions attributable to infection, renal, cardiovascular, or other causes (P = .90).

	DISCUSSION

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Despite advances in supportive care, including the multidisciplinary team approach,^15,16 effective treatment of hypercalcemia with rehydration and bisphosphonates,¹¹ granulocyte colony-stimulating factor therapy,²³ and use of antibiotics, up to 10% of newly diagnosed MM patients registered onto MRC trials still die within 60 days of their diagnosis. Such deaths occur before the maximal beneficial effect of chemotherapy in reducing tumor load. Knowledge of the causes of these deaths and associated comorbidities will raise awareness of the early complications seen in myeloma and may help with developing strategies for their prevention. In 5% of these cases, the outlook is perceived to be so poor that active treatment is withdrawn.

Alexanian et al²⁴ were able to show improved early survival when comparing patients diagnosed before 1965 with patients diagnosed after 1975. That effect was largely attributed to the effect of combination chemotherapy in patients with a high tumor mass. The development of hematology as a specialty and assertive management of complications may have also played a role. However, recent series do not show further improvement, with 10% to 25% of patients dying within 6 months of diagnosis.^1,3,4 In two trials run from 1985 to 1994, Bladé et al²⁵ found that 7.9% of patients died within 2 months of diagnosis; increasing age and higher doses of combination chemotherapy were significant risk factors. These current data confirm these findings and show that for patients treated with ABCM therapy, there was no significant improvement in the early mortality rate over the past 20 years.

Various predictive models for survival exist, and a recently devised model based on serum beta 2-microglobulin and albumin levels provides an easy and fairly effective prediction of outcome.¹³ By using a six-factor prognostic index based on serum beta 2-microglobulin, performance status, age, blood urea, platelet count, and serum calcium as continuous variables, a more accurate prediction can be calculated.¹⁴ When applied to these early death patients, even this model suffers from poor sensitivity (61%) and specificity (73%). It is therefore important to consider that all newly diagnosed patients are at high risk of death during the first 2 months after diagnosis and to remain vigilant during this period.

Myeloma patients are predisposed to infection because of immunoparesis²⁶ with poor response to vaccination,²⁷ neutropenia, lymphocytopenia,²⁸ placement of vascular catheters, and impaired mucosal integrity owing to the effect of chemotherapy/radiotherapy. Many of these patients suffer from bone pain that impairs ventilation, reduces the clearance of secretions, and often requires narcotic analgesics that may suppress ventilation. The risk of infection in the first 6 months after diagnosis ranges from 20% to 55%,^1,9 and 20% of deaths within 2 months have been attributed to infection.²⁵ In this study, infections caused 135 deaths, 45% of total deaths within 60 days of diagnosis; two thirds of these infective deaths were from pneumonia. One third of these infections developed at home and in half of cases there was delay in obtaining medical treatment ranging to several days, suggesting that prompt hospital admission is an aspect of management that could be improved.

Effective control of pain is important, particularly where respiratory function is compromised. Better control of pain and other symptoms could lead to fewer patients opting to withdraw from treatment before its beneficial effect.

One small study has shown prophylactic cotrimoxazole to be effective²⁹ at reducing infection rates in the first 2 months after diagnosis. Levofloxacin and cotrimoxazole have been shown to reduce infection rates, hospitalization, and the requirement for intravenous antibiotics for neutropenic patients.³⁰ These measures were shown to be well tolerated and cost effective. Larger studies are currently underway to help confirm these findings in MM.

The role of gamma globulin replacement therapy has been assessed for newly diagnosed patients and those in plateau phase.^31,32 Although the treatment was effective at preventing infection in plateau phase,³² no effect was demonstrated for those with newly diagnosed myeloma receiving intramuscular³¹ or intravenous replacement therapy (unpublished data; placebo-controlled randomized MRC trial).

Patients presenting with renal failure may not be considered for renal dialysis because of perceived extremely poor prognosis.³³ Renal replacement therapy is worthwhile,^6-8,34,35 and many patients with renal impairment can be expected to tolerate high-dose therapy with stem-cell support.³⁶ Renal failure should be promptly recognized, and aggravating factors, such as dehydration and hypercalcemia, should be treated vigorously. This may be difficult in older/frail patients where there is less renal reserve and in whom serum creatinine may not reflect renal function. Non steroidal anti-inflammatory drugs and other nephrotoxic agents should be identified and avoided.^8,37-39 Dose reduction is required for many commonly used medications in the setting of renal failure.

Reversal of established renal failure remains challenging. Plasma exchange where serum-free light chains are removed was effective in a small series of newly diagnosed patients who presented with renal failure.⁴⁰ This study was limited by several methodologic problems and a higher than expected early death rate in the control population. Confirmation is awaited from the United Kingdom Myeloma Forum MERIT study.⁴¹

Vascular disease may be responsible for early death, consistent with the age group of these patients. Premorbid conditions may be overlooked when faced with a new diagnosis of malignancy. The improved long-term outlook for myeloma as well as effective secondary and primary prevention studies for vascular disease suggest that ongoing meticulous care is worthwhile.^42,43

Deaths caused by gastrointestinal bleeding were associated with thrombocytopenia and therapy with corticosteroids. Careful consideration of these factors, past history of peptic ulcer disease, and current upper gastrointestinal symptoms should prompt consideration of prophylactic proton pump inhibitor therapy.⁴⁴ Platelet replacement therapy is indicated when platelet count decreases to less than 10 x 10⁹/L or if there is any evidence of active bleeding in thrombocytopenic patients.⁴⁵

Patients with myeloma may be at increased risk of pulmonary embolism, particularly those with poor performance status. Further risk of thromboembolic disease has been associated with thalidomide, especially when it is used in combination with cytotoxic therapy and corticosteroids.⁴⁶ High-risk patients should be identified and offered prophylaxis, including compression stockings and formal anticoagulant therapy. Careful individual appraisal in patients who are thrombocytopenic or have other bleeding risk factors will be required.

This article describes the complications and related mortality that occur soon after diagnosis of myeloma is made. Better supportive care has improved survival of patients receiving intensive chemotherapy in hospital, but in this study, any changes in supportive care for patients receiving standard chemotherapy largely as outpatients has not improved early survival in the last 20 years. Accurate identification of these early causes of mortality can provide better insight to areas where active intervention as well as education strategies may be focused. Ongoing work is in progress to assess the effect of strategies, such as the use of prophylactic antibiotics in newly diagnosed patients and the role of plasma exchange for patients with renal failure at presentation. Better understanding of disease biology and the introduction of new therapeutic options, together with prevention or prompt recognition and treatment of complications are likely to lead to improved outcome for myeloma patients. Preventing early deaths will be an important contributory aspect.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the clinicians who entered patients into these trials.

	NOTES

 
Presented in poster form at the American Society of Hematology, December 4-7, 2004, San Diego, CA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted June 23, 2005; accepted September 22, 2005.

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