What do you do, with an M protein? Cancer Day for Primary Care Emily Rimmer MD FRCPC January 31, 2014 emily.rimmer@cancercare.mb.ca
Disclosure of Potential for Conflict of Interest Name of presenter: Emily Rimmer Name of presentation: What do you do, with an M protein? FINANCIAL DISCLOSURE Grants/Research Support: None Speaker bureau/honoraria amounts: None Consulting fees: None Other: None
Objectives List the most common indications for ordering a serum protein electrophoresis (SPEP) Understand the difference between a polyclonal and monoclonal gammopathy Develop a logical approach to the investigation of an M-protein
Monoclonal Gammopathies n = 46,739 Lymphoproliferative SMM 4% (1,780) N = 46,739 3% (1,410) Solitary or extramedullary AL amyloidosis plasmacytoma 2% (899) 9.5% (4,490) Macro 2.5% (1,236) Multiple Myeloma 18% (8,336) Other 4% (2,036) MGUS 57% (26,552) Mayo Clinic 1960-2002
Definition of monoclonal protein Monoclonal immunoglobulin secreted by an abnormally expanded clone of plasma cells in an amount that can be detected by immunofixation of serum and/or urine/other fluids Also know as: M protein Paraprotein M-spike M-component M-band
Type of M-protein Intact immunoglobulin (heavy & light chain) Light chain only Heavy chain only Associated plasma cell disorders Myeloma Other lymphoproliferative disorders Waldrenstrom macroglobulinemia Light chain myeloma Light chain deposition disease (usually kappa) AL amyloidosis (usually lambda) Heavy chain disease (alpha, gamma, mu) Heavy chain deposition disease
When to order an SPEP to look for an M band? To make a diagnosis: When clinically suspicious of the disorders associated with an M band Unexplained anemia / weakness / fatigue / ESR Unexplained renal insufficiency Heavy proteinuria in patient >40yrs Bence Jones proteinuria Hypercalcemia Hypergammaglobulinemia Immunoglobulin deficiency Peripheral neuropathy (5% will have MGUS) Recurrent infections Unexplained bone pain / pathologic fracture / lytic lesion
When to order an SPEP to look for an M band? For prognosis: Risk of progression into symptomatic disease for MGUS and smoldering myeloma For monitoring: Response assessment Progression/relapse
Serum Protein ElectroPhoresis Serum protein migrate into bands based on their size and charge Limitations: Not sensitive when M- protein is small Cannot classify type of M-protein
Serum immunofixation Used to determine clonality Monoclonal versus polyclonal Not able to quantitate the concentration of the M band Must be done in conjunction with the SPEP Does not give the concentration of the M- protein
SPEP interpretation Normal No M protein present
SPEP interpretation Polyclonal gammopathy Liver disease Connective tissue disease Chronic infection normal Polyclonal pattern
SPEP - Interpretation Monoclonal gammopathy
Biclonal gammopathy IgG lambda IgM kappa
Beyond the SPEP If only SPEP is done about 15% of myeloma/other disorders WILL BE MISSED because SPEP will be negative
Bence Jones protein: are you still testing urine? (UPEP) Batched test with slow turnaround. Incomplete 24 hr collection. Urine smelly Labour intensive Based on renal metabolism Less sensitive and non numerical. What is the alternative? Testing the serum for free light chains Serum free light chain analysis: Bradwell AR 2008
Serum Free light chain index (SFLCI) Does not rely on urine collection nor renal function Diagnosis Non-secretory, oligosecretory, light chain myeloma, and amyloidosis Prediction of risk of progression for MGUS, smoldering myeloma, and plasmacytoma More sensitive than SPEP for monitoring for residual disease
AND
Diagnostic criteria MGUS SMM MM M protein in serum <30g/l and M protein >30g/l and / or Any level of M protein (none in non-secretory) and Clonal BMPCS<10% and low level of infiltration on trephine and Clonal BMPCS >10% and Clonal BMPCS >10% and No myeloma related CRAB No evidence of other B cell LPD or light chain associated Amyloidosis or other tissue damage No myeloma related CRAB Myeloma related CRAB Kyle et al, Leukemia 2010;24:1121-7
Myeloma related CRAB C = hypercalcemia (Ca >2.8mmol/L) R = renal failure (Cr >173) A = anemia (Hb<100 or > 20g below baseline) B = bony lesions (lytics, severe osteopenia, pathological fractures or plasmacytoma) Others: nephrotic syndrome, constitutional symptoms, neuropathy, hepatosplenomegaly etc
MGUS is common Kyle et al, NEJM 2006;354:1362-9
Risk of progression of MGUS to Myeloma 58% = HIGH RISK 37% 21% 5% = LOW RISK 3 adverse risk factors: 1. M band >15g/L 2. Non-IgG subtype 3. Abnormal FLC ratio (<0.25 or >4) Rajkumar et al, Blood 2005;106:812-7
Risk of progression of SMM to Myeloma 10%/year 3%/year 1%/year 3 risk factors: 1. M band >30g/L 2. Bone marrow Plasmacytosis >10% 3. Abnormal FLC ratio (<0.125 or >8)
Biology of response and relapse in MM: a treatable but at this time, incurable malignancy 10 Asymptomatic Symptomatic M protein (g/dl) 5 2 MGUS or smouldering myeloma Active myeloma Plateau remission Relapse Refractory relapse Therapy Therapy Therapy ~ 31,500 cases annually in Europe ~21,500 deaths annually in Europe International Agency for Research on Cancer (IARC) GLOBOCAN 2002. Available from: www-dep.iarc.fr/
Goals of therapy Overall response rate (ORR) CR: strict or unconfirmed VGPR PR Quality of response Event free or progression free survival Overall survival strongly associated with the quality of response
Current standard of care in Manitoba Transplant eligible Induction chemotherapy: x 3-4 cycles Bortezomib/Dexamethasone 40mg D1-4, 9-12, 17-20 Adding cyclophosphamide for suboptimal response Upfront HDT-ASCT Followed by maintenance therapy: thalidomide, lenalidomide Transplant ineligible Few comorbidities: bortezomib-based regimens or Imid based VMP, V-CWAP Rd, MPT, MPR Multiple comorbidities/poor performance status MP (melphalan & prednisone) CWAP (cyclophosphamide with alternating prednisone)
Take Home Message Monoclonal proteins are common Order an SPEP / immunofixation when clinically suspicious of the disorders associated with an M band When an M band is identified investigate for myeloma related CRAB symptoms referral to hematologist is appropriate
Questions