Case Study: Use of Biomarkers in Multiple Myeloma

At the 2013 conference of the Global Biomarkers Consortium, which took place October 4-6, 2013, in Boston, Massachusetts, David G. Roodman, MD, PhD, director, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, discussed the use of personalizing therapy in the management of multiple myeloma.

Outcomes associated with multiple myeloma (MM) have improved dramatically in recent years with the development of the serum free light chain (sFLC) assay, the advent of gene expression profiles that predict cytogenetic abnormalities, and the introduction of novel agents for treatment.

Case: Lower Lumbar Pain Increasing in Intensity

A 65-year-old female presents with low lumbar back pain that has increased in intensity over the past 6 months despite conservative therapy. Otherwise, she has been in her usual state of health. Her Eastern Cooperative Oncology Group performance status is 1.

Other diagnoses besides lumbosacral strain are considered. The diagnostic evaluation includes a blood workup that reveals anemia (hemoglobin 11.5 g/dL) and renal dysfunction (serum creatinine 2.5 mg/dL) on routine screening, whereas these values were normal 1 year earlier. Her total serum protein is elevated.

The laboratory values prompted her physician to order urine electrophoresis, with the suspicion of a plasma cell proliferative process.

Table 1

Serum protein electrophoresis reveals no monoclonal protein, but the free kappa light chain level is 7600 mg/L (normal up to 19.4 mg/L); lambda light chain is 3.22 mg/L. Kappa/lambda ratio = 4520. Her albumin is 3.5 g/dL, and her ?2-microglobulin is 3.5 mg/dL.

“One of the major advances in following patients with MM is the development of the sFLC assay,” said Roodman. “Immunoglobulins are made of light chains and heavy chains, and there are hidden epitopes when the light chains and heavy chains are combined. Once they break apart, these epitopes are exposed. Kappa- lambda light chain epitopes that are exposed when taken apart can be used to follow the patient and determine their risk.”

Because of their short half-life (approximately 6 hours in serum), light chain assays can rapidly determine response to therapy as well as early relapse.

Serum albumin and ?2-microglobulin are important markers in MM; ?2-microglobulin reflects tumor burden. An International Staging System (ISS) for symptomatic MM, developed in 2005 (Table 1), uses serum albumin and ?2-microglobulin. At the time the ISS was developed, patients who met the criteria for stage 1 disease had a median survival of about 5.5 years, and those who met stage 3 criteria – indicating a high tumor burden – had a median survival of about 2.5 years. Median survival has changed over time since the introduction of novel therapies, said Roodman.

A skeletal survey should be performed when MM is suspected, as MM is the most frequent cancer to involve the skeleton, he said.

High-Risk Features
Her bone marrow aspirate reveals 30% kappa-restricted plasma cells, and her cytogenetics and fluorescence in situ
hybridization (FISH) studies are consistent with high-risk MM. A bone survey reveals lytic lesions at T8, T9, and T10.

Cytogenetics and FISH of the plasma cells should be part of the evaluation, said Roodman.

MM is an extremely heterogeneous disease in terms of its genetics. “Ninety-eight percent of MM patients have some abnormal genetic subtype,” he said. “About half are hyperdiploid in terms of the karyotype and half are hypodiploid.”

Molecular characterization of the tumor cells, along with ?2-microglobulin level, gene expression profiles, proliferative index, and the type of monoclonal protein, can help differentiate between high-risk and low-risk myeloma. MM risk categories on the basis of these risk factors are shown in Table 2.

Table 2

Patients with t(11;14), (6;14), (4;14), or (14;16) and hyperdiploidy or low ?2-microglobulin have “good-risk” MM, with a median survival of about 8 years. Those patients with deletion 17p have a much worse prognosis, with a median survival of only 2.5 years. “Usually patients with 4;14 translocation have deletion 13p by cytogenetics, which is a high-risk feature,” he said. “If they don’t have the deletion, they’re intermediate risk.”

Diagnosis: MM ISS Stage 2

This woman was diagnosed with active MM ISS stage 2 with high-risk features due to adverse cytogenetics and FISH studies. The patient is a transplant candidate. Her initial therapy is bortezomib, lenalidomide, and dexamethasone, with monthly zoledronic acid. She achieves a complete response 3 months later.

Bortezomib-containing regimens may improve outcomes in patients with poor prognostic characteristics based on age, renal impairment, and high-risk cytogenetics. The addition of bortezomib to thalidomide and dexamethasone improves progression-free survival (PFS) in poor prognosis subgroups, including those with t(4;14) and deletion 17p.

Short induction with weekly bortezomib followed by maintenance resulted in similar response rates but shorter PFS and overall survival in high-risk versus standard-risk cytogenetic groups.

After 15 months, her kappa light chain is found to be 7400 mg/L, and multiple new lesions are found on her skeletal survey. She is entered into a clinical trial to receive carfilzomib, lenalidomide, and dexamethasone.

Multiple novel treatment options are already available for MM, and more than 40 new targets are being pursued in clinical trials.

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