Mieloma múltiplo : experiência de cinco anos em um Hospital Universitário Multiple myeloma : five-year experience at a University Hospital

objective: To present a descriptive analysis of patients diagnosed with multiple myeloma, correlating it with mortality. Methods: A retrospective study that analyzed consecutive patients diagnosed with multiple myeloma under follow-up at the Faculdade de Medicina do ABC from 2006 to 2010. results: The median age was 58.5 years. Anemia was observed upon diagnosis in 87% of patients, hypercalcemia in 38%, and creatinine levels higher than 2 mg/dL in 19%. M protein was detected in 85.7%. The five-year survival rate was 74.6%. Multivariate analysis showed statistical significance for Durie-Salmon staging (p = 0.037). The International Staging System and immunoglobulin type did not correlate significantly with survival of the group. Conclusion: This set of cases from a tertiary public healthcare service reflect the approach of multiple myeloma in a predominantly young population with advanced clinical staging, with results comparable to those of the literature.


INTRODUCTION
Multiple myeloma (MM) is defined as a malignant and incurable disease of B cells, characterized by proliferation of plasma cells that secrete monoclonal immunoglobulin into the blood or urine (1) , which can occur as the evolution of a monoclonal gammopathy of undetermined significance (MGUS) (2) .
Myeloma corresponds to 10% of hematologic neoplasms, and its incidence increases with age, with a median age of 67 years; however, 3% of the patients at diagnosis are under the age of 40 years (3,4) .The progression rate of MGUS for MM is estimated at 0.6 to 3% a year (4,5) .
Knowledge of pathophysiology of the myeloma and its secondary clinical manifestations enabled the creation of the Durie-Salmon staging system (DSS) in 1975 (4) .The DSS subdivides patients into three groups, according to the values of hemoglobin, serum calcium, creatinine, levels of paraprotein, and extension of lytic bone lesions, and for more than 25 years it was the primary form of classification.In 2005, however, the International Staging System (ISS) was published, which also proposes three stages, but is based on laboratorial markers of disease activity: beta-2 microglobulin and albumin (4) .
The ISS is validated for various population groups, including the Brazilian population, and is considered the most modern and trustworthy form of staging when compared to DSS (6) .Currently, risk stratification is added to cytogenetic evaluation with the objective of detecting survival-modifying genetic markers, such as hypodiploidia, deletion of chromosome 13 or 17p13, and translocations (4,14), (4,16) (7) .
The advent of therapy with the so-called "new drugs" (thalidomide, lenalidomide, and bortezomib) and the high rates of response produced by regimes that incorporate them have revolutionized the treatment of myeloma, and have led to a reevaluation, in some cases, of the indication of autologous bone marrow transplantation (ABMT).
Currently, literature shows that the primary objective in the initial treatment of myeloma is to reach a complete response, regardless of the initial therapeutic regime chosen (4) .

OBJECTIVE
To present a descriptive analysis of patients diagnosed with MM followed at a hematology outpatient clinic with priority of data related to diagnosis, staging, and treatment, as well as a correlation with survival.

METHODS
An observational cohort study based on the analysis of records of data from 77 clinical files of patients with MM followed at the Ambulatório Universitário de Hematologia da Faculdade de Medicina do ABC (FMABC) from January 2006 to October 2010.
The medical files were retrieved at the Medical and Statistical Archives Service (SAME) of the Faculdade de Medicina do ABC and, in case of posterior hospitalization and death, from the SAME of the Hospital Estadual Mario Covas, a reference hospital.
Exclusion factors used were incomplete data, noncompliance with outpatient visits, and diagnosis of non-MM plasmatic cell dyscrasias (MGUS, solitary plasmocytoma, and plasma cell leukemia), as well as cases of smoldering mieloma.
Of the total number of patients, 14 were excluded as per the following criteria: 2 for MGUS, 3 for isolated plasmocytoma, 1 for plasma cell leukemia, 2 for smoldering myeloma, and 6 for incomplete data or no follow-up, resulting in 63 patients analyzed.
At the time of diagnosis, patients were assessed as to age, gender, associated comorbidities, clinical manifestations, and laboratory parameters (hemogram/CBC, creatinine, 24-hour proteinuria, total or ionizable calcium, serum or urine electrophoresis or immunoelectrophoresis, immunoglobulin dosing, albumin, beta-2 microglobulin or plasmocytes in bone marrow).Due to differences among laboratory methods for analyzing calcium, we chose to merely describe the presence or absence of hypercalcemia.The laboratory results obtained after the diagnosis were recorded as absent since they did not reflect the true condition of patients at diagnosis.
For staging, criteria established by DSS and by ISS were used.Bone lesions seen by imaging methods (long bone X-rays) were separated as per criteria also proposed by Durie-Salmon: (0) normal bone, (I) osteopenia, (II) osteolytic lesions, and (III) skeletal destruction (8) .
As to treatment, evaluation was made of the chemotherapy schemes employed, number of chemotherapy lines, referrals for transplants, and response obtained with induction chemotherapy and transplantation.
Refractory myelomas were considered those nonresponsive to two lines of chemotherapy, in which the second line was rescue therapy, or those who relapsed within less than 60 days.The response to chemotherapy was classified according to the criteria established by the International Myeloma Working Group (4) .However, due to unavailability of the immunofixation technique at the institution evaluated, there was a deficiency in the criteria applied for a complete answer.
Patient evolution was documented according to the date of the last follow-up visit, which included the data of the last outpatient visit or the time of death.In cases where the patient was lost to follow-up, the date considered was the last time in which the patient was evaluated at the institution.Data on deaths were retrieved by a search in the reference hospital hospitalization service (Hospital Estadual Mario Covas) or by reports from family members.
Statistical analysis was conducted by means of data coding and application of the Statistical Package for the Social Sciences (SPSS) program.Clinical, laboratorial, and therapeutic characteristics were analyzed descriptively.The independent variables (age, comorbidity, staging, treatment utilized, and lines of chemotherapy) were assessed with bivariate analysis using Pearson's χ2 test.Survival was observed by Kaplan-Meir's method.The level of confidence adopted was 95%.

Population characteristics
Diagnostic criteria for MM were satisfied in 63 cases followed at the Ambulatório Universitário de Hematologia da FMABC during the period of January 2006 to October 2010.
In this population, age varied from 34 to 85 yeas (median: 58.5 years), distributed as 44% (n = 28) of the female gender and 56% (n = 35) of the male gender (Table 1).hypothyroidism (n = 7); eight patients had an association between diabetes mellitus and systemic arterial hypertension and five between hypothyroidism and systemic arterial hypertension and/or diabetes mellitus.Among the other comorbidities, we point out HIV (n = 2), cardiovascular disease (n = 3), and thromboembolic events (n = 3).The antecedent of non-hematological neoplasm occurred in five cases; two of these were of the breast, two of the prostate, and one of the skin.
Anemia was observed in 87% of the cases.At diagnosis, mean hemoglobin values were 9.6 g/dL (4.2 to 14.6 g/dL) (Table 1), and were similar for female and male genders.
The mean value of creatinine levels was 1.6 g/dL (0.6 to 8.9 g/dL); of these, 19% had creatinine ≥ 2 mg/ dL (Table 1).Levels higher than 150 mg/day of protein in 24-hour urine specimens occurred in 80% of the 30 patients evaluable.On the other hand, hypercalcemia was evidenced in 38% of the 52 patients analyzed.
Albumin levels under 3.5 g/dL were noted in 41.8% of the valid population, with a mean value of 3/4 g/dL (1.3 to 4.7 g/dL).Beta-2 levels inferior to 3,500 mg/dL occurred in 30.4% and superior to 5,500 mg/dL were seen in 19.7%, with a mean of 5,419.6 mg/dL (1,851 to 20,000 mg/dL) (Table 1).
The presence of immunoglobulin peaks in serum protein electrophoresis occurred in 88% of the 51 cases evaluable; of these, 84.4% were in gamma, 9.8% in beta, and in 5.8% there was no separation.In urine protein electrophoresis, there was a peak in 29% of the 18 cases evaluable, with a predominance of the gamma fraction (75%).
Patients classified as non-secretors were 5.6% (n = 3); in these, there was evidence of anemia in one case, and there was no modification of renal function in any of these patients (Table 1).
The presence of more than 10% of plasmocytes in bone marrow was seen in 81.8% of the 44 evaluable patients, with a mean of 39.3% (0 a 92%).There was evidence of associated plasmocytoma in 31.7%(n = 20) of the total, and in two cases this fact preceded the diagnosis of myeloma.
The radiological study of the skeleton demonstrated 74% of osteolytic lesions (45/61), with predominance of advanced bone lesions (Table 1).
Staging of patients as per the criteria of Durie-Salmon and ISS is presented on Table 1.We point out that 78.7% of the patients had DSS III (n = 48), with In 62% of the patients, associated comorbidities were present.The most prevalent were systemic arterial hypertension (n = 22), diabetes mellitus (n = 12), and

Treatment
The treatment used in patients with diagnoses of myeloma is presented on table 2.
The total response rate to a second line was 53.1%.Among these patients, it was noted that half had received dexamethasone alone as fi rst-line treatment.
Two more treatments were necessary in 22 patients, in which 74.6% belonged to stage III and 82.3% satisfi ed criteria for refractoriness.
The use of bisphosphonate occurred in 62.3% of the population studied, and radiotherapy, in 15.8%.

Survival
With a clinical follow-up that varied from 1 to 145 months, the overall survival rate was 73%, and the survival median was not reached.In 60 months, the rate of survival was 74.6% (Figure 1).
There was no difference with statistical signifi cance between the rate of mortality and the presence of As fi rst line of therapy, the main treatments used were the association of thalidomide with dexamethasone (35.5%) and of melphalan and prednisone (29%).After induction treatment, 12 of the 62 patients treated (19.3%) were consolidated with ABMT.
The patients that used thalidomide and dexamethasone had a median age of 57 years (36 to 56 years) with a predominance of stage III as per Durie-Salmon (90.9%; n = 22).At the time of assessment, 36.3% (n = 8) were using the medication.Of the 14 patients that had completed treatment, 50% had obtained some form of response (partial and complete), 35.7% had clinical stability, and 14.3% had progressed.
The median age of the population under fi rst-line treatment with melphalan and prednisone was 69.5 years (41 to 85 years), also with a predominance of stage III (61%; n = 18).In this group of patients, the response rate was 38.9%; however, no patient satisfi ed the criteria for disease progression.
Overall, in evaluating the total population of patients evaluable for response, in 50 cases, a 42% response rate was attained among the various regimes.
A second line of induction was used in 34 patients, in which 55.8% used thalidomide alone or associated, and 23.5% used alchilating agents (melphalan and cyclophosphamide) (Table 2).In the population studied, there was a predominance of advanced stages of the disease according to Durie-Salmon criteria (78.7% stage III).In these, there were 100% of deaths, divided into 93.3% of stage IIIA and 6.7% of stage IIIB, with statistical signifi cance (p = 0.037).As to the other stages, 1.6% belonged to the stage I and 19.7%, to stage II (Figure 2).At the end of follow-up of the cases consolidated with transplantation, 72.3% were alive.This fact did not demonstrate statistical significance (p = 0.364), as well as the response obtained prior to the transplant (p = 0.083).
The use of bisphosphonates also did not interfere with survival (p = 0,567).

DISCUSSION
The median age found in follow-up of the 63 patients diagnosed with MM showed data slightly inferior to that reported in national literature, in which a study carried out by Hungria et al. with 16 Brazilian institutions demonstrated a median of 60.5 years (9) .On the other hand, the publication by Kyle et al., at the Mayo Clinic, reported a median age of 66 years (20 to 92 years), with a case distribution of 38% over 70 years of age, surpassing the findings in this study by 11% (10) .
As expected, according to the age bracket of myeloma incidence, most patients presented with associated comorbidities, such as hypertension and diabetes.Nevertheless, it was noted that 3.2% were seropositive for HIV.
Among the diagnostic data evaluated, most of the patients presented with anemia, which is known to be the most common hematological complication in MM (4) .Although the current findings have proved greater than those in literature, when compared to the data of Brazilian groups, it was noted that the percentage found was greater than the data found at the Federal University of Minas Gerais (UFMG), where 81.2% had hemoglobin levels lower than 12 mg/dL, although lower than those of the University of the South of Santa Catarina state (Unisul) -95.7% (11,12) .
There are various mechanisms that explain the drop in values of hemoglobin in myelomas, such as inadequate use of iron, deficiency of erythropoietin, hemolysis, and bone marrow infiltration, in which the latter may be associated or not with the other cytopenias (4) .In this study, 5% coursed with plateletopenia and 17% with leukopenia; these finding are concurrent with other similar publications (10,13) .
As was true with anemia, renal disease is secondary to lesion of the target-organ in myeloma, as was demonstrated in this study by the mean values of creatinine and with 19% of the cases with levels higher than 2 mg/dL (4) .
Despite a mean value of creatinine greater than that found by the Mayo Clinic (1.2 mg/dL), the percentage greater than 2 mg/dL was similar (10) .Nevertheless, this datum is not in agreement with the description given by Hungria et al. for the Brazilian population, according to which creatinine values higher than 2 g/dL occur with greater frequency (23%) (13) .
Additionally, Hungria et al. reported the presence of hypercalcemia in 23.8% of the patients assessed in his multicentric study, a figure that is inferior to those identified in our group and to those of Kyle et al. (28%) (10,13) .
Complementing the clinical evaluation, almost all patients presented with bone lesions, 74% with lytic lesions, and 61% of Grade III.Such findings are greater than and not similar to those of Kyle et al. (66% of lytic lesions) nor those of Hungria et al., in which the bone lesion values described are greater than those found in international medical literature (85.1%) (10,13) .
The M protein was detected in a large number of cases, demonstrating agreement with literature as to the predominance of MM producers of IgG (48.1%), but there was disagreement with Kyle et al. as to the producers of isolated light chains, described as 16%, a datum inferior to that of this study (10) .
As to staging, there was predominance of stage III by Durie-Salmon and II by the ISS criteria.
Our findings are relatively similar to the multicentric Brazilian study in which stage III of the Durie-Salmon system occurred in 76.5%, and ISS was distributed as follows: 20.1% in stage I, 48.7% in stage II, and 31.2% in stage III (13).
Medical literature defends the position that ISS is a more trustworthy prognostic method, since, besides reflecting the related survival, this staging system does not use data that cause biases in the related survival, such as hypercalcemia, which is considered an independent factor of poor prognosis (13)(14) .The ISS system, however, is validated for the Brazilian population (13) .
Analyzing the overall survival found in this study, we identified a rate of practically 75% in 60 months.These data compare favorably with those of literature, since, according to epidemiological data published by Brenner et al., relative survival in 5 years after the advent of the new drugs is 48.2%, and in 10 years, 28.6% (15) .
Among the reasons that can explain the correlations described, we find the smallest number of cases in which the ISS classification is known, since clinical staging can be retrieved 61 patients and the ISS in only 45, which reduces the statistical power to detect significant survival differences between more or less severe stages of the disease.
Despite the data described having traced the prognosis in MM, currently, literature has emphasized the importance of treatment in the evolution of symptomatic patients.This is because prior to the use of alchilating agents, survival was lower than 1 year, and it attained an accentuated increase with the advances that have occurred, especially transplantation and the "new drugs" (15) .Kumar et al. compared two groups of MM patients as to the moment when they relapsed, defined as before the year 2000 or after the year 2000, meaning, before or after the new drugs, noting that the second group had a mean survival of 23.9 months versus 11.8 months in the first group (16) .
In this paper, with the exception of one case that used bortezomib at the time of diagnosis, due to availability in the public healthcare services, the drug used, from the most modern group, was thalidomide, with the alchilating agents reserved for the group of patients not eligible for ABMT.Therefore, the median age of patients with thalidomide was 57 years, and with melphalan, it was 69.5 years.
Accordingly, the response rate to the schemes of melphalan/prednisone and thalidomide/ dexamethasone is in agreement with literature references, albeit at the lower limit.The first obtained with first-line treatment a rate of 38.9%, similar to that in literature that reports response rates that varied from 35 to 47%, and the second obtained a 50% response rate, similar to series in literature that report rates of 48.5 to 72% (4,17) .

CONCLUSION
The analysis of patients with a diagnosis of MM followed in the outpatient clinic of hematology identified staging of the cases, treatment, and rates of survival similar to those in medical literature, with the resources available at a public and university healthcare institution.

Figure 1 .
Figure 1.Survival curve in 60 months of patients diagnosed with multiple myeloma followed up at the University Hematology Outpatients' Clinic -Faculdade de Medicina do ABC.

Table 1 .
Demographic and laboratory characteristics of patients diagnosed with multiple myeloma followed-up at the University Hematology Outpatients' Clinic -Faculdade de Medicina do ABC

Table 2 .
Chemotherapeutical regimens used as fi rst and second line treatment of multiple myeloma patients followed up at the University Hematology Outpatients' Clinic -Faculdade de Medicina do ABC VAD -vincristine, adriamycin and dexamethasone