Relapsed and Refractory Myeloma

Case 1

James R. Berenson, MD

Medical & Scientific DirectorInstitute for Myeloma & Bone Cancer Research

Los Angeles, CA

Disclosures

• Speakers’ bureau, research support, and consulting: Amgen, Celgene, Millennium, and Onyx

Relapsed/Refractory Multiple Myeloma Case 1

• 76 year-old white female presented in Oct ‘11 w/ – Severe mid-back pain– Anemia w/ hemoglobin 10.0– Workup:

• Labs– IgG 3760– M-protein 2.62– 24-hour urine paraprotein 650 mg – B2M 3.7, albumin 3.3 (Stage 2 ISS)– Creatinine 1.5

• Bone marrow 40% plasma cells• Bone survey w/ lytic lesions throughout the axial skeleton and long

bones and T10 VCF • Patient received initial treatment

– Kyphoplasty at T10– Zoledronic acid 4 mg monthly– Cyclophosphamide, bortezomib and dexamethasone

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

• Course– Back pain resolved following kyphoplasty– After 4 cycles of initial therapy

• IgG 1170 (from 3760)• M-protein 0.59 (from 2.62)• 24-hour urine M-protein 45 mg (from 650 mg)• Other labs- creatinine 1.0, hemoglobin 11.7

– Patient continued treatment for 3 additional cycles w/ myeloma labs increasing

• IgG 1500• M-protein 0.79• 24 hour urine paraprotein 81 mg• Other labs- creatinine 1.1, hemoglobin 11.5

Relapsed/Refractory Multiple Myeloma: Case 1

At this point, you should1. Start lenalidomide and oral steroids 2. Stop CYBORD3. Repeat labs4. Continue present regimen5. Start another bortezomib-containing

combination

Relapsed/Refractory Multiple Myeloma: Case 1

Labs were repeated 1 month later– IgG now 1800– M-protein 1.01– 24 hour urine M-protein 237 mg– Creatinine 1.5; hemoglobin 10.6

What next?

Individualize Your Choice for the Myeloma Patient Based on:

Co-morbid conditions

DiseaseWork/

Lifestyle

Renal,Bone,Marrow,Subjective,Rate of ProgressionGenetics?

How active is the patient?Mobility?Is potential neuropathy an issue? (e.g.- surgeon, pianist)

Diabetes mellitus (steroids)Cardiac (Doxorubicin, PLD)Neuropathy(Thalidomide)

Prior treatments

Responseand for how long?Side effects and tolerability

Principles of Treating Relapsed/Refractory Multiple Myeloma

• Be sure a patient has really progressed before changing therapy– REPEAT MYELOMA LABS!

• Try to use drugs patient has not seen before• HOWEVER,

– progression on one drug in combination does not mean that drug will not be effective w/ another agent

• e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD

• Even different drugs in the same class may be active so that– bortezomib+melphalan failures may respond to other alkylating agents-

cyclophosphamide or bendamustine– LEN failures may respond to THAL or POM and vice versa– bortezomib failures respond to carfilzomib

– pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN

– the same combination may be effective again if the patient has not seen the combination in a long time

Bortezomib + PLD vs. Bortezomib in Previously Treated MM

1° Endpoint: TTP2° Endpoints: OS*, ORR

BORT 1.3 mg/m2 PLD 30 mg/m2

N=646

RANDOMI ZE

1 4 8 11Days

(n=324)

(n=322)

q 3 weeks up to 8 cycles

q 3 weeks up to 8 cycles

*Not enough events to determine statistical significance in overall survival.ORR=overall response rate; OS=overall survival; TTP=time to progression.

Ddoxorubicin HCl liposome injection Prescribing Information, Distributed by Ortho Biotech Products, L.P., Raritan, NJ. Rev’d May 2007

Bortezomib + Pegylated Liposomal Doxorubicin (PLD) + Dexamethasone for

Patients with Previously Untreated Myeloma:A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 29

Cycle repeatsBortezomib: 1.0 mg/m2 IV

PLD: 5 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al. Brit J Haematol, 2011

MR: 86% Reduced incidence of PN & PPE

Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial

Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1.

Berenson et al. Brit J Haematol 2012

No DLT was observed at any dose level50 mg/m2 (n = 5)70 mg/m2 (n = 4)90 mg/m2 (n = 5)

The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD Overall response rate

Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR)At MTD (90 mg/m2) 52%Bortezomib-exposed (n=31) 42%Alkylator-exposed (n=28) 46%

Bendamustine & Bortezomib: Results

CR, complete response; nCR, near complete response; Len + Dex,lenalidomide, dexamethasone; PR, partial response; ORR, overall response rate; RRMM, relapsed/refractory multiple myeloma.

Lenalidomide + Dexamethasone in R/R MMLenalidomide + Dexamethasone in R/R MMPhase 3 Trials–ResponsePhase 3 Trials–Response1,21,2

1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.

• CR rates were significantly higher in the Len + Dex arm of each trial compared with Placebo + Dex (P < .001)

• Both OS & TTP superior in Len + Dex arm

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2

Years’ Follow-up1

Richardson PG et al. ASH 2010, abstract #3049

–Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety

–Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies

–Study design: – Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against

herpes zoster were required

Richardson PG et al. ASH 2010, abstract #3049

–Safety: • Median cycles received:

11 (range 1–48)

• Median treatment duration: 7.9 months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs

Best response,%

CR/nCR 11/14

PR/VGPR 36/3

ORR (≥MR) 78• Median duration of ≥MR: 8.3 months

• Median duration of ≥PR: 8.4 months

Outcomes

Median, mos

1-yr, %

2-yr, %

TTP 9.5 37 16

PFS 9.5 36 15

OS 26 86 55

• Results: 62 pts evaluable for response

Gr ≥3 AE, % VRD (n=64)

Neutropenia 30

Thrombocytopenia 22

Lymphopenia 11

Leukopenia 9

Hyperglycemia 9

Hyponatremia 8

Hypophosphatemia 8

Fatigue 5

Diarrhea 3

Limb edema 3

Pain in extremity 2

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up

DVD-R (Bortezomib + Pegylated Liposomal Doxorubicin + Dexamethasone + Lenalidomide) for

Patients with R/R MM: A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29

Cycle repeatsBortezomib: 1.0 mg/m2 IV

PLD: 4 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al. Leukemia 2012

Len 10 mg po qd d1-14

MR: 85% No PPE; PN only 25%

Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial

• R/R MM patients• N=29• Regimen (28-day cycles)

– B 75-100 mg/m2 d1 & 2– L 5-10 mg qd d1-21– Dex 40 mg PO weekly

• MTD: B 75/ L 10/ D 40• Results (only 25 considered evaluable for response)

– ORR (> PR): 52% w/ 24% VGPR– MR 24%– PFS: 6.1 mo

Lentzsch et al. Blood 2012

Retreatment w/ IMiD compounds for MM Patients

• Retrospective study in 140 pts treated firstline w/– THAL/DEX- 58%– LEN/DEX- 42%

• Retreatment w/ a regimen containing– THAL- 24%– LEN- 76%

• # of treatments before retreatment - median of 2 (range 1-6)

• 89% received IMiD compound w/ DEX

• 113 considered evaluable for response– 44% > PR– MR not reported

Madan et al. Blood 2011

LEN

LEN

(n=48)

LEN

THAL

(n=11)

THAL

LEN

(n=58)

THAL

THAL (n=23)

> PR 54% 20% 48% 30%

Relapsed/Refractory Multiple Myeloma

For patients failing CYBORD regimens upfront, treatment options include all of the following except

1. PLD w/ BOR +/- steroids2. Bendamustine w/ BOR3. Len w/ steroids4. Len w/ steroids + BOR5. Len w/ oral melphalan