The incidence of extramedullary (EM) infiltration in MM is approximately 13% [6], including primary EM disease that is present at the time of initial diagnosis and secondary EM disease that occurs after the progression of MM. A previous study found that the pleura, liver, lungs, breasts, pancreas, lymph nodes, soft tissue, skin, central nervous system, and urogenital system could be involved in EM infiltration. Although the organs or tissues involved in primary and secondary EM disease are different, the results are significant reductions in overall survival (OS) and progression-free survival (PFS). MPE is a very rare complication that occurs when myeloma cells infiltrate the pleura.
In this study, there were 272 (55.5%) and 45 (9.2%) MM patients with PE and MPE, respectively, which were significantly higher than the 6% and 1% reported by previous studies [7, 8]; however, previous results were from single-center studies. Considering that there may be selection bias in different centers, the exact incidence of MM combined with PE or MPE needs to be validated in larger multicenter clinical studies.
In addition, proteasome inhibitors such as carfilzomib and bortezomib are widely used in patients with repetitive/refractory MM, which can lead to adverse reactions, including lung injury, pulmonary hypertension, and respiratory failure. Although adverse events rarely occur, it is still worth noting that the use of such drugs may cause lung injury, which may exacerbate the occurrence of MPE [9–11]. Therefore, the timely and accurate diagnosis of MPE is essential for the adjustment and selection of treatment options. For patients with MM suspected of having MPE, imaging can be used as a preliminary screening method, but PE also needs to be collected for biochemical, cell morphology, and immunological phenotype examinations and immunohistochemical staining of pleural biopsy to support the differential diagnosis.
In our study, patients with PE had lower levels of total protein and albumin than those without PE. Through multiple regression analysis, we found that decreased serum albumin and total protein levels were both risk factors for PE. The main reason might be that the consumption of nutrients by the tumor can lead to anemia, decreased BMI, and hypoproteinemia. Hypoproteinemia is associated with a decrease in the plasma osmotic pressure, which can easily cause the leakage of PE [12]. Furthermore, the production of PE is also related to congestive heart failure, renal insufficiency, and pulmonary embolism secondary to MM.
The complement system is an important immunoregulatory factor and can be activated through the classic, alternative, or lectin pathway. Some previous studies have found that hypocomplementemia is related to MM, and it has been speculated that the complement system is activated through the classic and alternative pathways in the early stages of MM [13, 14]. In this study, we found that MM patients with PE were associated with low complement C3 levels, but the relationship with C4 levels was not statistically significant (P > 0.05); this indicated that the formation of PE in MM patients was caused by the activation of the complement bypass pathway. However, further verification is needed.
The presence of MPE indicates a rapid progression of MM and a poor prognosis. The serum LDH level is one of the indicators reflecting the tumor burden. Some previous studies [15, 16] have found that the level of serum LDH was positively correlated with MPE, and its specificity and sensitivity in distinguishing between benign and malignant PE were high. This study showed that the level of LDH in MPE patients was significantly higher than that in non-MPE patients.
Many studies have shown that the level of ADA in MPE patients was lower than that in non-MPE patients; in contrast, this study showed that the level of ADA in MPE patients was significantly higher than that in non-MPE patients (P < 0.05). Moreover, some case reports on MM [14, 15, 17] indicated that the level of ADA in MPE patients may be higher than that in non-MPE patients, which is consistent with the results of our study. Thus, the association of the level of ADA with MPE is still controversial. The cause of increased ADA levels in MPE patients may be related to the expression of ADA in a small number of myeloma cells, as well as the activation of inflammatory and T lymphocyte cells [15]. However, the elevated MPE levels in many studies were not caused by MM but by other diseases, primarily tuberculosis.
When the tumor metastasizes to the pleura, the integrity of the walls of the pleural blood vessels is impaired, resulting in high blood vessel permeability and a consequent increase in the concentration of tissue fluid. Therefore, our study showed that the level of total protein in MPE was significantly higher than that in non-MPE, which in turn promoted the formation of MPE. The results of multiple regression analysis showed that a high nuclear cell count, total protein level, and ADA level and a low LDH level in PE were independent risk factors for MPE.
Unfortunately, there is very little research on the correlation between MM and MPE. Yuping Zhong [16] and Young-Uk Cho et al. [14] performed a correlation analysis on MM patients with PE, but the sample size of MPE patients was very small, even fewer than our 45 patients, and other studies only reported individual patients. In total, these studies lack detailed information on indicators related to MPE and were unable to analyze the mechanisms underlying the development of MPE in MM patients (Table 5)
The treatment of MM has made significant progress in recent years, and a variety of treatment options, such as proteasome inhibitors, immunomodulators, and hematopoietic stem cell transplantation, have greatly improved the prognosis of MM. The prognosis of patients with extramedullary (EM) disease is still poor. Rosiñol L et al [24] found that thalidomide was effective in patients with advanced MM but not in patients with EM disease. Monoclonal antibody and chimeric antigen receptor T cell therapy might improve the prognosis [25]; however, large sample size studies with long-term follow-up are still needed to confirm the effectiveness of these therapies.
There are some limitations of this study. First, this study was a retrospective study with potential publication bias; thus, the results need to be confirmed by large-scale clinical studies. Second, the clonal evolution and heterogeneity of plasma cells are closely associated with the progression, recurrence and drug resistance of MM. The occurrence of MPE often indicates the end stage of MM. In the future, in-depth studies on the immune function, cytogenetics and molecular biology of MPE patients will be needed to elucidate the pathogenesis.