Therapy Options for Relapsed/Refractory Multiple Myeloma

Therapy for Relapsed/
Refractory Multiple Myeloma
Robert Z. Orlowski, Ph.D., M.D.
Director, Myeloma Section
Professor, Departments of Lymphoma/Myeloma & Experimental Therapeutics
Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma
Chair, Southwest Oncology Group Myeloma Committee

Clinical Scenario
• 59 yo F with IgG κ multiple myeloma
• Hgb 9.2 and lytic lesions, so symptomatic
• Albumin 3.8 and β2m 5.8, so ISS stage III
• FISH and cytogenetics normal
• What induction regimen would you recommend?

Induction Options
• 1: Bortezomib/dexamethasone
• 2: Lenalidomide/dexamethasone
• 3: Bortezomib/thalidomide/dexamethasone
• 4: Bortezomib/doxorubicin/dexamethasone
• 5: Bortezomib/cyclophosphamide/dexamethasone
• 6: Bortezomib/lenalidomide/dexamethasone
• 7: Thalidomide/dexamethasone
• 8: Vincristine/doxorubicin/dexamethasone (VAD)
• 9: Dexamethasone

Alternate Clinical Scenario 1
• FISH shows del 17p, cytogenetics are normal

Alternate Clinical Scenario 2
• FISH and cytogenetics are normal
• Serum creatinine 5.0 (vs. prior baseline of 1.0)

Clinical Scenario Resumed
• FISH and cytogenetics normal
• The patient receives thalidomide + dexamethasone
induction, and after 6 cycles is in a VGPR
• She then undergoes autologous stem cell
transplantation, and receives thalidomide
maintenance, which produces a CR

Second Line Options
• While on thalidomide maintenance, the patient
develops new bony pain and anemia
• Laboratory studies show a recurrent monoclonal
protein, and the creatinine has risen to 2.0
• Your choice for second line therapy at this point
would be

Induction Options
• 1: Bortezomib/dexamethasone
• 2: Lenalidomide/dexamethasone
• 3: Bortezomib/liposomal
doxorubicin/dexamethasone
• 4: Bortezomib/cyclophosphamide/dexamethasone
• 5: Bortezomib/lenalidomide/dexamethasone
• 6: Thalidomide/dexamethasone
• 7: Vincristine/doxorubicin/dexamethasone (VAD)
• 8: Dexamethasone

Definitions of Relapse
• Relapse from CR
– Reappearance of serum and/or urine M-protein
• Confirm with repeat study; not oligoclonal banding
– ≥5% clonal plasma cells on aspirate or biopsy
– New or increased lytic bone lesion(s) or plasmacytoma(s)
– Hypercalcemia not attributable to other factor
• Relapse from less than a CR
– Confirmed >25% increase in serum M-protein of 0.5 g/dL≥
– Confirmed >25% increase in BJP of 200 mg/24 hrs≥
– >25% increase in marrow plasmacytosis ( 10% increase)≥
– Criterion 3 or 4 from above

Definitions of Refractory
• Progressing on current treatment
• Progression within 60 days of completing a
previous treatment
• Most recent treatment did not induce at least a
minor response (25% reduction in disease
burden)

Biochemical vs. Symptomatic Relapse
• Not all patients who suffer a biochemical
relapse have disease that requires
immediate salvage therapy
• Patients who have asymptomatic disease
progression may be candidates for a
watchful waiting approach, or “window”
trials of novel agents/approaches

Types of Relapse
Alegre, A et al. Haematologica. 87:609, 2004.

Major Treatment Goals
• Achieve disease response
• Reduce active symptom burden
• Prevent any additional morbidity
• Prolong the patient’s overall survival
• Ultimately, to cure multiple myeloma
altogether

What Disease Response is Best ?
Depth of response Time to progression
MR
PR
VGPR
nCR
CR
sCR
Treatment initiation
Time
iCR
• Depth of response is related to TTP
Adapted from: Niesvizky, R et al. Br J Haematol. 143:46, 2008. Harousseau, J-L et al.
Blood 114:3139, 2009. Chanan-Khan, AA et al. J Clin Oncol. 28: 2612, 2010.

Other Treatment Goals
• Target rational pathway
– Multiple key downstream targets to pathobiology
• Maximize the quality of life
– Enhance TTNT, TFI
• Minimize the toxicities of therapy
– Use agents with predictable and manageable side effects
• Exploit the potential of synergistic interactions
– Ability to reuse and recombine regimens
• Administer medically- & cost-effective therapies
– Don’t break the bank while breaking multiple myeloma

2013 NCCN Guidelines in Relapse
• Bortezomib (Category 1)
• Bortezomib/liposomal doxorubicin (1)
• Lenalidomide/dex (1)
• Bendamustine
• Repeat primary therapy (if relapse at > 6 mos.)
• Bortezomib/dex
• Bortezomib/lenalidomide/dex
• Cyclophosphamide + VD or + Rd
• Thalidomide/dex
• Dex, or DCEP, or DT-PACE ± Bortezomib

APEX : Bortezomib vs. Dex
78% improvement in median time-to-progression
Time (days)
P = .0001
Proportionofpatients
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Median TTP
Bortezomib
Dexamethasone
Bortezomib
Dexamethasone
0
All Pts Post-1st relapse
6.2 mos
3.5 mos
7.0 mos
5.6 mos
Richardson, PG et al. N. Engl. J. Med. 352:2487, 2005.

Bortezomib : Early vs. Late Relapse
Sonneveld, G et al. Haematologica 90:146, 2005.
Bortezomib
1 prior therapy
n = 132
> 1 prior therapy
n = 200
Median TTP (months) 7.0 4.9
CR (%) 10%* 7%†
CR + PR (%) 51%* 37%†
Median Duration
of Response (months)
8.1 7.8
1-year Survival 89% 73%

SC Bortezomib
Moreau, P et al. Lancet Oncol. 12:431, 2011.
Response rate, %
Bortezomib IV
± dex (N=73)
Bortezomib SC ±
dex (N=145)
ORR (CR + PR) 52 52
CR* 12 10
PR 40 42
nCR 10 10
VGPR 3 5
≥VGPR (CR + nCR + VGPR) 25 25
Response improvement (cycle 4 → 8)
in patients who received dex, n/N (%)
n=39 n=82
PR → CR 2/15 (13%) 4/31 (13%)
<PR → PR 7/23 (30%) 14/47 (30%)

TTP of SC vs. IV Vd
Moreau, P et al. Lancet Oncol. 12:431, 2011.
100
90
80
70
60
50
40
30
20
10
0
PatientswithoutPD(%)
IV : 9.4 months
SC: 10.4 months (0.839 HR; P-value 0.38657)
Days from randomization
74 60 56 50 36 24 16 10 7 5 4 3 1
148 126 109 93 72 51 32 18 13 8 5 2 1
No. patients at risk
IV
SC
0 50 100 150 200 250 300 350 400 450 500 550 600
ORR identical
after 4 cycles

Bortezomib/PLD vs. Bortezomib
PLD + Bortezomib
9.3 months
Bortezomib
6.5 months
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
p = 0.000004
PercentofPatientsProgression-Free
0 100 200 300 400 500
020406080100
Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.

Other Bortezomib Combinations
Kaufman, J et al. Curr Hematol Malignant Rep. 4:99, 2009.
Author/Year N Regimen
Overall
Response
Rate (%)
CR/nCR
Rate (%)
Median
PFS
(mos)
Median
OS (mos)
Pineda-Romané/2008 85 BTD 63 22 – 22
Jakubowiak/2005 20 BD + PLD 56 33 – –
Biehn/2007 22 B + PLD 63 36 9.3 (TTP) 38.3
Popat/2005 22 B + Iv Mel +/- D 43 5 6.8 (TTP) –
Palumbo/2007 30 V Mel PT 67 17 61% (1 yr) 84% (1 yr)
Reece/2008 37 B + Cy + P 95 54 >12 >12

Len/Dex vs. Dex
Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.

Lenalidomide-based Combinations
Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood.
2009;113:4137-4143; Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et
al. Ann Oncol. 2006;17:1766-1771; Richardson PG et al. J Clin Oncol. 2009;27:5713-5719;
Anderson KC et al. 2009 ASCO Annual Meeting. Abstract 8536.
Author/Year N Regimen
Overall
Response
Rate (%)
CR/nCR
Rate (%)
Median
PFS
Median
OS
Schey/2009 31 LCD 81 36 (VGPR) – –
Knop/2009 66 LDoD 73 15 40 weeks 88% (1 year)
Reece/2009 15 LCP 74 45 (VGPR) – –
Baz/2006 52 L PLD ViD 75 29 (nCR) 1 year 84% (1 year)
Richardson/2009 35 LBV+/- D 60 >MR 8 7.7 months 37 months
Anderson/2009 62 LBVD 69 26 12 months 29 months

Thal/Dex
Lonial, S & Richardson, PG. Clin Cancer Res. 17:1264, 2011.

RV ± d in Relapsed Disease
Richardson, PG et al. J Clin Oncol. 27:5713, 2009.
• 61% MR or better

V ± T ± d
Pineda-Roman, M et al.
Leukemia 22:1419, 2008.
• Excellent
regimen in
salvage
setting even
after heavy
prior
treatment

VMPT
Palumbo, A et al. Blood 109:2767, 2007.
• VMPT is one option to
consider
• Response rate of ~80%
as second line therapy

Single Agents or Combinations?
Garderet, L et al. J Clin
Oncol.30:2475, 2012.
• Better salvage
therapy results in
better long-term
outcomes

Response and Prior Lines
Kumar, SK et al. Mayo Clin Proc. 79:867, 2004.
• 578 patients; median age 65 years
• Follow-up 55 months
• Overall survival
• One year 72%
• Two years 55%
• Three years 22%
• 84% died in 5 years
Figure 3. Duration of response to each treatment
0
2
4
6
8
10
12
1 2 3 4 5 6
Treatment number
Medianresponse
duration(months)

Overall Survival and Prior Lines
Kumar, SK et al. Mayo Clin Proc. 79:867, 2004.
00.20.40.60.81.0
0 2 4 6 8 10
CumulativeProbability(%)
Years From Start of Regimen
Regimen 1
Regimen 2
Regimen 3
Regimen 4
Regimen 5
Regimen 6

Carfilzomib : Approved in July, 2012
Siegel, DS et al. Blood 120:2817, 2012.
• Results from PX-
171-003-A1 study
of carfilzomib in
patients with
relapsed and
refractory myeloma

Long-term Outcomes

Toxicities
• Most notable for the
lower risk of
peripheral
neuropathy overall,
and especially for
the low rates of
grade 3 or 4 events
in this category

Activity in Bortezomib-naïve Cohort
Vij, R et al. Blood 119:5661, 2012.
• Response rate with
carfilzomib for patients
who received 20 mg/m2
was 42.4%
• ORR increased to 52.2% if
the dose was escalated to
27 mg/m2

Infusional Carfilzomib
Lendvai, N et al. ASH Abstract 947, 2012.
Continue single-agent CFZ
POD
≥ PR after 2 cycles
Single arm, open-label, Ph II
Continue CFZ + low-dose
DEX
≥ SD
Add low-dose DEX (20 mg)
< PR after 2 cycles
Relapsed or refractory symptomatic MM
Previous therapy with BTZ & IMiD
Single-agent infusional CFZ (28-day cycle)*
Cycle 1 • 20 mg/m2
on Days 1, 2
• 56 mg/m2
on Days 8, 9, 15 & 16
Cycles 2≥ • 56 mg/m2
as tolerated

Best Response Rate
N=38*
Best response, n
CR 1 (3%)
VGPR 9 (24%)
PR 10 (26%)
MR 1 (3%)
SD 11 (29%)
POD 6 (16%)
ORR 53%

Response Durability
Progression-free Survival
6mo: 57% (42–75%)
12mo: 44% (29–67%)
Median: 7.6 mo (2.8–NR)
Duration of response
Median 95% CI
10.0 mo (5.8–NR)
Overall Survival
6mo: 64% (50–82%)
12mo: 50% (36–71%)
Median: Not reached (NR)

Grade 3 or 4 Adverse Events
N=41
Hematologic Anemia 8 (20%)
Thrombocytopenia 14 (37%)
Non-hematologic Hypertension 8 (20%)
Pneumonia 6 (15%)
Pulmonary edema/CHF 4 (10%)
Sepsis 3 (7%)
LV systolic dysfunction 2 (5%)
Dyspnea/hypoxia 2 (5%)
Fatigue 2 (5%)

Pomalidomide : Approved in February, 2013
Vij, R et al. ASCO Abstract 8016, 2012.
• Approval based on the results of the MM-002 study

Response Rates
• Outcomes shown in dual-refractory patients

Responses by Prior Therapies

Overall Survival

Grade 3 and 4 Adverse Events

Data from the MM-003 Study
Dimopoulos, MA et al. ASH Abstract LBA-6, 2012.
(n = 302)
POM: 4 mg/day D1-21 +
LoDEX: 40 mg ( 75 yrs)≤
20 mg (> 75 yrs)
D1, 8, 15, 22
Follow-Up for OS
and SPM Until
5 Years Post
Enrollment
(n = 153)
HiDEX: 40 mg ( 75 yrs)≤
20 mg (> 75 yrs)
D1-4, 9-12, 17-20
28-day cycles
PD* or
intolerable AE
PD* Companion trial
MM-003C
POM 21/28 days
Thromboprophylaxis was indicated for those receiving POM or with DVT history

Prior Therapies
POM + LoDEX
(n = 302)
HiDEX
(n = 153)
Median number, n (range) 5 (1-14) 5 (2-17)
Prior DEX, % 97 99
Prior THAL, % 57 61
Prior SCT, % 71 69
Prior LEN, % 100 100
Prior BORT, % 100 100
LEN-refractory, % 93 90
BORT-refractory, % 78 77
LEN- and BORT-refractory, % 73 71

0 4 8 12 16
0.0
0.2
0.4
0.6
0.8
1.0
Progression-Free Survival (months)
ProportionofPatients
Median PFS
POM + LoDEX (n = 302) 3.6 months
HiDEX (n = 153) 1.8 months
HR = 0.45
P < .001

PFS in Dual Refractory Patients
0.0
0.2
0.4
0.6
0.8
1.0
0 4 8 12 16
HR = 0.48
P < .001
Progression-Free Survival (months)
Median PFS
POM + LoDEX (n = 221) 3.2 months
HiDEX (n = 108) 1.7 months

Overall Survival
Overall Survival (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 4 8 12 16
Median OS (95% CI)
POM + LoDEX (n = 302) Not Reached (11.1-NE)
HiDEX (n = 153) 7.8 months (5.4-9.2)
HR = 0.53
P < .001

OS in Dual Refractory Patients
0.0
0.2
0.4
0.6
0.8
1.0
Overall Survival (months)
0 4 8 12 16
HR = 0.56
P = .003
Median OS (95% CI)
POM + LoDEX (n = 221) Not Reached (8.5-NE)
HiDEX (n = 108) 7.4 months (4.3-9.2)

Adverse Events
7% of POM + LoDEX and 6% of HiDEX patients discontinued due to AEs
HiDEX
POM+LoDEX
All grades
% of patients experiencing ≥ grade 3 adverse event
Neutropenia
Febrile neutropenia
Anemia
Thrombocytopenia
Infection
Pneumonia
Hemorrhage
Glucose intolerance
Fatigue
VTE*
PN*
*
0 10 20 30 40 50

Carfilzomib/Pomalidomide
Shah, JJ et al. ASH Abstract 74, 2012.
1 2 8 9 15 16
1 8 15 22
1 21
Carfilzomib
Pomalidomide
Dexamethasone
•Cycle 1-6: 28 day cycle

Hematologic AEs
G 1 G 2 G 3 G 4 Total
Anemia 1 7 11 1 20
Thrombocytopenia 5 4 7 2 18
Neutropenia 1 8 13 5 27
Febrile neutropenia 0 0 2 0 2

Non-Hematologic AEs
G 1 G 2 G 3 G 4 total
Diarrhea 8 2 0 0 10 (31%)
Fatigue 9 8 1 0 18 (56%)
Dyspnea 9 0 0 0 9 (28%)
Skin, Rash, Pruritis 5 1 1 0 7 (21%)
Creatinine elevated 5 2 1 0 8 (26%)
Hypocalcemia 7 4 0 0 11 (34%)

Response Rates
N = 30
Overall Response Rate ( ≥ PR) 15 (50%)
VGPR 4 (13%)
PR 11 (37%)
MR 5 (17%)
SD 7 (23%)
PD 3 (10%)

Outcome
Car-Pom-d
(N = 32)
Response rates
(n = 30), %
 ORR 50
• ≥ VGPR 13
• PR 37
 Minor response 17
 SD 23
 PD 10
Median PFS, mos 7.4
1-yr OS, % 90
PFS(%)
Time in Study (Mos)
Car-Pom-d PFS (N = 32)
95% CI
Median PFS: 7.4 mos
0 3 6 9 12
100
90
80
70
60
50
40
30
20
10
0

Pomalidomide/Bortezomib/Dex
Richardson, PG et al. ASH Abstract 727, 2012.
3 + 3 Design (21-day cycles)
Evaluation
Every 21 Days
(± 3 Days)
Follow-Up for
OS and SPM
Until 5 Years
Post-enrollment
Cohort
POM
(D1-14)
BORT
(D1, 4, 8, 11*)
LoDEX
(D1-2, 4-5, 8-9, 11-12†
)
1 (n = 3) 1 mg/day 1 mg/m2
20 mg‡
2 (n = 3) 2 mg/day 1 mg/m2
20 mg‡
3 (n = 3) 3 mg/day 1 mg/m2
20 mg‡
4 (n = 3) 4 mg/day 1 mg/m2
20 mg‡
5 (n = 3) 4 mg/day 1.3 mg/m2
20 mg‡
Expansion cohort (n = 6) at MTD/MPD
*For cycles 1-8, then D1, 8 for cycles 9+; †
For cycles 1-8, then
D1-2, 8-9 for cycles 9+; ‡
10 mg for pts aged > 75 yrs

DLTs
Cohort Dose-Limiting Toxicity
Cohort 1 (n = 3) None

Adverse Events
Patients (%)

Response Summary
• ORR (≥ PR): 73%; VGPR: 27%; SD: 27%
• Median time to response: 1 cycle (range 1-2)
• Most responses are ongoing
Cohort Best Response
Cohort 1 (n = 3) 1 VGPR, 1 PR, 1 SD
Cohort 2 (n = 3) 1 PR, 2 SD
Cohort 3 (n = 3) 2 VGPR, 1 PR
Cohort 4 (n = 3) 1 VGPR, 2 PR
Cohort 5 (n = 3) 2 PR, 1 SD

Response Duration
VGPR
PR
SD
Ongoing
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Discontinued PD
2 3 4 5 6 7 8 9 10
Discontinued PD
PD
Completed Treatment
11
*
*

Novel Agents : Elotuzumab + Len/Dex
Elotuzumab
10 mg/kg
Elotuzumab
20 mg/kg Total
Pts, n 31 32 63
≥ PR, n (%) 28 (90) 23 (72) 51 (81)
Stringent CR, n (%) 1 (3) 1 (3) 2 (3)
CR, n (%) 2 (7) 1 (3) 3 (5)
VGPR, n (%) 10 (32) 8 (25) 18 (29)
PR, n (%) 15 (48) 13 (41) 28 (44)
SD, n (%) 3 (10) 7 (22) 10 (16)
PD, n (%) 0 (0) 0 (0) 0 (0)
Not evaluable, n (%) 0 (0) 2 (6) 2 (3)
Richardson, PG et al. 2010 ASH Abstract 986.

Other Antibodies : Daratumumab
Plesner, T et al. ASH Abstract 73, 2012.
Expansion
cohort
Dose-
escalation
cohorts
Part 2
Open label, single arm, i.v. infusion
weekly: 8 weeks
every other week: 16 weeks
every fourth week: up to 96 weeks
8 mg/kg, 16 patients
Part 1
Open label, weekly i.v. infusion, 8 weeks
Dose-escalation: 3+3 scheme*
0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg

Paraprotein Responses
9 2
5
1 20
19 10 12 31
16 29
8 13
4 26
15
3 7 11
17
14
33
27
21 6 30
18
34
23
32
22 28
-100
-50
0
50
100
Reletivechangeinparaproteinefrombaseline(%)
Patientnumber
A AA A AA A
AA
A
AA AA AA AA AAB
B
B B
C
A
C C C
CC C
2 mg/kg2 mg/kg 4 mg/kg4 mg/kg 8 mg/kg8 mg/kg 16 mg/kg16 mg/kg 24 mg/kg24 mg/kg< 1 mg/kg

PFS vs. Drug Exposure

Other Novel Agents : ARRY520

Toxicities
Adverse Events, %
ARRY-520
(n = 32)
ARRY + Dexamethasone
(n = 21)
Grade 3 Grade 4 Grade 3 Grade 4
Nonhematologic
 Pneumonia -- -- 10 10
 Fatigue 12 3 10 --
 Arthralgia -- -- 5 --
 Back pain 6 -- -- --
 Hypokalemia 3 3 5 --
 Upper respiratory tract
infection
-- -- 5 --
Hematologic
 Neutropenia 19 28 24 38
 Thrombocytopenia 22 25 38 19
 Anemia 31 6 43 5
 Febrile neutropenia 3 -- 5 --

Outcomes
Outcome
ARRY-520
(n = 32)
ARRY-520 +
Dexamethasone
(n = 18)
Overall best response, %
 PR 16 22
• MR + PR 19 33
 SD 44 28
 PD 34 28
 Not evaluable 3 11
Median duration of response (≥ PR),
mos (range)
8.6 (1.4-20.0) 5.4 (2.5-9.0)

Len/Thal/Dex

Study Design
1 8 15 22
1 21
Lenalidomide
Dexamethasone
Cycle 1-8: 28 day cycle
Dexamethasone dosing for cycle 1-2: 40 mg days 1-4, 9-12, and 17-20; all subsequent cycles weekly dosing
Last cohort of 10 patients with Lenalidomide refractory disease: weekly dosing started with cycle 1
Thalidomide
1 28

DLTs/RP2D
Patients DLT
Cohort 1 (len15 / thal 100) 3 0
DLT in cohort 2:
Steroid induced toxicity, requiring reduction in dex dosing in cycle 1
DLT in cohort 3:
G3 rash; asymptomatic G2 atrial fibrillation
G3 hypertensive crisis and volume overload due to dexamethasone
MRD : Lenalidomide 25 mg / Thalidomide 100 mg / Dex

Response Rates
N = 61
Overall Response Rate ( ≥ PR) 31 (51%)
Stable Disease 15 (25%)
Minimal Response 8 (13%)
Partial Response 19 (31%)
VGPR 4 (7%)
nCR/CR 8 (13%)
Progressive Disease 7 (11%)
Clinical Benefit Ratio (≥ MR) of 64%

Outcomes in Len Refractory Disease
N = 41*
Overall Response 13 (34%)
Stable Disease 12 (29%)
Minimal Response 8 (20%)
Partial Response 11 (27%)
VGPR 1 (2%)
CR / nCR 2 (5%)
Progressive Disease 7 (17%)
Lenalidomide Refractory: Clinical Benefit Ratio ( MR) of 51%≥
Lenalidomide Naïve: Overall Response (≥ PR) of 14/16 (88%)

Median PFS 8.0 months

Overall Survival
Median OS 29
months

Outcomes in Del 17p
Progression Free Survival Overall Survival
Not Del 17p
Del 17p
Not Del 17p
Del 17p

Second Autologous Transplant
AHCT2 AHCT1 AHCT2
Response at 1 year (%)
- CR
- PR
82
43
39
68
25
43
- Relapse at 3 years (%) 80 82
- Median time to relapse
(months)
18 12
Saad, A et al. ASH Abstract 504, 2011.

Overall Survival
ProbabilityofOS,%
Years
0 2 4 986
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
N = 187
1 3 75
Survival (95% CI):
@ 1 yr: 83% (77-89)
@ 3 yrs: 46% (37-54)
@ 5 yrs: 29% (21-38)

Non-relapse Mortality
Incidence,%
Years
0 2 4 986
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
1 3 75
NRM (95% CI):
@ 1 yr: 2% (1-5)
@ 3 yrs: 4% (2-8))

Multivariate Analysis
Reference group *
NRM Relapse/PD
Treatment
Failure/ PFS
Mortality/OS
HR P HR P HR P
Time from AHCT1 to
relapse :
<36 mo vs. >36 mo
NO
significant
covariates
1.58 0.036 1.52 0.04 1.91 0.02
Year of AHCT2
(after vs. before 2004)
- - - - 0.61 0.026

OS and Time to First Relapse
ProbabilityofOS,%
Years
0 2 4 986
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
<36 months (N = 151)
1 3 75
≥36 months (N )= 38
(HR 1.91, P = 0.02)

Other Factors That Influence Choice
DISEASE-DISEASE-
RELATEDRELATED
DOR to initial therapyDOR to initial therapy
FISH / cytogeneticsFISH / cytogenetics
REGIMEN-REGIMEN-
RELATEDRELATED
Prior drug exposurePrior drug exposure
Toxicity of regimenToxicity of regimen
Mode of administrationMode of administration
Previous SCTPrevious SCT
PATIENT-PATIENT-
RELATEDRELATED
Pre-existing toxicityPre-existing toxicity
Co-morbiditiesCo-morbidities
AgeAge
Performance statusPerformance status
Stage generally does not influence salvage therapy choice.
Lonial, SL. ASH Educational Book, 303, 2010.

Conclusions
• 2nd
generation PI carfilzomib & 3rd
generation
IMiD pomalidomide approved
• Studies of rationally designed combination
regimens are underway and showing promise
• Mabs such as elotuzumab and daratumumab
bring new approach into play against myeloma
• Novel agents with new mechanisms of action
such as ARRY-520 and dinaciclib are entering
the fray

MDACC Lymphoma & Myeloma Center
• Clinical faculty
– Dr. Raymond Alexanian
– Dr. Robert Orlowski
• rorlowsk@mdanderson.org
• Twitter: @Myeloma_Doc
• http://bit.ly/bM3sqS
– Dr. Jatin Shah
– Dr. Sheeba Thomas
– Dr. Michael Wang
– Dr. Donna Weber

Therapy Options for Relapsed/Refractory Multiple Myeloma

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