EHA 2025 | The role of therapeutic plasma exchange in managing plasma cell disorders

So, here I’ll start with a few words explaining what therapeutic plasma exchange, or TPE, as we call it, is. So, basically, it’s a technique where a patient’s plasma containing pathogenic substances is separated and removed from the whole body, while the cellular component is returned to the patient via an apheresis machine. So, because of its ability to remove the pathogenic substances from the plasma, including immunoglobulins, TPE has proven efficacious in the management of plasma cell disorders, which are characterized by the abundant secretion of non-functional immunoglobulins. So, currently, there are three indications of therapeutic plasma exchange in plasma cell disorders. 

So, the first one, of course, is cast nephropathy in the setting of multiple myeloma. Cast nephropathy is the most common etiology of kidney failure in patients with multiple myeloma and has a significant impact on patient outcomes. So, in cast nephropathy, the pathogenic serum-free light chains can result in obstruction of the kidney tubules along with inflammation and atrophy. Therefore, a swift and efficient reduction of serum-free light chains is very, very important to mitigate permanent kidney damage and improve patient survival in this setting. 

So, current treatment guidelines and expert opinions recommend the rapid initiation of systemic plasma cell-directed therapy and consideration of TPE with the goal of a quick reduction in the circulating serum-free light chain. So, the International Myeloma Working Group and the American Society of Apheresis do recommend TPE as adjunctive therapy along with plasma cell-directed therapy. So, our current approach for patients with newly diagnosed multiple myeloma and cast nephropathy with free light chain above 1500 is to start plasma cell-directed therapy and daily TPE. For patients that have relapsed/refractory multiple myeloma and cast nephropathy, I would say TPE is considered on a case-by-case basis. We certainly need better prospective studies to evaluate TPE and cast nephropathy, especially in the contemporary era of frontline daratumumab use that has also shown to decrease pretty quickly the free light chains. 

So, the second indication for TPE in plasma cell disorders is the presence of hyperviscosity syndrome, which is most commonly seen in Waldenström’s macroglobulinemia. So, this is a complication due to the elevated monoclonal immunoglobulins, most commonly IgM type. So, symptoms of hyperviscosity syndrome are pretty variable and they can range from vision impairment, dizziness, headaches, mucosal bleeding, or more important ones such as seizures and respiratory failure. So, because hyperviscosity syndrome can be potentially life-threatening, prompt treatment is critical. 

So, when hyperviscosity syndrome is suspected, which is usually most of the times a clinical diagnosis, TPE should be immediately started for paraprotein removal along with systemic therapy targeted at the underlying malignant clone. So, duration of treatment is directed basically by symptoms and daily or every other day TPE is recommended usually until symptom improvement. Most commonly, one to three sessions of TPE are sufficient. For patients with Waldenström’s macroglobulinemia and IgM levels above 4,000, prophylactic TPE should be performed prior to receiving rituximab even in the absence of hyperviscosity syndrome symptoms because rituximab can cause a transient IgM increase or IgM flare, as we call it, causing emergence or deterioration of existing symptoms. In these cases, a single prophylactic TPE session is most often adequate before systemic rituximab initiation. 

So, the third indication where TPE is recommended in plasma cell disorders is type 1 cryoglobulinemia. So, cryoglobulinemia is a systemic disorder that is characterized by the presence of cryoglobulins, which are basically immunoglobulins that precipitate at cold temperatures. So, cryoglobulins are classified into three categories, depending on the type of cryoglobulin and the underlying process driving its production. So, type 1 cryoglobulinemia is usually symptomatic and typically treated by hematologists and it’s driven by monoclonal immunoglobulins – most commonly, it’s an IgG or an IgM immunoglobulin that is produced by an underlying plasma cell clone or a B-cell clone. And this clone is most, in most cases benign and rarely could be also malignant. So, in type 1 cryoglobulinemia, the clinical manifestations are related to the aggregation of cryoglobulins in small blood vessels leading to obstruction and end-organ damage, and that typically occurs in cold temperatures. So, the skin is the most frequently involved organ. Peripheral neuropathy is also common. Raynaud’s phenomenon and arthralgias can also happen. Kidneys are very uncommonly involved. The gastrointestinal and respiratory tracts and central nervous system are typically spared in type 1 cryoglobulinemia. 

So, the treatment of type 1 cryoglobulinemia includes clone-specific systemic therapy. TPE is effective at reducing the circulating cryoglobulin burden and potentially improving symptoms. Thus, we can use that when urgent removal of cryoglobulin is required, and I would say that’s usually in cases that are severe, such as cases where we have severe renal involvement, skin ulcerating disease, or debilitating neuropathy. So, TPE has a category 2 indication for the treatment of severe cryoglobulinemia according to the ASFA guidelines. And they basically recommend TPE as second-line treatment. And it can be used either as monotherapy or in conjunction with systemic therapies. 

In addition, TPE could be helpful as a sole therapy in more frail patients who might not be able to tolerate chemotherapy or patients who have become refractory to clone-directed therapies. The frequency of TPE is usually according to each individual patient’s needs. Sometimes we can consider maintenance therapy with TPE for some patients to prevent symptom recurrence, especially those with advanced renal or neurological involvement.

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