Multiple myeloma in Latin America

ABSTRACT Introduction Multiple myeloma in Latin America (LATAM) face multiple challenges related to the lack of resources according to low- and middle-income in the region. Areas covered in this narrative review, several aspects of myeloma multiple epidemiology, diagnostic methods and risk stratification, medication commonly employed, and treatment results in LATAM are discussed. Conclusion Patients usually are diagnosed in an advanced stage of the disease, and routine and risk evaluations are usually not ideal due to lack of access to different studies. Treatment is limited in many cases to the use of thalidomide and dexamethasone with and without cyclophosphamide. Access to autologous stem cell transplantation is far from ideal. Efforts must be made at the national health system level in our countries to offer our vast majority of MM patients a real chance to improve results in the diagnostic, risk stratification, and treatment. Currently, several groups in our region are working to make an impact in the field of MM.


Introduction
Multiple myeloma (MM) is a disease with many faces. Usually, the diagnosis is based on clinical and laboratory manifestations including bone pain, weakness, hypercalcemia, renal damage, anemia, and bone osteolytic lesions (CRAB). The presence of more than 10% of neoplastic plasma cells in the bone marrow and the abnormal secretion of cytokines and clonal gamma globulin explain the clinical presentation. However, is not uncommon to observe patients without signs or symptoms, but with laboratory or radiologic abnormalities, with any or more of the following biomarkers of malignancy: clonal bone marrow plasma cell percentage ≥ 60%, involved/uninvolved serum-free light chain ratio ≥ 100, and > 1 focal lesions in MRI studies, that suggest the diagnosis [1].
The MM incidence in the world has risen by more than 126% in recent years. In the USA, more than 34,000 new cases are diagnosed each year, and more than 588,000 people worldwide [1]. Currently, there is information regarding the incidence of MM in South America, where the rate was 1.7 cases and its mortality 1.3/100,000. It is important to note that access to sophisticated healthcare in low-and middle-income countries (LMIC) is far from ideal, therefore, population data is not always complete. In this narrative review, several aspects of epidemiology, diagnostic methods, medications commonly employed, and treatment results in Latin America (LATAM) are discussed [1][2][3][4][5].
Latin American MM demographics LATAM includes many countries (17) and more than 600 million inhabitants in America. Information in this setting might not be accurate, but efforts to obtain demographic information on the MM incidence have been made. The Hemato-Oncology Latin America (HOLA) study was designated to describe several characteristics of hematologic malignancies in this region, including MM. The study was not perfect, it was multicenter, retrospective, and data was obtained from the medical chart review of patients with MM, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. From 2006 to 2015, 5,140 patients were included from 6 countries, and 1,518 had MM. As expected, most patients were between 50-70 years old, and median age at diagnosis was 61 years (range 23-91 years), males accounted for 50.7% [2].
The majority of MM patients had one or two comorbidities (53%); hypertension most frequently observed followed by diabetes mellitus. It is important to note that 35% had renal failure and this clinical condition was very similar in all the countries involved in the study [2].
In another study from Mexico, male predominance and median age of 60 years were similar to the HOLA study [3]. Remarkably, almost identical data has been informed from other LATAM countries [3,5].

MM diagnosis and risk evaluation
The diagnosis of MM requires several studies. Besides the clinical history, physical exam, and routine tests, the NCCN guideline includes beta-2 microglobulin, serum quantitative immunoglobulins, serum protein electrophoresis, serum immunofixation electrophoresis, 24-h urine study for total protein, urine protein electrophoresis, urine immunofixation electrophoresis, serum-free light chain assay, plasma cell FISH, unilateral bone marrow aspirate and biopsy, including immunohistochemistry and/or multi-parameter flow cytometry and bone marrow panel cytogenetics [del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14:20), 1q21 gain/amplification, 1p deletion] [6]. Furthermore, the search for bone lesions must be made and currently, the whole-body CT scan or FDG PET-CT are considered ideal. However, access to these kinds of studies is limited and their cost precludes the routine practice of the 'complete' MM evaluation in LATAM [4] where in public hospitals > 20% of physicians report having no access to serum protein electrophoresis, less than 60% have access to urinary electrophoresis, and 60% have no access to serum-free light chains [4].
In relation to prognostic factors, it is reasonable to accept that MM is a hematological malignancy with many variables to consider, including the clinical status of the patients and those related to plasmatic clonal cells. Initially, the combination of serum albumin concentration with the level of serum B2 microglobulin was proposed in the International Staging System (ISS) as a useful predictor of response [7]. This classification is easy to obtain, has low cost, and therefore is practical in LATAM, however, other factors related to tumor biology, such as cytogenetics and additional sophisticated markers are not included. Until now, we lack precise information in this setting. Efforts to improve this initial risk evaluation were made and the revised ISS (R-ISS) included serum B2 microglobulin, serum albumin, chromosomal abnormalities by FISH, and LDH concentration (Table 1) [8]. However, it is important to note that only a few patients in LATAM had access to R-ISS evaluation; in a recent study from Uruguay, only 22.89% of patients had this evaluation [9].
In this region of the world, MM patients are usually diagnosed in advanced phases, in the HOLA study, more than 50% of patients were in advanced phase (ISS II or III) of the disease, 15.4% were in ISS I, but more than 30% of patients included had incomplete or no information [2]. Furthermore, as mentioned before, sophisticated risk evaluation is far from complete, as an example, only around 20% of 1,103 LATAM patients in the HOLA study have the R-ISS evaluation at diagnosis [2].

Treatment
A shift in the treatment of MM has allowed an unprecedented improvement in the short-and long-term outcomes for these patients. Chemotherapy plus dexamethasone had limited impact on the disease, but the appearance of new drugs like IMiDs or proteasome inhibitors greatly improved the outlook for MM patients. Thalidomide was the first drug that showed efficacy and was already available in several LATAM countries, such as Mexico and Brazil, fortunately, its cost was low and, therefore, affordable in this region. Combinations of this drug with dexamethasone or with dexamethasone and alkylating agents were included in MM therapy. Unfortunately, in many Latin American countries, access to other novel and better therapies (e.g. lenalidomide), and proteasome inhibitors (e.g. bortezomib) is limited due to their high cost, local reimbursement policies, and reduced access to clinical trials (Table 2) [3,4] Even the autologous stem cell transplantation (ASCT), a very effective treatment for MM,  which is not so costly, compared to the cost of novel therapies, is unavailable or of limited access in many LATAM countries. In a retrospective cohort including 1,103 Latin American MM patients, 33.9% underwent ASCT, and the first-line treatment regimen was primarily thalidomide-based (54.9%) or bortezomib-based (29.1%), with thalidomide-based therapy and chemotherapy as first-line treatment declining significantly over the study period, particularly among ASCT patients and at private clinics. In contrast, the use of bortezomibbased therapy, bortezomib plus thalidomide, and newer agents, such as lenalidomide, was higher in more recent years [2]. Countries like Argentina and Colombia, where most patients in the sample were treated at private clinics, were characterized by high rates of ASCT and bortezomib utilization in the first-line setting, relative to Brazil and Mexico, where most patients were treated at public hospitals [3,4]. As previously stated, the possibility of adding novel drugs in our region is limited due to economic restrictions and, in addition, patients not promptly identified lead to delayed treatment. Moreover, it has been shown that patients treated with triplet combinations, such as bortezomib, thalidomide, and dexamethasone (VTD) or bortezomib, lenalidomide, and dexamethasone (VRD) obtain better results, including very good partial response and complete response. One study from Mexico, followed by another from LATAM, confirm this observation and as expected, event-free survival and overall survival were much better with these approaches [3,10]; however, it is important to note that access to treatment triplets was by far more frequent in patients treated in private practice since resources access usually give the patient the opportunity to be treated with almost any therapeutic option [3,4,10]. In a study from Mexico, patients in private health system demonstrated better response rates and survival; 65% of patients treated in private versus 41% treated at public hospitals achieved a very good partial response or better. The median progression-free survival and median overall survival were 23 and 51 months, respectively, for patients treated at public and 41 and 79 months, respectively for those treated in private [3]. Another study from Argentina [10] comparing VTD versus cyclophosphamide, bortezomib plus dexamethasone conclude that VTD combination remains as the preferred induction regimen based on better complete response and also very good partial response, in this setting, it is important to note that the use of VRD in LATAM is limited by cost issues. Furthermore, the authors confirmed that ASCT plays a critical role in improving the prognosis of patients with MM, particularly in countries where access to drugs is limited. In this setting, when compared to African-Americans or Caucasians, Hispanic patients with MM who had up-to-date treatment, including transplant, seem to have a better prognosis [10,11].
In conclusion, results of MM diagnosis, risk stratification, and treatment for patients living in the LATAM region have improved in the recent past, particularly for those patients who have access to contemporary agents. Comparisons of 3-drug combinations against 'older' options have confirmed the advantages of those triplets and the use of antibodies, such as daratumumab in our region [11][12][13][14]. Practical recommendations have been made to improve the care of MM in LATAM [13], including better access to drugs, and ASCT. However, great efforts at the national health system level are urgently required in our countries to offer to our vast majority of MM patients a real chance to improve their lives.

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Funding
The author(s) reported there is no funding associated with the work featured in this article.