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Contributed by Russell Silowash, DO and Bruce Rabin, MD,PhDFINAL DIAGNOSIS
Multiple Myeloma
DISCUSSION
Multiple myeloma is a bone marrow plasma cell neoplasm that has an associated M-protein in serum and/or urine, and has end organ damage characterized by hypercalcemia, renal insufficiency, anemia, and / or lytic lesions of the bone. A bone marrow biopsy with evidence of clonal plasma cells is required for diagnosis. Multiple myeloma accounts for 1% of all malignant tumors and 10-15% of hematopoietic neoplasms. Ninety percent of cases occur in adults over the age of 50 with a median age of 70[1]. HIV positive patients with multiple myeloma tend to be younger (approximately 33 years of age), and there is a 4.5 fold increased risk of developing multiple myeloma. The propensity for HIV patients to develop myeloma may be related to immune dysregulation, elevated serum interleukin-6 levels, chronic antigenic stimulation from infections including HIV, disorganization of the bone marrow microenvironment, and uncontrolled proliferation of Epstein-Barr virus-driven infected B lymphocytes. HIV patients tend to develop aggressive plasma cell tumors, large malignant effusions, hyperviscosity syndrome, and multiple extramedullary plasmacytomas[7]. This patient presented with lytic lesions to the spine, sternum, pelvis and calvarium. He was normocalcemic but had anemia and renal insufficiency as demonstrated by his elevated blood urea nitrogen and creatinine levels. These findings along with a bone marrow biopsy of Kappa-restricted plasma cells comprising 90% of the specimen, strongly suggest the diagnosis of multiple myeloma is well founded.
Most cases of multiple myeloma are monoclonal IgG (50%). IgA monoclonal gammaglobulins account for 20%. Light chains account for 20% of cases, and monoclonal IgD, IgE, IgM, or biclonal gammaglobulins account for less than 10% of cases; non-secretory cases account for 3%[1]. Sixty to seventy percent of multiple myeloma patients have both free light chains and a serum monoclonal (M) protein[12]. The identification of κ bands in serum protein electrophoresis and immunofixation makes this case an example of a light chain-only multiple myeloma. The combination of serum protein electrophoresis and immunofixation studies makes the detection of M protein sensitivity equal to approximately 97%. Serum protein electrophoresis has a sensitivity of only 82% while serum immunofixation alone is 93% sensitive[2]. This patient's serum protein electrophoresis identified a monoclonal protein in the gamma region. To identify the κ clonality of the gammaglobulin, immunofixation was needed.
The International Myeloma Working Group identified several uses for serum free light chain analysis in multiple myeloma. When combined with serum protein electrophoresis and serum immunofixation, serum free light chain assay is sufficient to screen for most pathological monoclonal plasmaproliferative disorders. The serum free light chain assay also plays an important role in prognosis[3]. Van Rhee and colleagues showed that patients with serum free light chain values greater than 75 mg/dL at baseline had inferior 24-month overall survival and event free survival than patients with lower levels of serum free light chains[13].
The free light chain ratio (κ/λ) is a calculation to determine if there is a monoclonal proliferation of plasma cells producing free κ or λ light chains. Normal κ /λ ratio values range from 0.26 to 1.65. Any value above 1.65 indicates increased production of λ free light chains while values below 0.26 indicate a proliferation of ? free light chains[3,5]. Kyrtsonis and colleagues demonstrated that elevated κ /λ or λ/κ values were associated with a poor prognosis. In their study, baseline serum free light chain ratio values correlated with creatinine, lactate dehydrogenase and the percentage of bone marrow infiltration. Their work also displayed improved three and five year survival rates among patients with low serum free light chain ratios (94% and 82% respectively) when compared to individuals with high baseline serum free light chain ratios (58% and 30%)4. This patient's κ /λ was 293.19, which indicated a proliferation of free κ light chains. In healthy individuals, free light chains are cleared rapidly through the renal glomeruli and are metabolized in the proximal tubules; little protein escapes into the urine. Large quantities of free light chains are required to overcome the kidney's ability to metabolize approximately 10 to 30 g of free light chain daily[3]. Table 1 shows that the serum free κ level in our patient was 5600 mg/L, which was greater than 200x the normal limit. These levels overwhelmed the kidney, causing free κ light chains to spill into the urine as seen in Figure 4.
Other factors that portend a poorer prognosis include light chain multiple myeloma, a creatinine ≥ 2 mg/dL, a C-reactive protein (CRP) ≥ 4 mg/L, an elevated lactate dehydrogenase, β2 microglobulin ≥ 5.5 mg/L, a bone marrow infiltration of ≥50%, spontaneous bone fractures, a hemoglobin less than 10 g/dL, and a platelet count less than 100 x 109/L[4]. Unfortunately our patient displayed almost all of these criteria (CRP was not reported), and therefore will more likely have a poorer outcome.
Patients can also be stratified into standard risk and high risk categories as done by Rajkumar and colleagues. High risk patients have any one of the following features: deletion 13 or hypodiploidy on metaphase cytogenetic studies, deletion 17p- or immunoglobulin heavy chain (IgH) translocations t(4;14) or t(14;16), or plasma cell labeling index of 3% or higher. High risk patients have lower survival (2-3 years) versus average risk multiple myeloma patients, who survive 6-7 years[2]. Therefore, fluorescence in situ hybridization (FISH) and/or cytogenetic testing should be performed in all patients[10]. FISH and cytogenetics testing on this patient were pending at the time of writing.
In young patients with multiple myeloma the standard of care is high dose Melphalan followed by autologous stem cell transplant. Older patients receive oral Melphalan. Newer treatments such as Bortezomib can be considered in high risk patients[2]. Optimum treatment for the treatment of multiple myeloma in HIV patients has not been well described[6]. Dezube et al reviewed the outcomes of HIV-related plasma cell dyscrasias. Their paper showed varying results. In terms of survival, one of the better results was a 45 year old male treated with radiotherapy, Vincristine, Adriamycin, and Dexamethasone (VAD), who had a relapse of myeloma at 6 years [6,7]. Another myeloma case died at 1 week after treatment with Melphalan and Prednisone [6,8]. One patient had undergone an autologous stem cell transplantation and VAD but died 13 months later [6,9]. The authors made two important points. The first was the importance of highly active anti-retroviral therapy (HAART ). Patients with HIV and multiple myeloma, who were on HAART therapy lived at least one year. The second important point was the properties of Thalidomide and their implications for treatment of HIV multiple myeloma patients. Thalidomide is non-myelosuppressive, stimulates CD4 and CD8 activity, directly inhibits HIV replication, and does not affect the pharmacokinetics of HAART[6].
In summary, multiple myeloma is a plasma cell neoplasm that arises in the bone marrow and causes end organ damage to patients. HIV patients are more likely to develop multiple myeloma and tend to be younger than non-HIV multiple myeloma patients. It is important to thoroughly work up patients with multiple myeloma. Work up includes serum protein electrophoresis, serum protein immunofixation, serum free light chain levels and κ/λ ratio, and FISH with cytogenetics. The prognosis is determined by serum free light chain levels, FISH and cytogenetics results, physical signs, and multiple lab values. Standard of care treatment is Melphalan with or without autologous stem cell transplant. Treatment of multiple myeloma in HIV patients is less clear. Thalidomide has implications in treatment due to its prohibition of viral replication, increased CD4 and CD8 activity, and no interference with concurrent HAART therapy.
REFERENCES
Contributed by Russell Silowash, DO and Bruce Rabin, MD,PhD
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