1. Relapsed and Refractory Myeloma Case 2
James R. Berenson, MD
Medical & Scientific Director
Institute for Myeloma & Bone Cancer Research
Los Angeles, CA

2. Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d)
Patient starts lenalidomide 10 mg qd d1-21, 7 d off, & methylprednisolone 40 mg po qod
After 4 months, IgG 1050 (from 1800), M-protein 0.50 (from 1.01), & 24 hour urine M-protein 50 mg (from 237 mg); hemoglobin 11.8
After 9 months, increasing back pain & fatigue
Work up
MRI shows new VCF at T7
Labs: IgG 1790, M-protein 1.33, 24 urine M-protein 287 mg, hemoglobin 9.8, creatinine 1.6
Treatment
Kyphoplasty at T7 w/ pain relief
Patient is continued on zoledronic acid monthly
What else would you do?

3. Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d)
What else could you do?
Add clarithromycin
Increase lenalidomide to 25 mg
Add bortezomib and/or PLD
Start carfilzomib
Start pomalidomide w/ steroids
All of the above are options

4. POM ± LoDEX in RRMM MM-002 Phase 2—Study Design
Objective: To determine the efficacy and safety of POM ± LoDEX
Primary endpoints: PFS
Secondary endpoint: ORR, safety, DOR, OS
R 1:1
N = 221
Age ≥ 18 y
RRMM
Prior Tx with LEN and BORTa
Measurable M-protein
≥ 2 prior therapies
Documented progression during or within 60 days of last Tx
28-day cycles
POM (4 mg) D1-21
(n = 108)
POM (4 mg) D1-21 +
LoDEX (40 mg/wk)b
(n = 113)
Discontinue and follow up for survival and subsequent treatment
Option to add LoDEX (40 mg/wk) (n = 64)
Progressive disease
Progressive disease
a Prior Tx with ≥ 2 cycles of LEN and BORT (separately or in combination); b Patients aged > 75 years had a starting DEX dose of 20 mg/week.
BORT: bortezomib; DOR: duration of response; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; POM: pomalidomide; R: randomized; RRMM: relapsed/refractory multiple myeloma; Tx: treatment.
Jagannath S. Blood. 2012;120: [oral presentation, abstract 450]. 4

5. POM ± LoDEX in RRMM MM-002 Phase 2—Response by EBMT Criteria
Response rates were higher with POM + LoDEX vs. POM
Median DORa was similar (8.3 and 8.8 mo; HR = 0.89; P = 0.734)
Median time to responsea was 1.9 and 3.7 mo, respectively
a For patients achieving ≥ PR. CR: complete response; DOR: duration of response; EBMT: European Group for Bone Marrow Transplant; HR: hazard ratio; LoDEX: low-dose dexamethasone; MR: minimal response; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma.
Jagannath S. Blood. 2012;120: [oral presentation, abstract 450]. 5

6. MM-003 POM + LoDEX vs HiDEX in RRMM Phase 3 —Trial Design
Primary endpoint: PFS
Key secondary endpoints: OS, ORR (≥ PR), DOR, safety
(n = 302)
POM: 4 mg D1-21
LoDEX: 40 mg (≤ 75 years) mg (> 75 years) D1, 8, 15, 22
Follow-up for OS and SPM until 5 years post- enrollment
(n = 153)
HiDEX: 40 mg (≤ 75 years) mg (> 75 years) D1-4, 9-12, 17-20
28-day cycles
PDa or intolerable AE
PDa
Companion trial MM-003C
POM 21/28 days
Thromboprophylaxis was indicated for those receiving POM or with DVT history
a PD was independently adjudicated in real time. AE: adverse event; D: day; DOR: duration of response; DVT: deep vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; MM: multiple myeloma; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy.
Dimopoulos MA. Blood. 2012;120: [oral presentation, abstract LBA-6]. 6

7. MM-003: PFS and OS
Survival Outcomes by Patient Group, Mos
POM + LoDEX
(n = 302)
HiDEX
(n = 153) HR
P Value
Median PFS
ITT population
3.6
1.8
0.45
< .001
Refractory to bortezomib
0.47
Refractory to lenalidomide
3.7
0.38
Refractory to bortezomib and lenalidomide
3.2
1.7
0.48
Median OS NR
7.8
0.53
8.1
0.56
.037
8.6
0.39
.003
7.4
In patients with poor renal function, POM + LoDEX provided longer PFS and OS as compared with HiDEX
Dimopoulos MA, et al. ASH Abstract LBA-6. 7

8. MM-005: A Phase I trial of Pom + Bortezomib Low-Dose Dexamethasone (PVD) in RR MM (Lenalidomide-Refractory)
MTD: Not reached
MPD: 21-d cycles
Bortezomib 1.3mg/m2 d1, 4, 8, & 11
Pomalidomide 4 mg qd d1-14
Dex 20 mg (10 mg for >75 yrs) d1, 2, 4, 5, 8, 9, 11, & 12
Response (n=20): 75% ORR (>PR), 30% >VGPR; median TTR: 1 cycle (1-3); responses seen in pts with adverse cytogenetics
Richardson PG et al. ASCO 2013., abstract # 8584 8

9. Phase I/II trial investigating Pom + Dex + PLD for R/R MM patients
A Phase 1/2 Study of Pomalidomide (Pom), Dexamethasone (Dex) and Pegylated Liposomal Doxorubicin (PLD) for Patients with Relapsed/Refractory Multiple Myeloma
Phase I/II trial investigating
Pom + Dex + PLD for R/R MM patients
Eligibility: progressive disease while on
Phase 1: any regimen
Phase 2: REFRACTORY to lenalidomide
28-d cycle containing
Pomalidomide: daily 2, 3 or 4 mg qd d1-21
3 mg is current dose for Phase 2 study
Dex IV: 40 mg d1, 4, 8, & 11
PLD: 5 mg/m2 on d1, 4, 8, & 11
Berenson et al. ASCO 2013

10. Results: Pom+PLD+Dex for RR MM
Best Response
# of Patients %
# evaluable for efficacy 36 PD 6
17% SD 9
25% MR 5
14% PR 15
41%
VGPR 0% CR 1 3%
Overall Response Rate
(PR+VGPR+CR) 16
44%
Clinical Benefit Rate
(MR+PR+VGPR+CR) 21
58%

11. Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Bortezomib-Treated
Cohort 1 (20 mg/m2 Carfilzomib)
n = 34
ORR
21%
CBR (> MR)
33%
Median TTP
8.1 months
Median DOR (> PR)
11.5 months
Bortezomib-naïve
Cohort 1 (20 mg/m2)
n = 59
Cohort 2 (20→27 mg/m2)
n = 70
ORR
42%
52%
CBR
59%
64% CR 3% 2%
VGPR
14%
27%
Median TTP
8.3 mo
Not reached
Median DOR
13.1 mo
Median PFS
8.2 mo
Stewart K, et al. Hematologica. 2010;95(S2). Abstract Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813. 11

12. A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing Bortezomib-Containing Regimens
Nontraditional intrapatient Phase I/II trial
Eligibility: Progressive disease while on bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen
Carfilzomib replaces bortezomib in combination with:
Alkylating agent
Anthracycline
Glucocorticosteroid
IMiD compound
Berenson et al. ASH 2013

13. Study Design (cont’d) Study treatment
Carfilzomib
starting at 20 mg/m2 for the 1st cycle
increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and 4, respectively if no DLT is observed
DLT considered > Grade 2
administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle
Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen
A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only)
Maximum # of cycles- 8

14. Efficacy PD 3 8% SD 6 16% MR 7 19% PR VGPR CR 2 Overall Response Rate
Best Response
# of Patients* (N=37) % PD 3 8% SD 6
16% MR 7
19% PR
VGPR CR 2
Overall Response Rate
(PR+VGPR+CR) 13
43%
Clinical Benefit Rate
(MR+PR+VGPR+CR) 18
62%
*- 5 pts not evaluable but counted in denominator

15. Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d)
For patients failing both bortezomib and lenalidomide, there is very little likelihood that other IMiD compounds or proteasome inhibitors will be effective
True
False

16. Treatment of Relapsed/Refractory Myeloma
CONFIRM PROGRESSION!
Some patients can be watched
Asymptomatic
Slow progression
No end organ damage that is new
Determinants of therapy
Cytogenetics/genetics ?
Pace of progression
Extent of end organ damage
Life and work styles
Co-morbid conditions (diabetes, CHF, etc.)

17. Treatment of Relapsed/Refractory Myeloma
The old rules no longer apply!
All of the following are often effective
Escalate doses (IMiD drugs, carfilzomib ?)
Add an antibiotic- clarithromycin
Resistance to a PI or IMiD drug in combination
Substituting another agent
Different class (PLD for CY failure)
Even the same class (bendamustine for CY or MEL failure)
Adding an IMiD drug to a PI failure or vice versa
Resistance to
PI (BORT) – substitute another PI (carfilzomib)
IMiD (Len)- substitute another IMiD drug (Thal or POM)