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

 
1. Rayner HC, Haynes AP, Thompson JR, et al: Perspectives in multiple myeloma: Survival, prognostic factors and disease complications in a single centre between 1975 and 1988. Q J Med 79:517-525, 1991[Medline]

2. Rajkumar SV, Greipp PR: Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am 13:1295-1314, 1999[CrossRef][Medline]

3. Murakami H, Hayashi K, Hatsumi N, et al: Risk factors for early death in patients undergoing treatment for multiple myeloma. Ann Hematol 80:452-455, 2001[CrossRef][Medline]

4. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21-33, 2003[Abstract/Free Full Text]

5. Cherng NC, Asal NR, Kuebler JP, et al: Prognostic factors in multiple myeloma. Cancer 67:3150-3156, 1991[CrossRef][Medline]

6. Irish AB, Winearls CG, Littlewood T: Presentation and survival of patients with severe renal failure and myeloma. Qjm 90:773-780, 1997[Abstract/Free Full Text]

7. Bladé J, Fernandez-Llama P, Bosch F, et al: Renal failure in multiple myeloma: Presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 158:1889-1893, 1998[Abstract/Free Full Text]

8. Analysis and management of renal failure in fourth MRC myelomatosis trial: MRC working party on leukaemia in adults. Br Med J (Clin Res Ed) 288:1411-1416, 1984

8. MacLennan IC, Chapman C, Dunn J, et al: Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis—The Medical Research Council Working Party for Leukaemia in Adults. Lancet 339:200-205, 1992[CrossRef][Medline]

9. Perri RT, Hebbel RP, Oken MM: Influence of treatment and response status on infection risk in multiple myeloma. Am J Med 71:935-940, 1981[CrossRef][Medline]

10. Sirohi B, Powles R: Multiple myeloma. Lancet 363:875-887, 2004[CrossRef][Medline]

11. McCloskey EV, MacLennan IC, Drayson MT, et al: A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma: MRC Working Party on Leukaemia in Adults. Br J Haematol 100:317-325, 1998[CrossRef][Medline]

11. Olojohungbe AB, Dunn JA, Drayson MT, et al: Prednisolone added to ABCM as treatment for multiple myeloma increases serological responses but not overall survival or the number of stable clinical responses. Br J Haematol 9:77, 1996

12. Jacobson JL, Hussein MA, Barlogie B, et al: A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience. Br J Haematol 122:441-450, 2003[CrossRef][Medline]

13. Greipp PR, San Miguel J, Duries BGM, et al: International Staging System for multiple myeloma. J Clin Oncol 23:3412-3420, 2005[Abstract/Free Full Text]

14. Dunn JA Drayson MT, Begum G et al: Prognostic factors in myeloma. Hematol J 4:196, 2003 (abstr)

15. Hillner BE, Smith TJ, Desch CE: Hospital and physician volume or specialization and outcomes in cancer treatment: Importance in quality of cancer care. J Clin Oncol 18:2327-2340, 2000[Abstract/Free Full Text]

16. Grilli R, Minozzi S, Tinazzi A, et al: Do specialists do it better? The impact of specialization on the processes and outcomes of care for cancer patients. Ann Oncol 9:365-374, 1998[Abstract/Free Full Text]

17. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003[Abstract/Free Full Text]

18. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996[Abstract/Free Full Text]

19. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 [Erratum: N Engl J Med 342:364, 2000][Abstract/Free Full Text]

20. Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100:3063-3067, 2002[Abstract/Free Full Text]

21. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003[Abstract/Free Full Text]

22. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. Br J Haematol 121:749-757, 2003[CrossRef][Medline]

23. Takagi T, Sawamura M, Sezaki T, et al: Clinical benefits of lenograstim in patients with neutropenia due to chemotherapy for multiple myeloma (MM). Support Care Cancer 9:397-399, 2001[CrossRef][Medline]

24. Alexanian R: Ten-year survival in multiple myeloma. Arch Intern Med 145:2073-2074, 1985[Abstract/Free Full Text]

25. Bladé J, San Miguel JF, Fontanillas M, et al: Increased conventional chemotherapy does not improve survival in multiple myeloma: Long-term results of two PETHEMA trials including 914 patients. Hematol J 2:272-278, 2001[CrossRef][Medline]

26. Fahey JL, Scoggins R, Utz JP, et al: Infection, antibody response and gamma globulin components in multiple myeloma and macroglobulinemia. Am J Med 35:698-707, 1963[CrossRef][Medline]

27. Robertson JD, Nagesh K, Jowitt SN, et al: Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer 82:1261-1265, 2000[CrossRef][Medline]

28. Luque R, Brieva JA, Moreno A, et al: Normal and clonal B lineage cells can be distinguished by their differential expression of B cell antigens and adhesion molecules in peripheral blood from multiple myeloma (MM) patients: Diagnostic and clinical implications. Clin Exp Immunol 112:410-418, 1998[CrossRef][Medline]

29. Oken MM, Pomeroy C, Weisdorf D, et al: Prophylactic antibiotics for the prevention of early infection in multiple myeloma. Am J Med 100:624-628, 1996[CrossRef][Medline]

30. Gracia Escudero A, Martin Gonzalez M, Gimenez Garrido F, et al: A prospective, controlled, non-randomized study of three cohorts to test the effectiveness of two antibiotics levofloxacin and cotrimoxazol on antibacterial prophylaxis in neutropenic patients. Med Clin (Barc) 15:321-325, 2003

31. Salmon SE, Samal BA, Hayes DM, et al: Role of gamma globulin for immunoprophylaxis in multiple myeloma. N Engl J Med 277:1336-1340, 1967[Medline]

32. Chapel HM, Lee M, Hargreaves R, et al: Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma: The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet 343:1059-1063, 1994[CrossRef][Medline]

33. Coward RA, Mallick NP, Delamore IW: Should patients with renal failure associated with myeloma be dialysed? Br Med J (Clin Res Ed) 287:1575-1578, 1983

34. Iggo N, Palmer AB, Severn A, et al: Chronic dialysis in patients with multiple myeloma and renal failure: A worthwhile treatment. Q J Med 73:903-910, 1989[Medline]

35. Badros A, Barlogie B, Siegel E, et al: Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 114:822-829, 2001[CrossRef][Medline]

36. San Miguel JF, Lahuerta JJ, Garcia-Sanz R, et al: Are myeloma patients with renal failure candidates for autologous stem cell transplantation? Hematol J 1:28-36, 2000[CrossRef][Medline]

37. Yussim E, Schwartz E, Sidi Y, et al: Acute renal failure precipitated by non-steroidal anti-inflammatory drugs (NSAIDs) in multiple myeloma. Am J Hematol 58:142-144, 1998[CrossRef][Medline]

38. Winearls CG: Acute myeloma kidney. Kidney Int 48:1347-1361, 1995[Medline]

39. Rota S, Mougenot B, Baudouin B, et al: Multiple myeloma and severe renal failure: A clinicopathologic study of outcome and prognosis in 34 patients. Medicine (Baltimore) 66:126-137, 1987[Medline]

40. Zucchelli P, Pasquali S, Cagnoli L, et al: Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 33:1175-1180, 1988[Medline]

41. UK Myeloma Forum and The Nordic Myeloma Study Group: Guidelines on the Diagnosis and Management of Multiple Myeloma. Br J Haematol 2005 (in press)

42. Spinler SA, Hilleman DE, Cheng JW, et al: New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines. Ann Pharmacother 35:589-617, 2001[Abstract]

43. Flemming KD, Brown RD Jr: Secondary prevention strategies in ischemic stroke: Identification and optimal management of modifiable risk factors. Mayo Clin Proc 79:1330-1340, 2004[Abstract/Free Full Text]

44. Non-variceal upper gastrointestinal haemorrhage guidelines. Gut 51:iv1-6, 2002 (suppl 4)[Free Full Text]

45. Zumberg MS, del Rosario ML, Nejame CF, et al: A prospective randomized trial of prophylactic platelet transfusion and bleeding incidence in hematopoietic stem cell transplant recipients: 10,000/L versus 20,000/microL trigger. Biol Blood Marrow Transplant 8:569-576, 2002[CrossRef][Medline]

46. Zangari M, Anaissie E, Barlogie B, et al: Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98:1614-1615, 2001[Abstract/Free Full Text]

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

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				M.-V. Mateos, J.-M. Hernandez, M.-T. Hernandez, N.-C. Gutierrez, L. Palomera, M. Fuertes, J. Diaz-Mediavilla, J.-J. Lahuerta, J. de la Rubia, M.-J. Terol, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study Blood, October 1, 2006; 108(7): 2165 - 2172. [Abstract] [Full Text] [PDF]

				M. Drayson, G. Begum, S. Basu, S. Makkuni, J. Dunn, N. Barth, and J. A. Child Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials Blood, September 15, 2006; 108(6): 2013 - 2019. [Abstract] [Full Text] [PDF]

				S. M. Korbet and M. M. Schwartz Multiple Myeloma J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2533 - 2545. [Full Text] [PDF]

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