Keeping Up With The Bence-Joneses

Dr Leonard MinukSeptember 29, 2019

Presenter Disclosure• Faculty / Speaker’s name: Leonard Minuk

• Relationships with commercial interests:– Grants/Research Support: Clinical trials funding through GSK,

Merck, Celgene, Janssen, Onyx, BMS, Millenium– Speakers Bureau/Honoraria: None– Consulting Fees: None– Other: None

Disclosure of Financial Support• I am not aware of any financial support or in kind support for this

program

• Potential for conflict(s) of interest:– I have received no funding for this program

Mitigating Potential Bias• I will not be endorsing any specific preferred therapies for

myeloma but will show our local treatment algorithm

Learning Objectives• review the pathophysiology of multiple myeloma • interpret free light chain escape results and assess

treatment response• differentiate between MGUS versus multiple myeloma • describe the standard of care for the treatment of

multiple myeloma • list new potential agents for the treatment of multiple

myeloma

• A bone marrow cancer characterized by uncontrolled proliferation of clonal plasma cells

• Disease manifests with CRAB symptoms

– C – Hypercalcemia

– R – Renal Failure

– A – Anemia

– B – Bone disease – lytic lesions/bone fractures

What is Multiple Myeloma?

Canadian Cancer Society Statistics 2015

Epidemiology of Multiple Myeloma

• 1% of all cancers and 15% of hematologic malignancies

• ~2,700 new cases in Canada in 2015 (estimated 80 new cases in Manitoba)

• Prevalence of ~7,500 across Canada

• Median age at diagnosis of 69 years

• Incurable malignancy characterized by multiple relapses

Canadian Cancer Society 2016

Bence Jones, Phil Trans R Soc Lond 1848

Sarah Newbury 39 female, first reported case of myeloma in 1844

What is a monoclonal gammopathy?• A monoclonal immunoglobulin detected in the serum

or urine during laboratory investigation (SPEP, UPEP, serum free light chain assay)

• This immunoglobulin can be an intact Ig molecule or a free light chain

• Secreted by clonally expanded plasma cells• Many synonyms:

– M-protein, M-peak, M-band, myeloma protein, paraprotein

Serum Protein ElectroPhoresis (SPEP) • 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

• Polyclonal gammopathy

– Liver disease– Connective tissue disease– Chronic infection

Polyclonal pattern

SPEP – interpretation

Normal

SPEP - Interpretation• Monoclonal gammopathy

SPEP - Interpretation• Monoclonal gammopathy

N = 46,739

MGUS57% (26,552)

MultipleMyeloma

18% (8,336)

AL amyloidosis9.5% (4,490)

Lymphoproliferative SMM 4% (1,780)3% (1,410) Solitary or extramedullary

plasmacytoma 2% (899)Macro 2.5% (1,236)

Other 4% (2,036)

Mayo Clinic 1960-2002

N=46,739

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 BMPC <10% and Clonal BMPC >10% and Clonal BMPC >10% and

No myeloma related “CRAB” No myeloma related “CRAB Myeloma related “CRAB”

No evidence of other B cell LPD or light chain associated Amyloidosis or other tissue damage

Or :BM plasma cells >60%FLCR >100>1 focal lesion on MRI

Rajkumar et al. 2014 Lancet Oncology

Rajkumar et al. 2014 Lancet Oncology

Types of Myeloma

• Intact immunoglobulin myeloma (~80%)– Production of intact immunoglobulins (M-protein)– IgG > IgA > IgD >>>> IgM– Commonly called myeloma

• Light chain myeloma (~15-20%)– Production of only light chains– Sometimes called light chain disease

• Nonsecretory myeloma (~3%)– M-protein is not present on SPEP, IFE, UPEP, uIFE, or SFLCR

• If only SPEP/IFE is done – about 15-20% of myeloma /other disorders WILL BE MISSED because SPEP will be negative– Including light chain myeloma, AL amyloidosis, light chain

deposition disease

• What can be done about this?– Urine protein electrophoresis (UPEP)– Serum free light chain ratio (SFLCR)

Beyond the SPEP

UPEP vs FLCUPEP

• Reabsorption of light chains in the tubules limits sensitivity

• 24 urine collection• Slow turn around time• Labour intensive• Compliance with testing 5-

40%

FLC

• Can be done on same sample as SPEP

• Rapid turnaround• Higher sensitivity• More prognostic information

Am J Clin Pathol 2013;140:890-897Blood 2016 :blood-2016-07-726778; doi:10.1182

Serum Free Light Chain Assay

Katzmann et al Clin Chem. 2002;428-44

Normal range for sFLC ratio rises with renal insufficiency (up to about 3)

Hutchison et al Clin J Am Soc Nephrol 2008

Free light chain interpretation - reactive

• 85 year old• Hemoglobin 93

Free light chain interpretation - CKD• 68 year old with diabetic nephropathy, now on

dialysis

Free light chain interpretation – myeloma

• 69 year old admitted with AKI, creatinine 600s• SPEP negative

Screening for plasma cell disorders

Clin Chem Lab Med 2016;54(6):907-919

• IMWG recommends SPEP and FLC as screening test for myeloma and other plasma cell dyscrasias (UPEP not necessary)

• AL amyloidosis may still require 24 hour UPEP for optimal sensitivity– 4% of AL amyloid patients missed by using only SPEP and FLC – Detected by UPEP– IMWG recommends SPEP/UPEP/FLC to screen for AL amyloidosis (therefore

may still be done for work up of nephrotic syndrome)

• UPEP on spot urine not necessary– FLC recommended in place

Take Home Message

Rajkumar et al. 2014 Lancet Oncology; 15:e538-48Clinical Chemistry 55:3 (2009)

Case Example• 54 male previously health presents to HSC ER with 2 week

history of fatigue/generalized weakness, hip/low back pain, chest pain

• WBC 9.4, Hb 70, MCV 93.3, plt 154 (normal differential)• Cr 157, LDH 345, ferritin 487• Seen by GI and endoscopy normal• Admit to family medicine short stay

Case Continued• Family MD concerned re unexplained severe anemia and AKI so

ordered further investigations• Calcium 3.52, albumin 21, B2 microglobulin 7.3, total protein

109• IgG 64, IgA 0.48, IgM 0.26• SPEP 56 g/L, immunofixation shows IgG kappa monoclonal• Serum FLC assay: free kappa 1890, free lambda 7.24, ratio 261

Hematology Consulted• Bone marrow biopsy

– Hypercellular marrow, 69% plasma cell infiltration– FISH cytogenetics: 1q duplication, trisomy 8, monosomy 13

and 14• Skeletal Survey:• “The pelvic osseous structures somewhat heterogeneous. There is suggestion of

some lucent lesionswithin the iliac wings and inferior pubic rami as well as in the proximal femoral and humeral head. Correlation with bone scan is recommended. There is a fracture the left posterolateral 2nd rib”

• Diagnosis: R-ISS stage III multiple myeloma

Treatment• IV saline and zoledronic acid to control hypercalcemia• Short course of dexamethasone• Transfused 2 units PRBC• Sent home shortly after as calcium normalized

Outpatient Treatment• Continued monthly zoledronic acid• CyBor-D chemotherapy (cyclophosphamide, bortezomib and

dexamethasone) X 4 cycles• Radiotherapy 800cGy in 1 fraction to whole pelvis and

lumbosacral spine for pain control• Achieved a VGPR with M protein reducing to 1 g/L• Sent for autologous stem cell transplant• Post transplant trace IgG kappa M protein on SPEP and normal

sFLC assay

Follow Up• Bloodwork monitored monthly• Originally planned for standard lenalidomide maintenance but

deferred due to patient reasons• 6 months post transplant:

– Kappa free light chains• 15 -> 27 -> 47 -> 116 -> 165

– SPEP remained unchanged (trace IgG kappa)– Drop in Hb from 120 to 90 (no change in Ca, Cr, or new

bone lesions)

IMWG Progressive Disease

Lancet Oncol 2016; 17: e328–46

• Increase by 25% from lowest confirmed response in any of the following:• Serum M-protein (absolute increase ≥5 g/L)

• Urine M-protein (absolute increase of ≥200 mg/24 hours)

• Bone marrow plasma cell percentage

• >10 percent increase

• Difference in the kappa and lambda FLC levels

• FLC ratio must be abnormal and

• absolute change must be >100 mg/L)

IMWG Clinical Relapse

Lancet Oncol 2016; 17: e328–46

• New soft tissue plasmacytoma or definite increase in size of existing plasmacytoma

• New bone lesions

• Hypercalcemia (Calcium > 2.8mmol/L)

• Decrease in hemoglobin by 20g/L (not related to therapy or other causes)

• Rise in serum creatinine above 177 umol/L or eGFR <40

• Hyperviscosity related to the paraprotein

Non Secretory and Light Chain Escape• Non-secretory escape

– Intact immunoglobulin at diagnosis but progression without increase in immunoglobulin or light chain

– Diagnosed by evidence of symptomatic disease (“CRAB”) and bone marrow biopsy showing increased plasma cells

– 1-2% of cases

• Light chain escape– Intact immunoglobulin at diagnosis but progression without increase

in immunoglobulin and detected by increase in light chains (by UPEP or sFLC assay)

– 1-2% of cases

Keats et al. Blood 2012; 120: 1067-76

Case Continued• Currently on second line therapy with KRD

(carfilzomib, lenalidomide, dexamethasone) with reducing light chains

Eligible for ASCT(Age <70 and good health)

Not eligible for ASCT(Age >70 or serious

comorbidity)

CBD X 4 cycles (cyclophosphamide, bortezomib, dexamethasone)

+ASCT (MEL 200)

Lenalidomide Maintenance(B maintenance for high risk cytogenetics)

CBD X 9 cycles

Progression

Lenalidomide and dexamethasonePlus one of:carfilzomib or daratumumab

1. Pomalidomide and dexamethasone2. Carfilzomib and dexamethasone

Lenalidomide+Dexamethasone until

progression

Progression

Bortezomib and dexamethasonePlus one of:Cyclophosphamide or daratumumab

Staging and Prognosis

Palumbo et al. JCO 2015;33:2863-9

`+

4.6 years 6.1 years

Kumar et al. Leukemia 2014;1122-28

- Mayo clinic 1038 patients diagnosed with myeloma between 2001 and 2010; median follow up of 5.9 years

- Current estimated OS is 6-8 years

-<1960 median OS <12 months

- 1960-1994 median OS 30 months

- 1994-2000 median OS 36 months

8+ years??

2018

Take Home Messages• 1) Order a serum protein electrophoresis AND a serum free

light chain assay when suspecting a diagnosis of myeloma• 2) There is limited utility to urine protein electrophoresis in

the diagnosis and follow up of myeloma• 3) Myeloma patients on treatment and in long-term follow up

should have BOTH SPEP and sFLC assays to monitor for disease relapse

Take Home Messages• 4) Differential diagnosis of monoclonal gammopathy

– MGUS, smoldering myeloma, multiple myeloma, plasmacytoma, AL amyloidosis, B cell lymphoproliferative disorder

• 5) How to differentiate MGUS from smoldering myeloma from symptomatic myeloma– CRAB and biomarkers

Question and Answer