Multiple Myeloma
Pamela S. Becker, MD, PhD
Associate Professor
Division of Hematology
Case I: 44 yo F
• 17 mo ago back pain
• 12 mo ago skin rash-annular then
maculopapular erythematous rash that
was biopsied R shoulder, then a second
biopsy posterior arm. Involved face, neck,
arms, chest. Occasional pruritus.
Case I, cont’d
• Sweet’s syndrome-Prescribed Prednisone 6 mo. Prior, 40
mg, then 2 mo. prior, 20 mg
• Sudden onset severe back pain 7/04-ambulance to hosp
• LABS: CBC: WBC 6.2, hemoglobin 10.6, hematocrit 31.1,
platelet count 232K
• Urinalysis: 3-5 white cells, Leuk esterase, 1+ protein,
E.Coli
• Chem: BUN 40, creatinine 2.0, uric acid 11.6, calcium
13.5, albumin 2.8, total bilirubin 0.18, alk phos 153, AST
35, ALT 40. TP 12.3, gamma globulin 6.2, Monoclonal
protein 5.8 gm/dl IgA kappa
• CT scans: 3.5 x 1.5 cm mass in the post L chest, a mass
in the right psoas, L1-L3,
• Bone marrow biopsy performed:80-90% plasma cells
MRIs
• L-spine: mass displacing right psoas
muscle laterally involving L1 and L2 neural
foramina on the right, with possible
erosion of L2 right lateral vertebral margin.
• T spine: comp fx of T5, T10, L1, and L2
• C spine: 3 x 3 cm mass.
Therapy
• 7-04-Chemotherapy
• 75 mg Doxorubicin, 1200 mg Cytoxan, 2
mg vincristine, Dexamethasone 4 mg qid,
and Aredia 30 mg X 2
• ANC 0.2 on day 7Neupogen 300 mcg
then 480 mcg
• RBC-4 units
• Seen on day 12-Recurrent rash, WBC
3.76, beta2 microglobulin 2.4
Next therapy
• Thalidomide/Dex began 8/04
• MRI end 9/04: mass L2 to L3 vertebral region
4.6 X 3.1 x 0.8 cm. R L2 and L3 neural foramina,
? R L3 nerve root. Comp fx L3, L4, L5. L lat
sacrum enhancing lesion 2.5 X 2 cm.
• Chest CT: cardiomegaly, mid T vertebrae
sclerotic changes,comp fx, acute kyphotic
deformity, possible fx through body of sternum.
• Monoclonal protein 5.8 (7/21)2.6 (7/28), 0.4
8/30, 0.6 (10/14), 0.9 (2/10)
• Radiation to L spine
• Began Velcade/Doxil-monoclonal protein down
to 0.8 post first cycle, now s/p 2nd cycle
Next treatment: Tandem transplant
• Auto
• Mini allo from HLA matched sister
Multiple Myeloma: Incidence and
Epidemiology
• 1% of all malignancies
• 10% of hematological malignancies (2nd
most common)
• 3-4 per 100,000 population
• 16,000 new cases/yr; 11,000 deaths/yr
• Median age: 65 yo; 3%<40 yo
• M>F
• Risk: radiation exposure
Myeloma: Pathogenesis
International Working Group
Classification
• Monoclonal gammopathy of undetermined
significance (MGUS)
• Asymptomatic (Smouldering) myeloma
• [Indolent myeloma]
• Symptomatic myeloma
• Non-secretory myeloma
• Solitary plasmacytoma of bone
• Extramedullary plasmacytoma
• Multiple, recurrent plasmacytomas
• Plasma cell leukemia
Multiple myeloma: Symptoms
•
•
•
•
•
•
Fatigue
Back pain
Increased infections
Hypercalcemia
Renal insufficiency
Hyperviscosity
Multiple Myeloma: Diagnosis
• Bone marrow containing more than 10%
plasma cells or a plasmacytoma, plus at
least one of the following:
1) a monoclonal protein in the serum,
usually more than 30 g/L
2) a monoclonal protein in the urine OR
3) lytic bone lesions
Bone Marrow Plasma Cells
Bone marrow plasmacytosis
Serum Protein Electrophoresis
(SPEP)
M-protein
Albumin
1
2


κ
λ
Rouleaux on peripheral smear
Multiple Myeloma: Durie-Salmon Staging
Multiple myeloma: New staging
(International Staging System)
•
Based on Beta 2 microglobulin and
albumin
I. β2M <3.5 + Alb ≥ 3.5 Med surv 62 m
II. In between
Med surv 44 m
III. β2M >5.5
Med surv 29 m
Multiple Myeloma: Indication for
Treatment: CRAB
•
•
•
•
Calcium (Hypercalcemia)
Renal insufficiency
Anemia
Bone lesions
Monoclonal Gammopathy of
Uncertain Significance
• Often Benign; Over Many Years May Eventually Develop
Into Myeloma or Other Lymphoproliferative Disorders;
May Be Associated With Tumors
– Monoclonal Gammopathy
– M-component Level
• Igg < 3.5 G/dl
• Iga < 2.0 G/dl
• BJ Protein < 1.0 G/24 H
– Bone Marrow Plasma Cells < 10%
– No Bone Lesions
– No Symptoms
Non secretory myeloma
– no secretion of protein (relatively rare if serum
and urine carefully studied for presence of Mprotein)
– prognosis same as myeloma or longer
Plasmacytoma
• Solitary plasmacytoma of bone
– Usually progress, slowly, to myeloma
• Extramedullary plasmacytoma
– Upper respiratory tract including nasal cavity,
sinuses, nasopharynx, larynx; other sites
possible
– some progress to myeloma
Plasma cell leukemia
– loss of adhesion molecules that localize in
marrow (CD56, VLA-5, MPC-1)
– greater than 20% plasma cells in blood and >
2000/ul
– more frequent: younger age,
hepatosplenomegaly, lymphadenopathy, few
lytic lesions, small M-protein, poor prognosis
Amyloidosis
• Amyloid: homogenous, amorphous extracellular material
with fibrillar structure; made of low MW proteins that
precipitate in tissues
Amyloidosis, cont’d
• Reactive systemic amyloidosis:
– Amyloid protein A derived from catabolism of serum amyloid Arelated protein (SAA), an acute phase protein; excess production
in chronic inflammatory or infectious disorders, may result in
deposition in tissues
• Amyloid Due to an Immunologic-related Disorder
– Insoluable Catabolic Product of the Variable Region of a Light
Chain, Lambda;
– May Occur As a Result of Myeloma or Waldenstrom’s
Macroglobulinemia
• Primary Amyloidosis
– Deposits in Joint Capsules, Ligaments, Tongue, Heart (CHF), GI
Tract (Diarrhea), Peripheral Nerves (Paresthesias, Weakness,
Orthostatic Hypotension), Small Vessel Fragility From Amyloid in
Walls (Purpura), Factor X Deficiency Due to Its Binding in the
Extracellular Tissues
Organ involvement by amyloidosis
POEMS (polyneuropathy, organomegaly,
endocrinopathy, M-protein, skin changes)
– Peripheral neuropathy usually first sign
– Papilledema, hyperpigmentation, organomegaly
– < 5% plasma cells in marrow
– Association with Castleman’s disease
– Anemia, rare; usually Hct normal or
polycythemia, thrombocytosis
– Single lytic lesions improved with radiation; may
have neurologic improvement as well
– Gynecomastia, atrophic testes, clubbing
Case 2-57 yo F
•
•
•
•
•
•
•
Referred for eval of leukopenia (WBC 3)
WBC 5.27, hgb 12.8, platelets 231K
ANA neg
SPEP 0.3 g/dl monoclonal IgG lambda
Quantitative Bence Jones: Negative
Skeletal survey: Negative
Bone marrow: Lambda restricted plasma cells 0.6%
by flow; 6% by morphology with rare multinucleated
plasma cells and some with prominent nucleoli
• DIAGNOSIS: ___________
• Follow-Up: 18 months later: SPEP: 0.4 g/dl
Case 3-48 yo Hisp M
• Right femur fracture on Orthopaedics
• Flow from OR specimen: 2.9% clonal
plasma cells
• SPEP 1.3 g/dl monoclonal IgG kappa, also
IgA lambda two bands
• UPEP: same as above, and faint kappa
light chains
• Bone marrow: 47% plasma cells
Case 3 cont’d
• Enrolled on Southwest Oncology Group
Trial of Lenalidomide vs. Placebo +
Dexamethasone
• Follow up studies at 3 months: SPEP:
progressive decline, down to 0.8 g/dl.
Bone marrow plasmacytosis: 15-20%
plasma cells
• 10 months: 0.5 g/dl
• 11 months: 0.7 g/dl
Case 4: 51 yo M
• Running track, developed back pain, difficulty
walking
• CT scan: L1 lytic lesion 1.9 X 2.3 cm
• Needle biopsy: Clonal plasma cells
• SPEP negative, UPEP negative
• Bone marrow survey by MRI negative
• PET scan negative
• DIAGNOSIS: ____________
• Treatment: Radiation Therapy
• Future: 80% of vertebral plasmacytomas
myeloma
Multiple Myeloma: Therapy
•
•
•
•
•
•
•
•
Melphalan/Prednisone
VAD (now DVD)
Thalidomide/Dexamethasone
Lenalidomide/Dexamethasone
Bortezomib and combinations
Autologous Stem Cell Transplant
Minimal myeloablative Allogeneic Transplant
Tandem Transplants
Use of Dexamethasone With or Without
Thalidomide in Frontline Therapy
• ECOG E1A00: phase 3, randomized,
controlled trial
Repeated monthly
for 4 mos
Newly diagnosed,
untreated
symptomatic
MM
(N = 207)
Thal/Dex arm
Thalidomide 200 mg/day PO +
Dexamethasone 40 mg/day
on Days 1-4, 9-12, 17-20
CR/PR/
Stable
(n = 103)
Dex alone arm
Dexamethasone 40 mg/day
on Days 1-4, 9-12, 17-20
Stop therapy
Any
progression
(n = 104)
Note: Use of prophylactic anticoagulant not required.
Rajkumar V, et al. ASH 2004. Abstract 205.
Stem-cell transplant or
continue therapy at
physician’s discretion
Use of Dexamethasone With or Without
Thalidomide in Frontline Therapy
Response after 4 cycles
Grade 3 or 4 toxicity
ThaI/Dex (n = 99)
Dex alone (n = 100)
ThaI/Dex (n = 102)
Dex alone (n = 102)
100
Patients (%)
80
70
73%
80
63%
60
50
90
P = .002
Patients (%)
90
100
50%
41%
40
70
60
50
30
30
20
20
4%
10
0
Response*
Corrected
Response†
0%
Complete
Response
* ↓ in serum M protein and urine M protein
† ↓ in serum M protein (no available urine M protein)
Rajkumar V, et al. ASH 2004. Abstract 205.
34%
40
10
0
17%
18%
3%
DVT
Gr > 3
7%
4%
Neuropathy All Gr > 4
Gr > 3
toxicity
11%
7%
Deaths
Use of Melphalan Plus Prednisone With or
Without Thalidomide in Frontline Therapy
• Interim analysis of prospective,
randomized trial
MPT arm
Oral melphalan 4 mg/m2 (7 days/mo)
Prednisone 40 mg/m2 (7 days/mo)
Thalidomide 100 mg/day (continuously)
Newly diagnosed elderly
myeloma patients
Median age, 72 yrs (60-85)
(N = 177 )
(n = 89)
MP arm
Oral melphalan 4 mg/m2 (7 days/mo)
Prednisone 40 mg/m2 (7 days/mo)
(n = 88 )
Palumbo A, et al. ASH 2004. Abstract 207.
6 mos
Use of Melphalan Plus Prednisone With or Without
Thalidomide in Frontline Therapy
100
90
Response (%)
80
Progression
8.4%
28%
14.5%
Partial response (50-99*)
70
60
50
40
49.4%
77.1%
PR (50-74*)
15.6%
CR+nCR
25.3%
PR (75-99*)
33.8%
30
41.3%
20
10
No response (0-50*)
5.4%
MPT
Palumbo A, et al. ASH 2004. Abstract 207.
PR (50-74*)
28%
PR (75-99*)
13.3%
27.7%
0
* % reduction in baseline M protein
MP
New Agents: Lenalidomide
• New agents needed to address concerns regarding high
rate of nonhematologic toxicity seen with thalidomide
• CC-5013 (lenalidomide) is a potent analogue of
thalidomide
– Promising results in relapsed or refractory MM
– Significantly fewer nonhematologic toxicities
• Less peripheral neuropathy, constipation, sedation
– However, associated with neutropenia and
thrombocytopenia
CC-5013 (Lenalidomide)
Thalidomide
Bortezomib With and Without
Dexamethasone in Frontline Therapy
• Phase 2 study evaluated use of bortezomib later
supplemented with dexamethasone to boost response in
newly diagnosed patients with MM
• Treatment schedule
– Bortezomib (1.3 mg/m2, twice weekly for 2 wks)
• Administered every 3 wks for up to 6 cycles
• Given alone for first 2 cycles
– Dexamethasone (40 mg/day) on day of and day after
bortezomib
• Added after 2 cycles if < partial response
• Added after 4 cycles if < complete response
Jagannath S, et al. ASH 2004. Abstract 333.
Combination Bortezomib, Thalidomide,
Plus Dexamethasone (VTD) in
Frontline Therapy
– Thalidomide (100-200 mg/day)
– Dexamethasone (20 mg/m2)
PO Days 1-4, 9-12, 17-20
– Bortezomib (1.0, 1.3, 1.5, 1.7,
1.9 mg/m2) Days 1, 4, 8, 11
– Every 4 wks for 2-3 cycles
Alexanian R, et al. ASH 2004. Abstract 210.
P = .04
100
Response Rate*, %
• Phase 1/2 trial of frontline
bortezomib combined with
thalidomide + dex
• 30 previously untreated
patients with MM received
94%
P = .18
80%
80
68%
64%
60
40
20
0
TD All doses
alone†
†Historical
≤ 1.3
≥ 1.5
VTD
controls from nonrandomized study
* Stringent response criteria:
 ≥ 75% reduction in serum M protein
 ≥ 95% reduction in Bence Jones protein
Pulsed Melphalan, Dexamethasone,
and Thalidomide in Frontline Therapy
• Multicenter, phase 2 study of pulsed melphalan,
dexamethasone, and thalidomide in 50 elderly patients with
untreated, symptomatic MM
– ≥ 75 yrs of age
– Poor performance status (58% had PS ≥ 2)
– Advanced-stage disease (58% had ISS 3)
• Treatment schedule (3 courses every 5 wks, all oral)
– Melphalan (8 mg/m2) Days 1-4
– Dexamethasone (12 mg/m2) Days 1-4 and 14-18
• Intensity less than half that of standard high-dose
dexamethasone
– Thalidomide (300 mg) Days 1-4 and 14-18
• Intermittent
dosing
used
Dimopoulos
MA, et al. ASH 2004.
Abstract 1482.
Pulsed Melphalan, Dexamethasone,
and Thalidomide in Frontline Therapy
• 68.2% of patients
responded
– Partial response,
61.4%
– Complete response,
6.8%
– Median time to
response, 2 mos
(range 0.5-14.0)
• Generally well tolerated
– 25 infectious episodes
• 1 fatality
Dimopoulos MA, et al. ASH 2004. Abstract 1482.
• Other adverse events
– Gr 3/4 neutropenia (15%)
– Gr 3/4 thrombocytopenia
(10%)
– Somnolence (35%)
– Constipation (30%)
– Tremors (25%)
– Xerostomia (15%)
– Headaches (10%)
– DVT (10%)
– Peripheral neuropathy
(10%)
Treatment of
Relapsed/Refractory Multiple
Myeloma
Bortezomib vs Dexamethasone in
Relapsed/Refractory Multiple Myeloma
• APEX: international, phase 3, randomized
trial
Bortezomib Arm
Stratified by:
• No. of prior therapies
• Refractory disease
• B-2 microglobulin
Patients with
relapsed or
refractory MM
(N = 669)
Induction: 1.3 mg/m2 IV Days 1, 4, 8, 11
q3 wks for 8 cycles
Maintenance: 1.3 mg/m2 IV Days 1, 8, 15, 22
q5 wks for 3 cycles
(n = 333)
Dexamethasone Arm
Induction: 40 mg PO Days 1-4, 9-12, 17-20
q5 wks for 4 cycles
Maintenance: 40 mg PO Days 1-4
q4 wks for 5 cycles
(n = 336)
Total days on therapy:
278 for bortezomib and 280 for dexamethasone
Trial halted 1 year early by data monitoring
committee due to superiority of bortezomib arm
Richardson P, et al. ASH 2004. Abstract 336.5.
Bortezomib vs Dexamethasone in
Relapsed/Refractory Multiple Myeloma
78% improvement in median time to progression (TTP) with bortezomib
1.0
Median TTP
Bortezomib
Dexamethasone
Proportion of patients
0.9
0.8
All Pts
6.2 mos
3.5 mos
Pts 1 relapse*
7.0 mos
5.6 mos
0.7
* Patients treated as secondline, after first relapse
0.6
0.5
0.4
P = .0001
0.3
Bortezomib
Dexamethasone
0.2
0.1
0.0
0
30
60
90 120 150 180 210 240 270 300 330 360 390 420 450
Time (days)
Richardson P, et al. ASH 2004. Abstract 336.5.
Bortezomib vs Dexamethasone in
Relapsed/Refractory Multiple Myeloma
41% decreased risk of death with bortezomib
1.0
P = .005
Proportion of patients
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Bortezomib
Dexamethasone
0.2
0.1
1-yr survival
Bortezomib
Dexamethasone
All Pts
80%
66%
Pts 1 relapse*
89%
72%
* Patients treated as secondline, after first relapse
0.0
0
30
60
90
120
150
180
210
Time (days)
Richardson P, et al. ASH 2004. Abstract 336.5.
240
270
300
330
360
MYELOMA:
STEM CELL
TRANSPLANT
Conventional
Dose Chemo
vs. Auto
Transplant in
Multiple
Myeloma
Tandem Auto Transplant
Auto then mini Allo
Figure 4. Kaplan-Meier estimates of overall survival and progression-free survival following
nonmyeloablative allografts for myeloma
Maloney, D. G. et al. Blood 2003;102:3447-3454
Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.
BMT Clinical Trials Network
• Tandem Auto VS
• Auto then mini-Allo (if have an HLAidentical sibling)