Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Robert A. Kyle, MDProfessor of Medicine

Mayo Clinic

MGUS MGUS Olmsted County MNOlmsted County MN

CriteriaCriteria

• Serum M-spike < 3.0 g/dLSerum M-spike < 3.0 g/dL

• Bone marrow plasma cells <10% if Bone marrow plasma cells <10% if donedone

• No evidence of other B-cell disordersNo evidence of other B-cell disorders

• No end organ damageNo end organ damage

MGUSMGUSOLMSTED COUNTY, MNOLMSTED COUNTY, MN

RESULTSRESULTS

• Olmsted County Residents Olmsted County Residents >> 50 years; 28,038 50 years; 28,038

• Serum samples obtained from population: 77%Serum samples obtained from population: 77%

Kyle et al., New Engl J Med, 2006, 354:1362

MGUSMGUSOlmsted County MNOlmsted County MN

CP1118008-35

Age No. No. %

50 – 59 8,373 141 1.7

60 – 69 6,019 178 3.0

70 – 79 4,508 205 4.6

≥80 2,563 170 6.6

Total 21,463 694 3.2

≥ 70 7,071 375 5.3

Age No. No. %

50 – 59 8,373 141 1.7

60 – 69 6,019 178 3.0

70 – 79 4,508 205 4.6

≥80 2,563 170 6.6

Total 21,463 694 3.2

≥ 70 7,071 375 5.3

M-proteinM-protein

Kyle et al., New Engl J Med, 2006, 354:1362

Age (yr)

Pre

vale

nce

of

MG

US

(%

) Prevalence of MGUS According to Age

Kyle et al., New Engl J Med, 2006, 354:1362Kyle et al., New Engl J Med, 2006, 354:1362

MGUS in African AmericansMGUS in African Americans

WhiteWhite African American African American

N SubjectsN Subjects3,250,1073,250,107 749,754 749,754

MGUS N, %MGUS N, % 1,312 (.40%)1,312 (.40%) 734 (.98%) 734 (.98%)

MM at 10 yrsMM at 10 yrs 15% 15% 17%17%

Langren, et al., Blood, 107:904, 2006Langren, et al., Blood, 107:904, 2006

MGUSMGUSSE MinnesotaSE Minnesota

Jan 1, 1960-Dec 31, 1994Jan 1, 1960-Dec 31, 1994

CP1118008-24

Male (%) 54

Age (med years) 72

<40 years (%) 1.7

M-spike (g/dL-med) 1.2

Male (%) 54

Age (med years) 72

<40 years (%) 1.7

M-spike (g/dL-med) 1.2

n=1,384n=1,384

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

Relative Risk of ProgressionRelative Risk of Progression

ObsObs Exp*Exp* RRRR

Multiple MyelomaMultiple Myeloma 7575 33 25 25

Lymphoma, IgMLymphoma, IgM 1919 7.87.8 2.42.4

AmyloidosisAmyloidosis 1010 1.21.2 8.48.4

MacroglobulinemiaMacroglobulinemia 77 0.20.2 46 46

CLLCLL 33 3.53.5 0.90.9

PlasmacytomaPlasmacytoma 11 0.10.1 8.58.5

TotalTotal 115 115 15.8 15.8 7.37.3

* Iowa SEER Registry* Iowa SEER Registry

MGUSMGUSSE MINNESOTASE MINNESOTA

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

MGUS SE MinnesotaMGUS SE Minnesota1960-19941960-1994n=1,384n=1,384

MGUS SE MinnesotaMGUS SE Minnesota1960-19941960-1994n=1,384n=1,384

0

5

10

15

20

25

30

0 5 10 15 20 25

12%12%

25%25%

30%30%

First progressionFirst progression

Full progressionFull progression

10%10%

21%21%

26%26%

Cu

mu

lati

ve p

rob

ab

ility

(%

)C

um

ula

tive

pro

ba

bili

ty (

%)

YearsYears

1,3841,384Patientsat risk(no.)

Patientsat risk(no.)

867867 423423 177177 5656 1717

CP1022686-6Kyle, et al., New Engl J Med, 346:564, 2002

0

20

40

60

80

100

0 5 10 15 20 25

Full Progression or DeathFull Progression or DeathFull Progression or DeathFull Progression or Death

CP971723- 6

Cu

mu

lati

ve in

cid

ence

(%

)C

um

ula

tive

inci

den

ce (

%)

YearsYears

6%6%

ProgressionProgression

DeathDeath

10%10% 11%11%

53%53%

72%72%76%76%

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

Relative Risk of Full Progression byRelative Risk of Full Progression bySerum M-Spike SizeSerum M-Spike Size

Relative Risk of Full Progression byRelative Risk of Full Progression bySerum M-Spike SizeSerum M-Spike Size

Serum m-spike valueSerum m-spike valueCP999081-2

Rel

ativ

e ri

sk o

f fu

llp

rog

ress

ion

Rel

ativ

e ri

sk o

f fu

llp

rog

ress

ion

Pro

bab

ility

of

full

pro

gre

ssio

nat

20

year

s (%

)P

rob

abili

ty o

f fu

ll p

rog

ress

ion

at 2

0 ye

ars

(%)

0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0

13.613.6

2525

5050

6565

33

99

55

77

11 13.613.6

15.615.6

41.241.248.848.8

24.624.6

6464

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

NN

RRRR

95% CI95% CI

Risk of ProgRisk of Prog

20 yr20 yr

%%

AbsoluteAbsolute Competing Competing riskrisk

M-protein < 1.5 g/dl,M-protein < 1.5 g/dl, IgG, Normal FLC IgG, Normal FLC

449449 11 55 22

1 risk factor, abn1 risk factor, abn 420420 5.45.4 2121 1010

2 risk factors, abn2 risk factors, abn 226226 10.110.1 3737 1818

3 risk factors, abn3 risk factors, abn 5353 20.820.8 5858 2727

MGUS and Free Light Chain (FLC)MGUS and Free Light Chain (FLC)

Rajkumar, et al., Blood; 106:1148, 2005Rajkumar, et al., Blood; 106:1148, 2005

Smoldering Multiple MyelomaSmoldering Multiple Myeloma

• Serum M-spike Serum M-spike ≥ 3 g/dl≥ 3 g/dl

and and

• Bone marrow plasma cells ≥ 10%Bone marrow plasma cells ≥ 10%

• No end organ damageNo end organ damage

Kyle RA and Greipp PR, NEJM, 302:1347, 1980.Kyle RA and Greipp PR, NEJM, 302:1347, 1980.

Smoldering Multiple MyelomaSmoldering Multiple MyelomaMayo ClinicMayo Clinic 1970 – 19941970 – 1994

NN %%Serum M-protein Serum M-protein ≥≥ 3 g/dl 3 g/dl and and 113113 3838Bone marrow plasma cells Bone marrow plasma cells ≥≥ 10% 10%

Serum M-protein < 3 g/dlSerum M-protein < 3 g/dl andand 158158 52 52Bone marrow plasma cells Bone marrow plasma cells ≥≥ 10% 10%

Serum M-protein Serum M-protein ≥≥ 3 g/dl 3 g/dl and and 3030 10 10 Bone marrow plasma cells < 10%Bone marrow plasma cells < 10%

TOTALTOTAL 301301 100100

Smoldering Multiple MyelomaSmoldering Multiple MyelomaTime to progression Time to progression Median yearsMedian years

Serum M-spike Serum M-spike ≥≥ 3 3Bone marrow plasma Bone marrow plasma 2.2 2.2 cells cells ≥≥ 10 10Serum M-spike < 3 Serum M-spike < 3 Bone marrow plasmaBone marrow plasma 7.8 7.8 cells cells ≥ 10≥ 10

Serum M-spike Serum M-spike ≥≥ 3 3Bone marrow plasmaBone marrow plasma 19 19 cells < 10 cells < 10

Total (N = 301) Total (N = 301) p= <0.001p= <0.001 5.5 5.5

years from diagnosis

per

cen

t

0 5 10 15 20 25

020

4060

8010

0Progression to Multiple Myeloma or Amyloid

51%

66%

73%

78%

years from diagnosis

per

cen

t

0 5 10 15 20 25

020

4060

8010

0Progression to MM or AL

14%

32%

39%

54%

43%

63%

70% 70%70%

78%

88%

4%

10%

16%

21%

M-spike>=3 & BMPC>=10

M-spike< 3 & BMPC>=10

M-spike>=3 & BMPC<10

MGUS

years from diagnosis

per

cen

t

0 5 10 15 20 25

020

4060

8010

0Progression to MM or AL

14%

32%

39%

54%

43%

63%

70% 70%70%

78%

88%

4%

10%

16%

21%

M-spike>=3 & BMPC>=10

M-spike< 3 & BMPC>=10

M-spike>=3 & BMPC<10

MGUS

years from diagnosis

per

cen

t

0 5 10 15 20 25

020

4060

8010

0Progression to MM or AL

14%

32%

39%

54%

43%

63%

70% 70%70%

78%

88%

4%

10%

16%

21%

M-spike>=3 & BMPC>=10

M-spike< 3 & BMPC>=10

M-spike>=3 & BMPC<10

MGUS

years from diagnosis

per

cen

t

0 5 10 15 20 25

020

4060

8010

0Progression to MM or AL

14%

32%

39%

54%

43%

63%

70% 70%70%

78%

88%

4%

10%

16%

21%

M-spike>=3 & BMPC>=10

M-spike< 3 & BMPC>=10

M-spike>=3 & BMPC<10

MGUS

MGUS and SMMMGUS and SMM

Standard of Care:Standard of Care:

Defer Treatment Until End Organ Defer Treatment Until End Organ DamageDamage

CC HyperHyperccalcemiaalcemia

RR RRenal Insufficiencyenal Insufficiency

AA AAnemianemia

B B BBone diseaseone disease

MGUS and SMMMGUS and SMM

Therapy justified only if Therapy justified only if

preventative strategy prolongs preventative strategy prolongs

survivalsurvival

MGUS/SMM SubcommitteeMGUS/SMM Subcommittee

Ann Farrell, M.D.Ann Farrell, M.D. FDAFDA

Rafael Fonseca, M.D.Rafael Fonseca, M.D. Mayo Mayo

Geraldine P. Schechter, M.D.Geraldine P. Schechter, M.D. VAVA

Robert A. Kyle, M.D.Robert A. Kyle, M.D. Mayo Mayo

MGUS Question MGUS Question

1.1. How often should the patient How often should the patient be monitored?be monitored?

2.2. Should “high risk” MGUS be Should “high risk” MGUS be treated?treated?

3.3. Why is MGUS increased in African-Why is MGUS increased in African-Americans?Americans?

SMM QuestionSMM Question

1.1. Should SMM have both M spike Should SMM have both M spike ≥ ≥ 3g/dl and plasma cells ≥ 10%.3g/dl and plasma cells ≥ 10%.

2.2. Should SMM be treated?Should SMM be treated?

3.3. Does reduction of M spike and Does reduction of M spike and plasma cells delay progression?plasma cells delay progression?