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A 59-year-old woman presented with three months of fatigue and severe joint pain involving the elbows, wrists, knees, and ankles, as well as anemia. She underwent a total of four diagnostic arthrocenteses, though the specific underlying cause of joint pain remained unknown.
A bone marrow biopsy was performed as part of the evaluation of her anemia, and demonstrated normal cellularity, but with 20-30% of cellularity comprised of an infiltrate of dysplastic, nucleolated, and multinucleate plasma cells, many of which exhibited intranuclear inclusions, or Dutcher bodies (Figure 1). The malignant cells expressed CD138 and were monotypic for lambda light chain. There was no evidence of myeloid or erythroid dysplasia. Serum protein electrophoresis and immunofixation identified an IgG lambda monoclonal protein. These findings confirmed a diagnosis of IgG lambda multiple myeloma.
Skeletal imaging with both plain x-rays and magnetic resonance imaging showed no distinctive myeloma-related bone abnormalities, such as lytic lesions or compression fractures of the spine, to explain the reported musculoskeletal symptoms. However, the diagnosis of multiple myeloma raised the possibility of secondary light chain (or AL) amyloidosis involving the joints, and indeed a subsequent fat pad biopsy confirmed the diagnosis of amyloidosis based on Congo Red staining showing characteristic apple-green birefringence (Figure 2).
The patient was treated with a chemotherapy regimen that included the immunomodulatory agent lenalidomide and the proteasome inhibitor bortezomib. Treatment with these agents continued over approximately 10 months, during which time the patient experienced resolution of joint symptoms and normalization of blood counts. She thereafter converted to treatment with lenalidomide only, which is taken at home as a pill once daily. She has monthly check-ups with her team at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) and continues to do well more than two years after she began treatment for her condition.
Combination chemotherapy for multiple myeloma incorporating an immunomodulatory drug and proteasome inhibitor was originally modeled in pre-clinical laboratory studies at Dana-Farber, and subsequent clinical trials led by the team in the DF/BWCC Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics confirmed the effectiveness of this therapeutic approach.
"There are now several effective therapeutic options for patients with multiple myeloma, with combination therapy providing the best platform for high-quality and durable responses due to the synergy of immunomodulatory agents and proteasome inhibitors," says Paul Richardson, MD, clinical director of the Jerome Lipper Multiple Myeloma Center. "The combination of lenalidomide and bortezomib has been shown to be particularly effective, as reflected in multiple investigative trials in which responses were excellent and tolerability was very favorable."
The presence of light chain amyloidosis as a complication of the patient's multiple myeloma was an important aspect of her presentation, and likely the explanation for the atypical joint symptoms. Robert Schlossman, MD, medical oncologist and clinical investigator in the Jerome Lipper Multiple Myeloma Center, explains, "Amyloidosis is a systemic disease in which abnormal proteins cause damage when they deposit in various parts of the body. Amyloidosis can occur as a consequence of an inherited abnormal protein or an acquired disorder leading to the production of an abnormal light chain, as seen in multiple myeloma." Describing the effects of amyloidosis, Dr. Schlossman adds, "Progressive amyloid formation can lead to damage of the heart, kidneys, GI tract, and nerves. Deposition of amyloid in the joints can cause progressive arthritis symptoms in shoulders, knees, wrists, and hands, as well as development of nodules."
Jacob Laubach, MD, MPP, the patient's DFCI/BWCC oncologist, reports that her joint symptoms were somewhat atypical for multiple myeloma and raised the prospect of secondary AL amyloidosis as a concurrent diagnosis. "When we initially met, the patient was severely debilitated with profound fatigue and multifocal joint pain," he says. "She had been hospitalized and undergone repeated testing of synovial fluid, but the underlying cause of joint pain hadn't been identified.
"An astute member of our fellowship training program, Amy Sievers, MD, presented the patient's case in clinic and questioned whether AL amyloidosis involving the joints might explain this puzzling aspect of her presentation. We considered performing a synovial biopsy, but because the patient had previously undergone four joint procedures, we opted instead for a more straightforward diagnostic procedure to assess for amyloidosis – an abdominal fat pad biopsy – which confirmed the diagnosis."
Dr. Laubach also notes that the patient's clinical course underscores the importance of individualized treatment in multiple myeloma. Her medical history included progressive visual loss related to both glaucoma and diabetic retinopathy, and visual symptoms had worsened substantially during a course of corticosteroid therapy in 2006 when she underwent treatment for ovarian cancer.
"Because the patient had significant visual impairment related to pre-existing medical conditions," Dr. Laubach says, "we avoided use of steroids as a part of her treatment plan, although these agents are typically incorporated into myeloma treatment regimens. Preservation of vision was an important priority, and we estimated that a successful outcome could be achieved without use of steroids."
As a result of ongoing research efforts at Dana-Farber and other institutions, treatment options for multiple myeloma continue to expand. It is anticipated that new drug classes currently being evaluated in clinical trials will further enhance the effectiveness of multiple myeloma therapy.
"There are a number of very promising new drugs currently being tested in phase II and III clinical trials," says Claudia Paba-Prada, MD, oncologist in the Jerome Lipper Multiple Myeloma Center. "Monoclonal antibody therapies directed at cell surface antigens on myeloma cells are particularly promising, including elotuzumab, which targets the glycoprotein CS1, and daratumumab, which targets CD38. We hope these agents and others will eventually become available to patients, such that options for treatment and the effectiveness of these options will continue to improve."
Special acknowledgment to Frida Rosenblum, MD, of Brigham and Women's Hospital's Department of Pathology, for her assistance with the figures above.