3093377-1

Arizona Multiple Myeloma Network Patient

Conference

March 18, 2017

Robert A. Kyle, MD

Mayo Clinic, Rochester, MN

Scottsdale,

ArizonaRochester,

Minnesota

Jacksonville,

Florida

Multiple Myeloma & Its Beginning

Monoclonal Gammopathy of Undetermined

Significance

Natural History in 241 Cases

CP1118008-16

241 patients with an M-protein in the serum

but initially no evidence of multiple

myeloma, macroglobulinemia,

amyloidosis, or lymphoma 1956-1970 were

collected and followed up.

Kyle RA, Am J Med 64:814, 1978

1956-1970

MGUSDevelopment of Myeloma or Related Disorder

CP1118008-18

No. % Median Range

Multiple myeloma 44* 69 10.6 1-32

Macroglobulinemia 7 11 10.0 4-16

Amyloidosis 8 12 9.0 6-19

Lymphoproliferative 5 8 8.0 4-19disease

Total 64 100 10.4 1-32

Interval todisease (yr)

*Dx of myeloma made after 20-yr F-U in 10 pt

N=64

Kyle RA, Am J Med 64:814, 1978

©2012 MFMER | 3206289-4

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Full Progression 1956-1970

Kyle RA, AM J Med 64:814, 1978Kyle RA et al, Mayo Clinic Proceedings 79:859, 2004

0

20

40

60

80

100

0 5 10 15 20 25

Cu

mu

lati

ve

pro

ba

bil

ity

of

pro

gre

ssio

n (

%)

Years

17%

34%39%

n=241

Monoclonal Gammopathy of

Undetermined Significance (MGUS)

CP1118008-33

•Serum M spike < 3 g/dL

•Bone marrow plasma cells < 10%

•No end-organ damage - CRAB (hypercalcemia, renal insufficiency, anemia, bone lesions.

Brit J Haematology 121:749, 2003

MGUSSE Minnesota (11 counties)

Jan 1, 1960-Dec 31, 1994

CP1118008-24

Male (%) 54

Age (med years) 72

<40 years (%) 1.7

M-spike (g/dL-med) 1.2

n=1,384

Kyle, et al., New Engl J Med, 346:564, 2002

3093377-7

Type of

ProgressionObserved Expected* RR 95% CI

Multiple myeloma 97 4.1 23.9 (19.4, 29.1)

Lymphoma 19 11.6 1.6 (1.0, 2.6)

AL Amyloidosis 14 1.6 8.8 (4.8, 14.7)

Macroglobulinemia 13 0.3 47.6 (25.4, 81.5)

CLL 3 4.9 0.6 (0.13, 1.8)

Plasmacytoma 1 0.08 12.7 (0.3, 70.3)

TOTAL 147 22.5 6.5 (5.5, 7.7)

Total Person-Years of Follow-up: 14,547

(years from MGUS diagnosis to date of progression or last follow-up)

*Iowa Seer Registry

Kyle et al., NEJM 346:2002 (updated 2016)

MGUS SE Minnesota 1384

©2016 MFMER | 3524786-8

MGUS SE Minnesota1960-1994

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40

Years from diagnosis of MGUS

Pe

rce

nt

Progression

No. at risk

1,384 892 560 352 229 115 51 17 5

10%

18%

28%

37%

N=1,384

Kyle et al: NEJM 346:564, 2002 (updated 2016)

37%

©2016 MFMER | 3524786-9

Cumulative Incidence of Progression With Death as a Competing Risk

0

20

40

60

80

100

0 10 20 30 40

Years from diagnosis of MGUS

Cum

ula

tive

in

cid

en

ce

(%

)

56%

79%

87% 88%

7%10% 11% 11%

Death

Progression to MM or related disorder

Kyle et al: NEJM 346:564, 2002 (updated 2016)

89%

11%

Natural History

Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

Clinical Presentation

• “End-organ Damage” or CRAB features

• HyperCalcemia

• Renal Insufficiency

• Anemia

• Bone Disease

Multiple Myeloma

Modification of “End Organ Damage”More than 80% risk of MM within 2 years

• Bone marrow plasma cells > 60%

• Serum free light chain ratio ≥ 100

• Renal insufficiency due to multiple myeloma

• Creatinine > 2 mg/dL or Creatinine Clearance < 40 ml/min

or

• Bone Disease

• MRI ≥ 2 focal lesions > 5 mm

Rajkumar SV, et al., Lancet Oncology 2014

Measurement of Monoclonal Protein in

Serum & Urine

• Electrophoretic M-spike in serum

• Nephelometry (IgG, IgA, IgM)

• Serum Free Light Chain (FLC)

• Electrophoretic M-spike in urine (24 hr collection)

Serum Protein Electrophoresis

Alb 1 2 CP1123175-6

Serum Free Light Chain (FLC)

mg/dL (95% CI)

Kappa () 3.3 – 19.4

Lambda ( ) 5.7 – 26.3

/ ratio 0.26 – 1.65

Katzmann et al., Clin Chem, 48:1437, 2002

N = 282

Age 21 – 90 yrs

Multiple Myeloma

Complications

• Hypercalcemia

• Spinal cord compression

• Infections

Multiple Myeloma

Symptoms of Hypercalcemia

• Weakness, fatigue

• Anorexia, nausea and vomiting

• Constipation

• Excessive thirst and urination (polyuria)

• Confusion

• Stupor

Multiple Myeloma

Therapy of Hypercalcemia

• Hydration

• Prednisone

• Bisphosphonates

Multiple Myeloma

Spinal Cord Compression

• Back pain and leg weakness

• Incontinence

• Paraspinal mass

• MRI

• Radiation therapy

• Surgical decompression

Multiple Myeloma

Infections

• Pneumococcal vaccine (13 & 23)

• Influenza vaccine

• Avoid live vaccines [(i.e. herpes

zoster (shingles)]

• Gamma globulin, IV

kyle.robert@mayo.edu