Multiple myeloma (MM) is a malignant tumor of plasma cells. Myeloma cells proliferate clonally in the bone marrow, causing osteolytic bone destruction, and myeloma cells secrete monoclonal immunoglobulins, and free light chains are excreted in the urine. Bone disease, hypercalcemia, renal insufficiency, anemia and susceptibility to infection are the most common and major complications of myeloma. This article focuses on the latest pathophysiological and therapeutic advances in the most common complications of myeloma.
I. Bone disease
1. Osteolytic bone lesions
Bone damage is due to suppressed osteoblast function and enhanced osteoclast function, enhanced bone resorption, and inhibited bone reconstruction, resulting in increased bone loss, diffuse osteoporosis and osteolytic lesions. IL-6, IL-1β, vascular endothelial growth factor, macrophage inflammatory protein-1α, osteoprotegerin, ReceptoractivatorofNFκB (RANK) and its ligand (RANKL) are all involved in myeloma. DKK-1, IL-3 and IL-7 inhibit osteoblast activity in MM patients, and osteocalcin and bone-specific alkaline phosphatase, which reflect osteogenesis, are not elevated, and there is no bone regeneration at or near the site of bone damage. Bone disease is an important manifestation feature of multiple myeloma, and skeletal-related complications including bone pain, osteolytic lesions, hypercalcemia, pathological fractures and spinal cord compression occur in 80%-90% of myeloma patients.
2.Biphosphonates inhibit osteolysis
Bisphosphonates can effectively inhibit bone resorption, and nitrogen does not affect bone tissue calcification. Clodronate, pamidronate disodium and zoledronic acid are able to delay and reduce bone damage in myeloma, reduce bone pain and improve daily activity and quality of life. Intravenous pamidronate disodium, zoledronic acid, or oral clodronate are the most commonly used treatment options. Bisphosphonates are safe and well tolerated, but severe renal damage and osteonecrosis of the jaw are rare. To reduce bisphosphonate-associated osteonecrosis of the jaw, intravenous bisphosphonates should be limited to once monthly for 1-2 years; if myeloma and symptomatic bone damage cannot be effectively controlled, long-term bisphosphonate use should be individualized for MM patients only if the benefits outweigh the risks. Before treatment with bisphosphonates, patients should undergo a comprehensive dental examination and necessary treatment; during the use of bisphosphonates, invasive dental treatment should be avoided and bisphosphonates should be discontinued if necessary. After the occurrence of osteonecrosis of the jaw, bisphosphonate therapy should be discontinued and the risks and benefits should be carefully evaluated if continued use is needed. After effective treatment about 2/3 of patients with bisphosphonate-related osteonecrosis of the mandible defective mucosa can be healed.
3.Treatment of hypercalcemia
Hypercalcemia occurs in about 15% of patients with myeloma, mainly due to increased bone loss and impaired renal function. Bisphosphonates are ideal for the treatment of hypercalcemia in myeloma, but their maximum effect of lowering blood calcium takes more than two days. Therefore, severe and symptomatic hypercalcemia requires other therapeutic measures, including intravenous saline, tab diuretics and high-dose steroid applications, also in combination with calcitriol. Rapid antimyeloma therapy is also an important measure in the treatment of hypercalcemia.
4. Treatment of bone pain and vertebral fractures
Pain is induced by osteolytic bone injury, pathological fracture or plasmacytoma compression in 60-80% of myeloma patients. Non-steroidal anti-inflammatory drugs (NSAIDs) such as paracetamol should not be used for the treatment of bone pain. Mild or strong opioid-like drugs should be used for effective pain control in myeloma patients. Bone injuries that lack response to analgesia can be treated with local radiotherapy; however, radiation therapy does not increase bone strength and produces permanent bone marrow damage in the area of radiation. Percutaneous vertebroplasty provides immediate pain relief and increases cone strength, but does not restore cone height, a procedure that is often prone to cement extravasation. Balloon kyphoplasty can be a safe alternative to percutaneous vertebroplasty, reducing the risk of cement extravasation and restoring the height of the collapsed cone.
5.New method of bone disease treatment
RANKL binds to RNAK on osteoclasts to promote osteoclast differentiation, maturation and enhance its activity, which is a key factor regulating osteoclast bone resorption and a potential therapeutic target. Denosumab, a fully human monoclonal antibody to RANKL, is a new drug expected to treat myeloma bone disease. Bortezomib, thalidomide and lenalidomide inhibit osteoclastogenesis by partially reducing RANKL production, and in addition, bortezomib regulates bone metabolism by stimulating osteoblasts. Bortezomib treatment resulted in an increase in bone alkaline phosphatase and a rapid decrease in the expression of the Wnt pathway inhibitor DKK-1. In the large sample phase III VISTA clinical trial, bone damage was less severe and progressed more slowly in the MP combined with bortezomib (V) group compared to the marfalan and prednisone (MP) group, with less need for subsequent radiation therapy and bisphosphonate therapy, and, only in the VMP group did bone healing with radiographic evidence unrelated to disease response occur.
II. Renal disease
1. Renal function impairment
Due to the abnormal proliferation of plasma cells, excessive free light chains are produced, which are filtered by the glomerulus, reabsorbed in the proximal tubule and concentrated in the distal tubule, and can coalesce in the tubule after reaching a certain concentration, forming a tubular pattern and blocking the tubule. In addition, light chains can be toxic after reabsorption in the proximal tubule and degradation in the lysosome, causing renal tubular damage. Most patients with multiple myeloma have hypercalcemia, and calcium deposition in the renal interstitium and tubules can aggravate light chain-induced renal tubular lesions. Renal insufficiency is further worsened in the presence of dehydration, hyperviscosemia and nephrotoxic drug use. Renal failure is an important complication of myeloma and is associated with increased early morbidity and mortality, requiring timely and appropriate interventional treatment.
2.Supportive treatment
Correction and removal of any predisposing factors that aggravate the progression of multiple myeloma nephropathy is the first principle of treatment. Supportive treatment of the kidney includes adequate hydration, management of hypercalcemia, and avoidance of nephrotoxic drugs such as NSAIDs, aminoglycosides, and intravenous contrast agents. Renal insufficiency also requires limiting the dose of bisphosphonates. The more severe the renal injury and the longer it lasts, the lower the chances of complete recovery of renal function.
3.Anti-myeloma treatment
In addition to supportive therapy, timely and efficient anti-myeloma treatment is also the key to correct renal insufficiency. Combination therapy based on thalidomide, lenalidomide and bortezomib has replaced traditional chemotherapy. Thalidomide is not metabolized by the kidney and does not require dose reduction, but lenalidomide is metabolized by the kidney and requires dose reduction based on creatinine clearance to avoid hematologic toxicity. Bortezomib is metabolized independently of creatinine clearance and has no renal toxicity. Bortezomib not only rapidly reduces toxic monoclonal light chains, but also reduces NF-κB-mediated renal tubular inflammation. Therefore, bortezomib-based therapeutic measures are the optimal treatment option for myeloma renal failure.
4.Plasma replacement
To reduce the concentration of light chains in plasma and decrease their toxicity to the kidney, plasma replacement can be used to remove the free light chains. However, there are no prospective randomized trial studies on plasma exchange. Recently, specialized hemodialysis membranes that remove circulating light chains have become available, and prospective randomized trials are underway to evaluate whether such membranes can be combined with bortezomib-based regimens to help restore kidney function.
III. Infections
Infections are likely to occur due to increased secretion of abnormal globulins that lack immune activity and decreased normal immunoglobulins. Such as infections of the respiratory and urinary tracts, sepsis, herpes zoster, etc. In the late stage of the disease, infection is the main cause of death. Patients with combined neutrophil deficiency can be treated with a combination of G-CSF. Fluoroquinolone antibiotics can be used briefly to prevent infection, and bensulfiram tablets are used to prevent pneumocystis in high-risk patients. For patients with low polyclonal IgG concentrations, recurrent or severe infections, monthly intravenous immunoglobulin can be used to prevent infection. Herpes zoster virus activation is a common complication of bortezomib-based therapy for myeloma and can be prevented with antiviral measures.
IV. Anemia
The incidence of anemia is 20%-60% in the first diagnosis, and almost all patients eventually develop anemia as the disease progresses. anemia due to MM is usually also an orthocytic orthochromic anemia, which is mainly caused by massive encroachment of myeloma cells into the bone marrow cavity, suppressed erythropoiesis, impaired renal function, chemotherapy-induced myelosuppression, and concomitant autoimmune hemolysis and hemorrhage. Erythropoiesis-stimulating agents (EPO) can increase hemoglobin concentration and reduce the need for blood transfusions to improve quality of life. EPO can be used when the hemoglobin concentration is below 10-11 g/dl, and iron supplementation is required for patients with iron deficiency. EPO in combination with lenalidomide immunomodulators increases the risk of venous thrombosis, so thromboprophylaxis should be performed when the two are used together.
V. Peripheral neuropathy
The main mechanisms of peripheral neuropathy in multiple myeloma include mechanical compression of nerves or nerve roots by bone injury, pathological fractures, soft tissue plasmacytoma, immune mechanisms, amyloid deposition and anti-myeloma therapy. More than 20% of new multiple myeloma has mild motor-sensory axonal neuropathy. Application of neurophysiological methods including skin biopsy to detect large and small intradermal nerve fibers reveals that the incidence of peripheral neuropathy can be as high as 54%.
VI. Rare complications
1.Plasmacytoma
Plasmacytomas are soft tissue plasma cell tumors that may be solitary or multiple, with or without the presence of monoclonal plasma cells in the bone marrow. Solitary plasmacytomas originate within the bone tissue, preferably in the mesial bone, or appear in extraosseous sites, mainly in the head or neck. M protein is found in serum or urine in 25-70% of patients with solitary plasmacytoma, with very low extramedullary manifestations, but free light chains can be detected to improve detection. Local radiation therapy provides better control of solitary plasmacytomas, requiring doses of about 40 Gy for tumors up to 5 cm, while systemic radiation therapy is required for larger, recurrent or additionally damaged tumors. Patients treated with high doses of pretreatment or highly aggressive are prone to progress to extramedullary plasmacytoma.
2.Plasma cell leukemia
Plasma cell leukemia is characterized by a marked increase in plasma cells in the peripheral blood and bone marrow. Most plasma cell leukemia is one of the end-stage manifestations of multiple myeloma and is characterized by a peripheral blood plasma cell count greater than 2×109/L or circulating plasma cells greater than 20%. Primary plasma cell leukemia accounts for 2-4% of patients with multiple myeloma, but secondary plasma cell leukemia is more common and is the end stage of relapsed or refractory multiple myeloma. Combination therapy containing new drugs is needed for multiple extramedullary plasmacytoma and plasma cell leukemia, and allogeneic bone marrow transplantation is performed for patients with suitable conditions.
3. Hyperviscosity syndrome
Hyperviscosity syndrome refers to a series of clinical symptoms specific to the increase in hemodynamic resistance caused by a significant increase in blood viscosity, including visual impairment due to venous extension, restrictive stenosis, hemorrhage and exudation in the fundus, dizziness, blurred vision, deafness, numbness in the hands and feet, and impaired consciousness. The incidence of hyperviscosity syndrome is about 2-6% in patients with multiple myeloma, but occurs in 10-20% of patients with Waldenstrom’s macroglobulinemia. Plasma exchange combined with antimyeloma therapy is the optimal treatment for hyperviscosity syndrome. IgM-type myeloma is very rare, but its high incidence of hyperviscosity and peripheral neuropathy limits the use of neurotoxic drugs such as thalidomide and bortezomib.
4. AL-type amyloidosis
Amyloid is a fibrin-like substance that can be deposited in different tissues and can be detected by Congo red staining. The average age of diagnosis of systemic AL amyloidosis is 65 years, and the clinical presentation varies greatly depending on the main organ involved. Patients with myeloma-associated AL amyloidosis have a worse prognosis. Marfan and prednisone have been the main therapeutic agents, but the results have been unsatisfactory. Stem cell transplantation has been beneficial in such patients, but this treatment is not indicated in patients with extensive cardiac or multi-organ involvement. New drugs have now been shown to have good efficacy in myeloma and primary AL amyloidosis, which raises hope for the treatment of myeloma-associated AL amyloidosis.
In conclusion, anti-myeloma therapy alone is often not enough, and supportive therapy has an important role in the treatment of myeloma. Optimized supportive care can reduce the occurrence of myeloma-related complications, improve the quality of patient survival, and create conditions for anti-myeloma therapy.