Relapsed and Refractory Myeloma

Case 2

James R. Berenson, MD

Medical & Scientific DirectorInstitute for Myeloma & Bone Cancer Research

Los Angeles, CA

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?

Relapsed/Refractory Multiple Myeloma: Case 2 (Case 1 cont’d)

What else could you do?

1. Add clarithromycin2. Increase lenalidomide to 25 mg3. Add bortezomib and/or PLD 4. Start carfilzomib5. Start pomalidomide w/ steroids6. All of the above are options

POM ± LoDEX in RRMM POM ± LoDEX in RRMM MM-002 Phase 2—Study DesignMM-002 Phase 2—Study Design

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].

• Objective: To determine the efficacy and safety of POM ± LoDEX

• Primary endpoints: PFS

• Secondary endpoint: ORR, safety, DOR, OS

R1:1

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)

28-day cycles

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

Progressive disease

POM ± LoDEX in RRMM POM ± LoDEX in RRMM MM-002 Phase 2—Response by EBMT CriteriaMM-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].

MM-003 POM + LoDEX vs HiDEX in RRMMPhase 3 ——Trial Design

• Primary endpoint: PFS• Key secondary endpoints: OS, ORR (≥ PR), DOR, safety

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].

(n = 302)

POM: 4 mg D1-21

LoDEX: 40 mg (≤ 75 years) 20 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) 20 mg (> 75 years) D1-4, 9-12, 17-20

28-day cycles

PDa orintolerable AE

PDa Companion trialMM-003C

POM 21/28 days

Thromboprophylaxis was indicated for those receiving POM or with DVT history

MM-003: PFS and OS

• In patients with poor renal function, POM + LoDEX provided longer PFS and OS as compared with HiDEX

Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.

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 3.6 1.8 0.47 < .001• Refractory to lenalidomide 3.7 1.8 0.38 < .001• Refractory to bortezomib and

lenalidomide3.2 1.7 0.48 < .001

Median OS        • ITT population NR 7.8 0.53 < .001• Refractory to bortezomib NR 8.1 0.56 .037• Refractory to lenalidomide NR 8.6 0.39 .003• Refractory to bortezomib and

lenalidomideNR 7.4 0.56 .003

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

• 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

A Phase 1/2 Study of Pomalidomide (Pom), Dexamethasone (Dex) and Pegylated Liposomal

Doxorubicin (PLD) for Patients with Relapsed/Refractory Multiple Myeloma

Berenson et al. ASCO 2013

Best Response # of Patients %

# evaluable for efficacy 36

PD 6 17%

SD 9 25%

MR 5 14%

PR 15 41%

VGPR 0 0%

CR 1 3%

Overall Response Rate (PR+VGPR+CR)

16 44%

Clinical Benefit Rate (MR+PR+VGPR+CR)

21 58%

Results: Pom+PLD+Dex for RR MM

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 monthsMedian DOR (> PR) 11.5 months

Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

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 reachedMedian DOR 13.1 mo Not reachedMedian PFS 8.2 mo Not reached

• 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

A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing

Bortezomib-Containing Regimens

Berenson et al. ASH 2013

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

Best Response # of Patients* (N=37)

%

PD 3 8%

SD 6 16%

MR 7 19%

PR 7 19%

VGPR 6 16%

CR 2 8%

Overall Response Rate (PR+VGPR+CR)

13 43%

Clinical Benefit Rate (MR+PR+VGPR+CR) 18 62%

Efficacy

*- 5 pts not evaluable but counted in denominator

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

1. True2. False

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.)

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)