Steering Committee
Rafael Fonseca, MD
Getz Family Professor of Cancer
Chair of Internal Medicine
Mayo Clinic in Arizona
Scottsdale, AZ
Sergio Giralt, MD
Chief, Adult Bone Marrow Transplant Service
Memorial Sloan-Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, NY
Faculty Speakers
Ajai Chari, MD
Assistant Professor of Medicine
Director of Clinical Research in the Multiple Myeloma Program
Mount Sinai Medical Center
New York, NY
Keren Osman, MD
Assistant Professor of Medicine
Mount Sinai Medical Center
New York, NY
Disclosures
All relevant financial relationships with commercial interests reported by
faculty speakers, steering committee members, non-faculty content
contributors and/or reviewers, or their spouses/partners have been listed
in your program syllabus.
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and Drug
Administration. PCME does not recommend the use of any agent outside of
the labeled indications. Please refer to the official prescribing information
for each product for discussion of approved indications, contraindications
and warnings. The opinions expressed are those of the presenters and are
not to be construed as those of the publisher or grantors.
Educational Objectives
At the conclusion of this activity, participants should be able to
demonstrate the ability to:
• Assess the prognosis of patients based on risk stratification and
patient- and disease-related characteristics that influence the
selection of optimal treatment in frontline, maintenance, and
relapsed/ refractory settings
• Review current and emerging maintenance therapy options
considered for MM
• Review treatment options for patients with relapsed/refractory MM
• Identify and manage common treatment-related toxicities in MM
• Evaluate clinical trial opportunities for patients with
relapsed/refractory MM
ARS Question 1
Pre-activity Survey
Please choose your degree:
A. MD/DO
B. Nursing Professional
C. PharmD
D. Other
ARS Question 2
Pre-activity Survey
Please choose your specialty:
A. Oncology/Hematology
B. Transplant
C. Internal Medicine
D. Other
ARS Question 3
Pre-activity Survey
Please rate your current level of confidence in treating and
managing patients with MM:
A. Not knowledgeable
B. Slightly knowledgeable
C. Somewhat knowledgeable
D. Highly knowledgeable
E. Expert
ARS Question 4
Pre-activity Survey
Please rate your current level of competence in using
emerging data from clinical studies to individualize treatment
options for patients with MM:
A. Not competent
B. Slightly competent
C. Somewhat competent
D. Highly competent
E. Expert
Multiple Myeloma: Epidemiology
• Approximately 22,400 new cases in 2013
– 10,800 associated deaths
• African Americans >2x
• Hispanics 1.7x
• Median age 66 years
– Age <50 years: 10%
– Age <40 years: 2%
Cancer Facts and Figures. American Cancer Society. 2013.
Diagnosis of Myeloma
CLINICAL CRITERIA
• Evidence of plasma cell clone
• Usually >10%, but not always
• Any level of protein
• Difference between SMM and MM is CRAB
LABORATORY TESTING
“M spike”
Alb.
a1 a2
Polyclonal hump
b
g
Monoclonal protein
Alb
a1
a2
b
Polyclonal protein
Picture courtesy of Drs. R. Kyle and J. Katzmann. Mayo Clinic; NCCN Clinical Practice Guidelines v2.2013.
g
Importance of Progression Events
CRAB CRITERIA
• Calcium elevation
• Renal disease
• Anemia
• Bone disease
Durie BG et al. Leukemia. 2006;20:1467-1473.
C A
R B
Multiple Myeloma: Prognosis
• Survival statistics unknown now
– If not high risk, many survive 10 years
– High risk = 3 years
• Some 10%-20% of patients have long-term control with SCT
• Prognosis dictated by host features and genetics
– High risk – 17p13, t(4;14), and t(14;16)
– Gene expression profiling
• Other markers: high LDH, hypodiploidy, IgA, plasmablastic
• International Staging System (ISS) is useful to compare
patients with published data
• ISS has replaced the Durie-Salmon staging system
Fonseca R et al. Leukemia. 2009;23:2210-2221.
OS by high risk cytogenetics
N= 256 all patients received RVD
High risk all received 3 drug
maintenance
Nooka et a, ASCO 2012
Case Discussions
Myeloma Tales of Two Cases
Case 1
Case 2
• 55-year-old female presents with
asymptomatic anemia of 10 g/dL
and total serum protein 10 g/L
• 55-year-old female presents with
asymptomatic anemia of 10 g/dL and
total serum protein 10 g/L
• Work-up reveals
• Work-up reveals
– 30% plasma cells
– 30% plasma cells
– Cytogenetic diploid
– Cytogenetic t 4,14
– IgA kappa peak of 3.2
– IgA kappa peak of 3.2
– Beta 2 microglobulin of
3.0/Albumin 2.0 g/dL
– Beta 2 microglobulin of 5.0
– Survey no lytic lesions
• What induction therapy should she
receive?
• What induction therapy should she
receive?
– Survey multiple lytic lesions
ARS Question 5
Which of the following treatment options is not a
suitable choice for Patients #1 & #2 at this point?
A. Thalidomide + dexamethasone (TD)
B. Lenalidomide + dexamethasone (RD)
C. Bortezomib + dexamethasone (VD)
D. Lenalidomide + bortezomib + dexamethasone (RVD)
E. Thalidomide + melphalan + prednisone (TMP)
ARS Question 5 Answer
Which of the following treatment options is not a
suitable choice for Patients #1 & #2 at this point?
A. Thalidomide + dexamethasone (TD)
B. Lenalidomide + dexamethasone (RD)
C. Bortezomib + dexamethasone (VD)
D. Lenalidomide + bortezomib + dexamethasone (RVD)
E. Thalidomide + melphalan + prednisone (TMP)
Multiple Myeloma Treatment Linesa
Front-line treatment
Induction
IMID:Thal-Len
Proteosome Inhibitor: Bor-Car
Steroids: Dex-Pred
Alkylator: Cyclo-Mel
Anthracycline: LipoDox-Dox
aTransplant
Consolidation
SCT
Maintenance
Relapsed
Maintenance
Observation
IMID: Thal, Len
Proteosome Inh: Bor
Steroids: Dex-Pred
Rescue
IMID: Thal-Len-Pom
Proteosome Inh: Bor-Car
Steroids: Dex-Pred
Alkylators: Mel-Cy-Benda
Investigational
eligible patients.
Bor = bortezomib; Dex = dexamethasone; Dox = doxorubicin; Thal = thalidomide; Len = lenalidomide;
SCT = stem-cell transplant; Pred = prednsione; Lipo/Dox = liposomal doxorubicin.
NCCN Clinical Practice Guidelines v2.2013.
Achieving a VGPR (or CR) should be the goal
Kaplan-Meier
Estimate
β2 mic (3 mg/L)
t(4;14) ± del (17p)
Achieving ≥VGPR after induction
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
RR
P Value
1.68
1.46
0.83
0.0001
0.034
0.0001
P<0.0001
No
0
10
20
Yes
30
40
50
Months
PFS
Median
≥VGPR
N=117
<VGPR
N=324
41 m
30 m
Harousseau JL et al. Presented at: 50th Annual ASH Meeting; December 2008; San Francisco, CA.
PETHEMA long term follow up
Functional cure?
Martinez-Lopez et al, Blood 2011
Who gets a CR?
● Alkylators
and Steroids
● Newer
Agents
– Predominately good risk
– Good and Poor risk
– Low stage
– Addition of new agents
overcomes some poor risk
features
– Hyperdiploid
– Low Proliferation
– CRs occur in the good and
the bad
This change in the spectrum of who
achieves a CR has changed who is ‘at risk’
and adds validity to the newer OS data
Combinations in the Upfront Treatment of MM
Combination therapy incorporating novel agents results in near 100% ORRs
Stewart AK et al. Blood. 2009;115:4006.
ECOG E4A03, Lenalidomide is better
Response
RD
N = 223
Rd
N = 222
P
≥ PR within 4 cycles
79%
68%
0.008
≥ VGPR within 4 cycles
42%
24%
< 0.008
RD
N = 223
Rd
N = 222
P
Any grade > 3 non-heme toxicity
52%
35%
< 0.001
Early deaths (< 4 months)
5%
0.5%
0.003
Grade 3 DVT
- after the addition of aspirin
26%
16%
12%
8%
0.003
Infections
16%
9%
0.04
Fatigue
15%
8%
0.08
Toxicity
RD: Lenalidomide + high-dose dexamethasone
Rd: Lenalidomide + low-dose dexamethasone
Rajkumar SV, et al. Lancet Oncol. 2010;11(11):29-37.
VD is better but more work to do
Bor / Dex*
n = 223
VAD*
n = 218
P
Post-Induction
15%
7%
0.003
After 1st ASCT
35%
18%
< 0.0001
After 2nd ASCT
39%
32%
< 0.0001
Post-Induction
39%
16%
< 0.0001
After 1st ASCT
54%
37%
0.0003
After 2nd ASCT
68%
47%
< 0.0001
36 mo
30 mo
0.057
CR + nCR
> VGPR
Median PFS
*+ DCEP.
DCEP did not increase the response rate.
Harousseau JL, et al. Blood. 2009:114(22). Abstract 354.
GIMEMA, VTD vs TD, Phase III
Bor / Thal / Dex vs Thal / Dex
Untreated
Multiple
Myeloma
< 65 Years
N = 460
Bort
Thal
1:1
Dex
CTX
Thal
Dex
Induction:
Melphalan
+
ASCT
Bort
Thal
1:1
Dex
Dex
Thal
Dex
3-21-day/cycle; Bortezomib 1.3 mg/m2, d1, 4, 8, 11; Thalidomide 100-200 mg/d,
d1-63; Dexamethasone 320 mg/cycle
Consolidation: 2-35-day/cycle; Bortezomib 1.3 mg/m2, d1, 8, 15, 22; Thalidomide 100 mg/d,
d1-70; Dexamethasone 320 mg/cycle
Cavo M, et al. Blood. 2009:114(22). Abstract 351.
Cavo M, et al. Blood. 2008:112(11). Abstract 158.
GIMEMA, VTD vs TD: Results
Response to Induction*
Bor / Thal / Dex
n = 236
Thal / Dex
n = 238
P
CR
19%
5%
< 0.001
CR + nCR
26%
9%
< 0.001
> VGPR
61%
28%
< 0.001
Bor / Thal / Dex
Thal / Dex
P
CR
57%
31%
0.0001
CR + nCR
70%
51%
< 0.0001
> VGPR
88%
72%
< 0.0001
> PR
95%
89%
0.01
30-month PFS
76%
58%
0.009
Response to Protocol*
• OS at 30 months was not significantly different
*Centrally assessed.
• PFS remained superior with VTD when analyzed by age, ISS stage, LDH level, albumin level,
del(13q), t(4;14), and del(17p)
Cavo M, et al. Blood. 2009:114(22). Abstract 351.
Progression-Free Survival
Probability of Survival
Without Progression
100
80
VTD
60
HR, 0.63 [CI: 0.45–0.88]
P=0.0061
40
TD
Probability at 3 yrs (%)
P=0.0057
VTD TD
68 56
20
37% relative reduction of risk of
progression or death in VTD arm
0
0
No. of patients at risk
VTD
236
TD
238
Cavo M et al. Lancet. 2010;376:2075.
6
12
18
24
30
36
42
48
111
99
55
51
21
13
2
2
Months
230
218
212
200
195
185
159
158
TD Failed to Overcome the Poor Prognosis
Related to the Presence of t(4;14) PFS
Probability of Survival
Without Progression
100
100
t(4;14)-negative
80
80
t(4;14)-negative
60
60
40
40
t(4;14)-positive
t(4;14)-positive
20
0
20
t(4;14)
Probability at 3 yrs (%) Pos. Neg.
37
63
P=0.0131
0
6
12
18
24
30
Months
Cavo M et al. Lancet. 2010;376:2075.
36
42
0
48
t(4;14)
Probability at 3 yrs (%) Pos. Neg.
69
74
P=0.66
0
6
12
18
24
30
Months
36
42
48
RVD, Phase II, Response
Response
All patients
N = 66
Phase II
N = 35
ORR ( > PR)
100%
100%
CR + nCR
39%
57%
> VGPR
67%
74%
R, lenalidomide; V, bortezomib; D, dexamethasone.
• With a median follow-up of 27.3 months median duration of response, PFS,
and OS have not been reached
– 18-month PFS: 75%; 18-month OS: 97%
• Stem cell collection (31 patients)
– Median: 5.6 x 106 CD34+ cells/kg
Richardson PG, et al. Blood. 2010;116(5):679-686.
Frontline Therapy for MM with RVD Regimen
• RVD is highly effective for previously untreated MM
– The first regimen to result in a 100% response rate (≥PR) without ASCT
– Remarkably high rates of CR/nCR and ≥VGPR
• Promising outcomes data; estimated 24-month PFS of 68% and OS of
95% with RVD ± ASCT
• Favorable tolerability over a lengthy treatment period
– Manageable toxicities
– Only 2% G3 sensory PN, 6% DVT; no treatment-related mortality
– All-grade PN 80%, but mainly G1/2 and reversible
– Stem cell mobilization feasible and successful in almost all patients
Richardson et al. Blood 116: 2010 (679-686); Anderson, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 8016)
What Toxicities Should You Monitor in These Patients?
IMID-associated Deep Venous Thrombosis
• Pathophysiology unclear
– MM, unlike solid tumor does not express tissue factor
– Platelet activation via cathepsin G
• Prevention is key
– Low risk aspirin
– High risk anticoagulation
•
High dose dex, immobility, prior DVT, comorbidity
• Pearls
– Continue until at least 1-2 months post completion
– Do not forget to bridge for surgical procedures
– Not a reason to abandon treatment
Palumbo A et al. Blood Rev. 2011;25:181-191.
Richardon PG et al. Leukemia. 2012;26:595-608.
Other Toxicities: Peripheral Neuropathy
• Peripheral neuropathy (PN) – one of the most important
complications of MM treatment
• PN can be caused by MM itself, and particularly by certain
therapies, including bortezomib, thalidomide, vinca alkaloids, and
cisplatin
• Up to 20% of MM patients have PN at diagnosis, and as many as
75% may experience treatment-emergent PN during therapy
• Bortezomib causes any grade PN in 31% to 47% patients
• Lower-than-expected rates of severe PN with bortezomib plus
lenalidomide combinations, with grade 3 PN rates of 3% and 2%
with bortezomib, lenalidomide, and dexamethasone (RVD) in
frontline and relapsed/refractory patients, respectively
Palumbo A et al. Blood Rev. 2011;25:181-191.
Richardon PG et al. Leukemia. 2012;26:595-608.
ARS Question 6
Which of the following is not a supportive care
consideration for a patient treated with
lenalidomide/dexamethasone alone?
A. There is a very high risk of peripheral neuropathy with this
regimen
B. Prophylactic treatment for deep vein thrombosis should be
initiated
C. Anticipate the possibility of infection
D. Long-term complications might include diarrhea and
fatigue
ARS Question 6 Answer
Which of the following is not a supportive care
consideration for a patient treated with
lenalidomide/dexamethasone alone?
A. There is a very high risk of peripheral neuropathy with this
regimen
B. Prophylactic treatment for deep vein thrombosis should be
initiated
C. Anticipate the possibility of infection
D. Long-term complications might include diarrhea and
fatigue
ARS Question 7
What would you recommend for Patients #1 & #2 at this
point?
A. Recommend participation in a clinical trial
B. Offer autologous transplantation after successful
induction therapy
C. Allogeneic transplantation after successful induction
D. RVD therapy without collection of stem cells or a
planned maintenance strategy
ARS Question 7 Answer
What would you recommend for Patients #1 & #2 at this
point?
A. Recommend participation in a clinical trial
B. Offer autologous transplantation after successful
induction therapy
C. Allogeneic transplantation after successful induction
D. RVD therapy without collection of stem cells or a
planned maintenance strategy
Autologous vs Allogeneic
AUTOLOGOUS
ALLOGENEIC
• High-dose therapy with
reinfusion of own
cryopreserved cells
• Immunosuppressive Rx with
infusion of cells from another
person
• Safer, TRM <5%
• Risk of rejection, GVHD
• Possible contamination with
malignant cells
• Higher risk, TRM 10%-40%
• No graft-vs-malignancy effect
• Lower risk of relapse
• Higher risk of relapse
• Graft-vs-malignancy occurs
• Can perform in diseases in
which blood and BM involved
Autologous Transplantation vs Conventional
Chemotherapy for Newly Diagnosed Myeloma
Barlogie et al
Lenhoff et al
Attal et al
Fermand et al
Blade et al
Child et al
Conventional*
HDT
Conventional*
HDT
Conventional
HDT
Conventional
HDT
Conventional
HDT
Conventional
HDT
Pts
(n)
116
123
274
274
100
100
96
94
83
81
200
201
CR
(%)
–
40
–
34
5
22
–
–
11
30
9
44
EFS
(mos)
22
49
27
18
27
19
24
34
43
20
32
* Historical controls
Fermand J. Blood. 1998;92:3131.
Blade J. Blood. 2001;98:815a.
Barlogie B. Blood. 1997;89:789.
Lenhoff S. Blood. 2000;95:7.
Attal M. N Eng J Med. 1996;335:91.
OS
(mos)
48
62
46% @ 48
61% @ 48
37
52% @ 60
50
55
67
67
42
55
PETHEMA long term follow up
Functional cure?
Martinez-Lopez et al, Blood 2011
BMT-CTN 0102 Trial: Survival Outcomes after the First Transplant
Auto-Auto vs Auto-Allo: Intent-to-treat Analysis (n=710)
100
Progression-free Survival
Overall Survival
Auto/Auto, 80% @ 3yr
90
90
Auto/Auto, 46% @ 3yr
80
80
Auto/Allo, 77% @ 3yr
70
Probability, %
100
70
60
60
50
50
Auto/Allo, 43% @ 3yr
40
40
30
30
20
20
10
P-value = 0.67
10
P-value = 0.19
0
Months
0
0
Auto/Auto 436
Auto/Allo 189
6
395
165
12
348
138
18
292
117
24
242
105
Krishnan et al. Lancet Oncol. 2011;12:1195-1203.
30
36
42
48
0
6
213
89
N U M B E R AT R I S K :
424
178
54
42 436
189
183
71
23
16
12
18
24
30
36
42
48
406
167
395
160
370
156
348
143
305
124
107
43
79
27
BMT-CTN 0102 Trial: Cumulative Incidence of Disease
Progression/Relapse and Treatment-related Mortality after
First Transplant
100
Progression/Relapse
Treatment-related Mortality
P-value = 0.41
Cumulative Incidence, %
90
100
P-value < 0.001
90
80
80
70
70
60
60
Auto/Auto, 46% @ 3yr
50
50
40
40
30
30
Auto/Allo, 40% @ 3yr
Auto/Auto, 4% @ 3yr
20
20
Auto/Allo, 12% @ 3yr
10
10
0
0
0
6
12
18
24
30
36
42
48 0
Months
Krishnan et al. Lancet Oncol. 2011;12:1195-1203.
6
12
18
24
30
36
42
48
Role of allogeneic transplant for MM
• Limited utility to most patients due to excessive TRM and
continued risk of relapse
• No evidence that allo grafting improves outcomes for high
risk disease, multiple negative trials
• Is a reasonable option when performed in the context of a
clinical trial testing a new approach, but may limit access
to new agents
Lenalidomide Maintenance After Transplantation
Comparisons
CALGB 100104
Thal- and Len-containing
regimens (74%)
None
One
Induction
Pre-AHSCT consolidation
Number of AHSCT
Post-AHSCT consolidation before
randomization
Median F/U at un-blinding
Median F/U from randomization
Dosing schedule
Time from first patient enrolled
Placebo patients crossed over to
lenalidomide at un-blinding
Second primary malignancies
Increase in AML/MDS
Increase in ALL/HL
Maintenance stopped
None
~18 months
31 months
10 mg (between 5 to 15 mg)
78 months
Yes (86 of 128 eligible
patients)
~3 fold increase
Yes
No
No
McCarthy PL. J Natl Compr Canc Netw. 2013;11:35-42.
IFM 2005-02
VAD (~52%) and VD (~44%)
DCEP (~25%)
One (79%), Two (21%)
Lenalidomide: 25 mg daily, 3 of
4 wks x 2 pre day ~100
~33 months
45 months
10 mg (between 5 to 15 mg)
62 months
No
~2.6 fold increase
No
Yes
Yes at a median of ~32 months
86 of 128 placebo patients
crossed over to lenalidomide
CALGB 100104, NEJM 2012
follow up to 10/31/2011
ITT Analysis with a median follow-up from transplant of 34
months. P < 0.001 Estimated HR=0.48 (95% CI = 0.36 to
0.63), Median TTP: 46 months versus 27 months.
Median follow-up of 34 months
CALGB 100104, NEJM 2012
follow up to 10/31/2011
35 deaths in the lenalidomide arm and 53 deaths in the
placebo arm. P = 0.028, 3 yr OS 88 vs 80%, HR 0.62 or a
38% reduction in death with the cross over
Treatment schedule
l 402 patients (younger than 65 years) randomized from 62 centers
l Patients: Symptomatic disease, organ damage, measurable disease
1°
2°
MPR
Rd*
four 28-day courses
R: 25 mg/d, days 1-21
d: 40 mg/d, days
1,8,15,22
R
A
N
D
O
M
I
Z
A
T
I
O
N
six 28-day courses
M: 0.18 mg/Kg/d, days 1-4
P: 2 mg/Kg/d, days 1-4
R: 10 mg/d, days 1-21
MEL200
two courses
M: 200 mg/m2 day -2
Stem cell support day 0
R
A
N
D
O
M
I
Z
A
T
I
O
N
NO
MAINTENANCE
MAINTENANCE
28-day courses until relapse
R: 10 mg/day, days 1-21
*Thromboprophylaxis randomization: aspirin vs low molecular weight heparin
R, lenalidomide; d, low-dose dexamethasone; M, melphalan; P, prednisone; MEL200, melphalan 200 mg/m 2
MPR vs MEL200
Overall survival
Progression-free survival
Median PFS
100
MPR
24 months
MEL200
38 months
5-year OS
100
75
75
50
50
HR 1.69
25
MPR
62%
MEL200
71%
HR 1.25
25
P <.0001
P =.27
0
0
0
10
20
30
40
Months
50
60
70
0
10
20
30
40
Months
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2
50
60
70
MPR vs MEL200 vs MPR-R vs MEL200-R
Progression-free survival
Overall survival
100
100
MEL200-R
75
75
MPR-R
MEL200
50
MPR
50
MEL200-R
MEL200
25
25
MPR-R
MPR
0
0
10
20
30
40
Months
50
60
0
70
0
10
20
30
40
50
60
70
Months
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance
Emory Risk based maintenance therapy
•
•
•
•
Standard risk, in CR, len vs observation (leaning len)
Standard risk not in CR, len maintenance
T (4:14), Bz maintenance
High risk ( PCL, t(14:16), del 17p) RVD maintenance off
protocol, Car/pom is next protocol
• For High risk patients (and all if possible) limit exposure to
alkylators in the front line
Myeloma Tales of Two Cases
CASE 1
CASE 2
• 55-year-old female presents with
asymptomatic anemia of 10 g/dL
and total serum protein 10 g/L
• 55-year-old female presents with
asymptomatic anemia of 10 g/dL
and total serum protein 10 g/L
• Receives RVD x 4 followed by
autologous SCT and lenalidomide
maintenance
• Receives RVD x 4 followed by
autologous SCT and lenalidomide
maintenance
• Achieves a CR
• Achieves a CR
• 3 years later has reemergence of
SPEP at 0.5 mg/dL
• 1 year later has reemergence of
SPEP at 0.5 mg/dL
• What should next step be?
• What should next step be?
Types of Relapse
Clinical Patterns of Relapses after
Autologous PBSC Transplantation
Alegre A et al. Haematologica. 2002;87:609-614.
Treatment Administered for Relapse of
Progression after Autologous PBSCT
New Patterns of Relapse
 64 out of 153 asymptomatic patients had routine imaging available.
 Twenty-five (40%) had new bone lesions by SS (n = 12), PET/CT (n = 11), or MRI
(n = 2) despite absence of any prior suspicion.
Zamarin D et al. Bone Marrow Transplant. 2013;48:419-424.
Case 3
• A 72-year-old male is diagnosed with MM. He started with back pain which
lead to the discovery of anemia (Hgb 9.1) and 3 compression fractures
• A BM showed 60% kappa plasma cells
• His IgG is 4200 mg/dL, kappa FLC is 79 mg/dL, beta 2 microglobulin 8,
creatinine 1.0, calcium is normal
• FISH shows hyperdiploidy and no -17 or -13
• He has a complicated PMH
–
–
–
–
–
–
CAD with stent 2 years previous
Depression
Type 2 diabetes, diet controlled
HTN
Obesity
Atrial fibrillation
• He is retired and recently widowed
Case 3 (continued)
• He is started on len-dex
• His creatinine has worsened and is now 1.7 mg/dL
– The patient self-reports poor PO fluid intake
• Len-dex is poorly tolerated – fatigue and insomnia
• After only one month the patient requests treatment
discontinuation or change
• He states he is interested only “in quality of life not
quantity”
ARS Question 8
Case 3: What change would you
recommend for this patient?
A.
B.
C.
D.
Stop treatment
Decrease lenalidomide from 25 to 10
Stop dexamethasone alone
Decrease dexamethasone from 40 mg weekly to 20
mg weekly
E. Change treatment
F. B, D or E
ARS Question 8 Answer
Case 3: What change would you
recommend for this patient?
A.
B.
C.
D.
Stop treatment
Decrease lenalidomide from 25 to 10
Stop dexamethasone alone
Decrease dexamethasone from 40 mg weekly to 20
mg weekly
E. Change treatment
F. B, D or E
Case 3: Second-line Treatment
• The patient is treated with CyBorD with lower doses of
dexamethasone (20 mg weekly)
– Bortezomib is given IV weekly
• He tolerates well the first cycles
• By cycle 3 he reports signs of early peripheral neuropathy
on his feet
• He also complains “his shoes don’t fit him anymore”
• He complains of mild SOB
SQ Administration of Bortezomib
•
•
•
•
•
Randomized Phase III study
1-3 previous lines of therapy
Up to eight 21-day cycles of bortezomib
Primary response was non-inferiority (4 cy)
222 patients assigned to receive Rx
– 145 SQ and 73 IV
• ORR same (42% vs 42%)
– After 8 cycles 52% vs 52%
Moreau P et al. Lancet Oncol. 2011;12:431-440.
Results SQ Bortezomib
• Median FU 11.8 mos, no difference in TTP
– 10.4 vs 9.4 mos
• One year OS 72% vs 76%
• Grade 3/4 events favored SQ (57% vs 70%)
• PN less common with SQ 38% vs 53% (P=0.04)
– Grade 2 or worse 24% vs 41% (P=0.012)
– Grade 3 or worse 6% vs 16% (P=0.026)
Moreau P et al. Lancet Oncol. 2011;12:431-440.
Case 3: Second-line Treatment
• Bortezomib is changed to weekly SQ
• Dexamethasone is lowered to 8 mg weekly
• You continue on treatment and have provided 7 cycles
• The patient returns for cycle 8 and is complaining of left
chest wall pain; No SOB
– EKG, TnT, and CxRay are fine
– A day later a vesicular rash develops
– You forgot to add a medication!
ARS Question 9
Case 3: Treatment-related Toxicities
Which of the following is true?
A. Cyclophosphamide causes drug rash commonly
B. Dexamethasone and bortezomib can elicit StevenJohnson like syndrome
C. Pemphigoid lesions are common in MM
D. Reactivation of herpes zoster is common with
proteasome inhibitors
ARS Question 9 Answer
Case 3: Treatment-related Toxicities
Which of the following is true?
A. Cyclophosphamide causes drug rash commonly
B. Dexamethasone and bortezomib can elicit StevenJohnson like syndrome
C. Pemphigoid lesions are common in MM
D. Reactivation of herpes zoster is common with
proteasome inhibitors
Case 3: Relapse
• After 18 months of observation, the patients shows
indicators of relapse. He still complains of symptoms from
his PN.
ARS Question 10
What drug could you use?
A. Repeat Lenalidomide, without dexamethasone
B. Carfilzomib or Pomalidomide
C. Repeat CyBorD
ARS Question 10 Answer
What drug could you use?
A. Repeat Lenalidomide, without dexamethasone
B. Carfilzomib or Pomalidomide
C. Repeat CyBorD
Carfilzomib PX-171-003-A1: Best Overall Responses
All patients
(n=257)
Patients with unfavorable
cytogenetic/FISH marker (n=71)
1 (0.4)
13 (5.1)
47 (18.3)
34 (13.2)
81 (31.5)
69 (26.8)
12 (4.7)
61 (23.7)
18.7 – 29.4)
95 (37.0)
31.1 – 43.2
3.7 (2.8 – 4.6)
7.8 (5.6 – 9.2)
3.0 (0.03 – 16.9)
0 (0)
3 (4.2)
18 (25.4)
3 (4.2)
28 (39.4)
15 (21.1)
4 (5.6)
21 (29.6)
19.3 - 41.6
24(33.8)
23.0 – 46.0
3.6 (2.3-4.6)
6.9 (3.7-8.5)
3.6 (0-11.1)
Response category, n(%)
CR
VGPR
PR
MR
SD
PD
Not evaluable
Overall Response, n(%)
95% CI
Clinical benefit rate, n(%)
95% CI
PFS, median (95% CI), mo
Median DoR, mo (95% CI)
Mean treatment duration, mo (range)
Key Inclusion Criteria: Relapsed MM; ≥2 prior therapies (including bortezomib and thalidomide and/or lenalidomide);
≤25% response to the most recent therapy or disease progression during or within 60 days of the most recent therapy
KYPROLIS [package insert]. Onyx Pharmaceuticals, Inc; 2012.
Siegel D et al. Blood. 2012;120:2817-2825.
Carfilzomib PX-171-003-A1 (N=257): PFS and OS
PFS (by response)
Adapted from Siegel D et al. Blood. 2012;120:2817-2825.
OS (by response)
Pomalidomide + Low-dose Dex for Relapsed
MM (MM-002): ORR, PFS, and DoR
POM + LoDEX
(n = 113)
34
45
Responsea
ORR (≥ PR) (%)
≥ MR (%)
POM
(n = 108)
15
31
Median DoR
Median PFS
100
POM + LoDEX (n = 113)
4.6 mos
POM (n = 108)a
2.6 mos
100
8.3 mos
POM (n = 16)
8.8 mos
80
Patients, %
80
Patients, %
POM + LoDEX (n = 38)
60
HR = 0.67
P = 0.002
40
60
20
20
0
0
0
5
10
15
PFS (mos)
Jagannath S, et al. Blood. 2012;120:abstract 450.
20
25
30
HR = 0.89
P = 0.734
40
0
5
10
15
20
Duration of response (mos)
25
Pomalidomide + Low-dose Dex for Relapsed MM
Lacy M et al. J Clin Oncol. 2009;27:5008-5014.
Pomalidomide + Dex in Relapsed MM
• Pom + LoDex vs HiDex significantly extended PFS and OS
in pts who failed LEN and BORT.
• Toxicity is manageable and consists primarily of
hematological toxicity
• Effective in high-risk patients
• Pomalidomide combinations should be explored (e.g,
Pom/Bor/Dex, second generation PIs, alkylating agents)
San Miguel et al, 2013, ASCO, abstr 8510; Lacy et al, 2009, JCO, 27(30): 5008-5014; Lacy MQ, et al. Haematologica. 2011;96(1):s21
Elotuzumab + Len/Dex Study
• Elotuzumab is a humanized IgG1 mAb targeting human CS1, a
cell surface glycoprotein
• CS1 is highly expressed on >95%
of MM cells
– Lower expression on NK cells
– Little to no expression on normal tissues
• Results look very good for this patient population and justify
phase III studies
– ORR 84% (92% in elotuzumab 10 mg/kg group)
– ORR 91% if 1 line of therapy
– PFS NR for 10 mg/kg and 18.6 months for 20 mg/kg
Lonial et al., ASCO 2012, Abstract 8020; Richardson et al., ASH 2012, Abstract 202.
Next Steps for Elotuzumab + Len/Dex
• Two ongoing Len/Dex +/- Elotuzumab studies
• Bor/Dex +/- Elotuzumab phase II study initiated (abstract
#92855)
• Can we do even better by combining elotuzumab with 3-drug
regimens or other agents?
– Is cost going to be a concern?
• How to use elotuzumab in LEN-refractory patients may need to
be addressed
• Lower PFS in high-risk patients is disappointing
– There is a potential for relative benefit
Lonial et al., ASCO 2012, Abstract 8020; Richardson et al., ASH 2012, Abstract 202.
Ixazomib (MLN8708) in Relapsed/Refractory
(R/R) MM: Phase I Data
• Phase I data suggest clinical activity in R/R MM patients (median 4
prior lines of therapy)
– ORR (≥PR) of 18%, plus 2% MR, and 30% SD
– Responses seen in patients with prior exposure to proteasome
inhibitors, including patients relapsed after bortezomib.
• Among 50 response-evaluable patients,
– 15 (30%) had M-protein reduction of ≥25%,
– 9 (18%) had best M-protein reductions of ≥50%, including 3 of
≥90% and 1 immunofixation-negative
• A phase III trial in R/R is current recruiting participants
(TOURMALINE-MM1; NCT015645347)
Kumar et al, ASCO 2013, J Clin Oncol 31, 2013 (suppl; abstr 8514).
MLN9708 (Ixazomib, a Novel Proteasome Inhibitor) in Combination with len + dex
in Previously Untreated MM: Evaluation of Weekly and Twice-weekly Dosing
Preliminary response in weekly dosing study: pts treated with ≥4 cycles
Response, n (%)*
Phase 1 (n=13)
Phase 2 (n=33)
Total (n=46)
Median number of cycles
6 (4–15)
5 (4–5)
5 (4–15)
Overall response (≥PR)
13 (100)
32 (97)†
45 (98)†
8 (62)
13 (39)
21 (46)
CR
5 (38)
7 (21)
12 (26)
VGPR
3 (23)
6 (18)
9 (20)
CR+VGPR
*Response assessed using IMWG uniform response criteria
†Only 1 pt did not reach the criteria for PR, but achieved a 46% reduction in M-protein by cycle 4 at the data cut-off
Preliminary response in twice-weekly dosing study
Response, n (%)
Overall (n=10)*
Patients treated with ≥4 cycles (n=6)
Median number of cycles
4 (1–8)
6 (4–8)
Overall response (≥PR)
9 (90)†
6 (100)
6 (60)
5 (83)
CR
1 (10)
1 (17)
VGPR
5 (50)
4 (67)
CR+VGPR
*1 pt was not response-evaluable at data cut-off
†Only 1 pt did not reach the criteria for PR, but achieved a 32% reduction in M-protein after cycle 1 at the data cut-off
Response appears to get better with time on treatment
Slides courtesy of Dr. Richardson
Presented at: ASCO 2012, Abstract 8033.
Daratumumab (GEN501): Phase I/II Data
• Progression-Free Survival
Lokhorst et al, ASCO 2013; J Clin Oncol 31, 2013 (suppl; abstr 8512^).
ARS Question 11
A 55-year-old female patient presents with asymptomatic anemia of
10g/dL and total serum protein 10 g/L. The workup reveals multiple
lytic lesions, an IgA kappa peak of 3.2, cytogenetic t4:14, 30% plasma
cells, and Beta 2 microglobulin of 5.0. Which of the following treatment
options is not a suitable choice for this patient?
A. Thalidomide + dexamethasone (TD)
B. Lenalidomide + dexamethasone (RD)
C. Bortezomib + dexamethasone (VD)
D. Lenalidomide + bortezomib + dexamethasone (RVD)
E. Thalidomide + melphalan + prednisone (TMP)
ARS Question 12
Which of the following is not a supportive care consideration that you
would discuss with your patient being treated with a lenalidomide +
dexamethasone regimen?
A.
There is a very high risk of peripheral neuropathy with this
regimen
B.
Prophylactic treatment for deep vein thrombosis should be
initiated
C.
Anticipate the possibility of infection
D.
Long-term complications might include diarrhea and fatigue
ARS Question 13
A 72-year-old male is diagnosed with MM. The work up revealed 3 compression
fractures; anemia; 60% kappa plasma cells; IgG 4200 mg/dL; kappa FLC 79
mg/dL; beta 2 microglobulin 8; creatinine 1.0, normal calcium; FISH shows
hyperdiploidy; and comorbidities include diabetes, hypertension, obesity, and atrial
fibrillation. He is treated with frontline lenalidomide + dexamethasone. However in
a month his creatinine worsened to 1.7 mg/dL and the regimen is poorly tolerated.
The patient complains of fatigue and insomnia and requests treatment
discontinuation or change.
What changes would you recommend for this patient?
A.
Stop treatment
B.
Decrease lenalidomide from 25 to 10
C. Stop dexamethasone alone
D. Decrease dexamethasone from 40 mg weekly to 20 mg weekly
E.
Change treatment
F.
B, D or E
ARS Question 14
A 72-year old patient diagnosed with MM relapses after frontline
treatment with lenalidomide-dexamethasone. He is switched to
CyBorD with lower doses of dexamethasone ( 20 mg weekly) and
weekly IV bortezomib. By cycle 3 he reports signs of early PN and is
switched to weekly SQ bortezomib and dexamethasone is lowered to
8mg weekly. After 18 months of observation, patient shows indications
of relapse.
Which of the following treatment options would you recommend for
this patient at this point?
A. Repeat Lenalidomide, without dexamethasone
B. Carfilzomib or Pomalidomide
C. Repeat CyBorD
ARS Question 15
Post-activity Survey
As a result of participating in this educational activity, please
rate your current level of confidence in treating and
managing patients with MM:
A. Not knowledgeable
B. Slightly knowledgeable
C. Somewhat knowledgeable
D. Highly knowledgeable
E. Expert
ARS Question 16
Post-activity Survey
As a result of participating in this educational activity, please
rate your current level of competence in using emerging data
from clinical studies to individualize treatment options for
patients with MM:
A. Not competent
B. Slightly competent
C. Somewhat competent
D. Highly competent
E. Expert
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