Monoclonal Gammopathy Case Studies

Mayo Clinic Laboratories provides evaluation and consultation for the diagnosis and treatment of patients with hereditary and acquired hematologic disorders.

We can assist with:

  • Cost-effective test utilization.
  • Test-panel interpretation and consultation.
  • Treatment and monitoring of patient care.

Case #1

Background

A 56-year-old female with a past medical history of an IgG kappa multiple myeloma, previously treated with bortezomib, lenalidomide, and dexamethasone followed by autologous peripheral blood stem cell transplant and lenalidomide maintenance, presented to the clinic with increasing M protein. The patient started on daratumumab, promalidomide, and dexamethasone. When the patient returned, routine follow-up labs were ordered without the need for a bone marrow procedure.

Laboratory Studies

  • Serum protein electrophoresis (SPEP) was negative, but immunofixation revealed a small monoclonal IgG kappa.
  • Free light chain measurements were normal.

MASS-FIX

  • Since immunofixation (IFE) reported an IgG kappa, the MALDI-TOF assay was performed to determine if the IgG kappa was the M protein or daratumumab. The result (Figure 1) detected the patient’s M protein and daratumumab.

Learning Points

  • New monoclonal therapeutics, such as daratumumab, are causing quandaries for clinical laboratories faced with determining the differences between M proteins and drugs.
  • M protein measurement by MALDI-TOF is one way to accurately assign the correct response criteria to patients on monoclonal therapeutic treatment.
Figure 1. IgG Kappa with Daratumumab

Case #2

Background

A 56-year-old female presented with Lambda chain persistent leg swelling and proteinuria

Laboratory Findings

  • 24-hour urine confirmed significant proteinuria of greater than 24 g per 24 hours.
  • Serum protein electrophoresis was negative with a pattern consistent with nephrotic syndrome.
  • Urine immunofixation was positive for a monoclonal lambda light chain.
  • Free light chain testing revealed elevated lambda free light chains 57 mg/dL (ref 0.57¬– 2.63 mg/dL) with a kappa-to-lambda ratio of 0.044 (ref. 0.26–1.65).

Clinical Studies

  • A kidney biopsy demonstrated weak Congo red deposits that were too small for further studies.
  • Electron microscopy revealed fibrils consistent with amyloid.
  • An abdominal fat aspirate did not confirm the presence of amyloid.

MASS-FIX Results

  • To confirm the presence of a monoclonal lambda free light chain in the serum, a MALDI-TOF MS spectrum was obtained. The result demonstrated a glycosylated monoclonal lambda light chain (Figure 2).

Outcome

  • A bone marrow biopsy demonstrated 10–15% lambda light chain with Congo red positive deposits.
  • Laser dissection, mass spectroscopy characterization revealed lambda light chain amyloidosis.

Learning Points

  • Patients with AL amyloidosis can often present with low-level M proteins.
  • Given the limited area of tissue sampling, amyloid deposits can be inadvertently missed.
  • Urine immunofixation (IFE) can add diagnostic sensitivity for detecting M proteins related to AL amyloidosis.
  • The MASS-FIX assay is capable of identifying M proteins with glycosylated light chains. Retrospective studies performed at Mayo Clinic Laboratories have documented that patients with glycosylated light chains are at higher risk for AL amyloidosis.
Figure 2. Large glycosylated Lambda chain

Case #3

Background

A 24-year-old African American male with a past medical history of prostatitis and recurrent urticaria had lymphadenopathy and hypergammaglobulinemia along with hyperviscosity. His other symptoms included weight loss, chest pain, and arthralgia in the wrists and knees.

Laboratory Studies

  • Complete blood counts were normal. • Serum protein electrophoresis (SPEP) revealed an M protein spike of 7.7 g/dL.
  • Kappa and lambda free light chains at 55.5 mg/dL and 8.9 mg/dL, respectively, with an abnormal kappa/lambda ratio of 6.2 (reference 0.26–1.65).
  • Infectious disease serologies were normal.
  • Serum viscosity of 2.7 centipoise.
  • Immunoelectrophoresis showed a biclonal IgG kappa and IgG lambda (Figure 3).
Figure 3.

Clinical Studies

  • The patient had a pericardial effusion and a right atrial mass on cardiac MRI. Bone marrow biopsy showed no evidence of lymphoproliferative or plasma cell disorder.
  • The lymph node biopsy also indicated only reactive changes, but no malignant features.

MASS-FIX Testing

  • Given his unexplained monoclonal gammopathy, the patient’s serum was analyzed using MALDI-TOF MS.
  • The results demonstrated that the hypergammopathy was polyclonal with a skewed kappa-to-lambda ratio of approximately 5 (Figure 4).

Outcome

  • The patient had mediastinal lymph node and pericardial biopsies, which were mostly consistent with IgG4 lymphoproliferative disease.
  • The patient was started on rituximab, and his symptoms significantly improved.

Learning Points

  • Patient’s diagnosis with an IgG4-related disease can be interpreted as a monoclonal gammopathy.
  • A biclonal IgG kappa plus IgG lambda in a patient with hypergammaglobulinemia should be interpreted with care.
  • Kappa-to-lambda free light chain ratios can be abnormal in IgG4-related disease.
  • IgG4 is a unique immunoglobulin with a normally skewed kappa-tolambda ratio of 4:1, which can be revealed by the MASS-FIX assay.
Figure 4.

Mayo Clinic Relevant Publications

  • Mills JR, Kohlhagen MC, Willrich, MAV, et al. A universal solution for eliminating false positives in myeloma due to therapeutic monoclonal antibody interference. American Society of Hematology Blood Journal. 2018. doi:10.1182/blood-2018-05-848986.
  • Kumar S, Murray D, Dasari S, et al. Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients. Springer Nature Leukemia. 2018. https://doi.org/10.1038/s41375-018-0194-x. Accessed July 6, 2018.
  • Mills JR, Kohlhagen, MC, Dasari S, et al. Comprehensive Assessment of M-Proteins Using Nanobody Enrichment Coupled to MALDI-TOF Mass Spectrometry. Clinical Chemistry. 2016;62(10):1334–1344.
  • Milani P, Murray DL, Barnidge, DR, et al. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol. 2017;92:772–779. doi:10.1002/ajh.24772.
  • Kourelis T, Murray, DL, Dasari S, et al. MASSFIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms. Am J Hematol. 2018;93(11):368-E370. doi:10.1002/ajh.25244. Epub 2018 Sep 21.
  • Mills JR, Barnidge DR, Dispenzieri A, Murray DL. High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. Blood Cancer Journal. 2017;7(590). doi:10.1038/bcj.2017.75
  • Kohlhagen MC, Barnidge DR, Mills JR, et al. Screening method for M-proteins in serum using nanobody enrichment coupled to MALDI-TOF mass spectrometry. Clinical Chemistry. 2016;62(10):1345-1352.

Samantha Rossi

Samantha Rossi

Samantha Rossi is a Marketing Associate at Mayo Clinic Laboratories. She supports marketing strategies for product management and specialty testing. Samantha has worked at Mayo Clinic since 2019.