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