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TRANSCRIPT
Management of Relapsed/Refractory Multiple Myeloma
Morie A Gertz, MD, MACPConsultant
Division of HematologyRoland Seidler Jr Professor and Chair
Department of MedicineCollege of Medicine
Mayo Distinguished ClinicianMayo Clinic
Rochester, Minnesota
Disclosures
Consulting Agreements
Amgen Inc, GlaxoSmithKline, Novartis Pharmaceuticals Corporation
Outline
• Doublet vs Triplet regimens for RRMM
• Management of the patient with renal failure
• Novel Strategies in RRMM
– Oprozomib
– Venetoclax
– Pembrolizumab
– CAR-‐T
ASPIRE Study Design
RdLenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
KRdCarfilzomib 27 mg/m2 IV (10 min)
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
RandomizationN=792
Stratification:• β2-microglobulin• Prior bortezomib • Prior lenalidomide
After cycle 12, carfilzomib given on days 1, 2, 15, 16After cycle 18, carfilzomib discontinued
28-day cycles
Primary Endpoint: Progression-Free SurvivalITT Population (N=792)
1.0
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n Surviving
With
out P
rogressio
n
KRdRd
0 6 12 18 24 30 36 42 48Months Since Randomization
KRd Rd(n=396) (n=396)
Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value (one-‐sided) <0.0001
No. at Risk:KRdRd
396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1
Secondary Endpoints: Interim Overall Survival AnalysisMedian Follow-‐Up 32 Months
Median OS was not reached;; results did not cross the prespecified stopping boundary (P=0.005) at the interim analysis
1.0
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n Surviving
KRdRd
0 6 12 18 24 30 36 42 48Months Since Randomization
KRd Rd(n=396) (n=396)
Median OS, mo NE NEHR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)P value (one-‐sided) 0.018
No. at Risk:KRdRd
396 369 343 315 280 191 52 2396 356 313 281 237 144 39 3
Carfilzomib, Pomalidomide and Dexamethasone (KPd) in Relapsed/Refractory myeloma
• 45 RRMM
• 60% m-‐SMART intermediate or high risk
• Median 4 prior Rx’s; 60% dual refractory V & R
• ORR 36% MR 7% Stable 23%
• Median OS 16.1 mos; if dual refactory 15.6
• Median PFS 3.3 mo; DOR 12.9
Hobbs M et al. Proc ASH 2016; Abstract 3337.
How serious is the cardiac signal from Carfilzomib?
Chari A et al. Proc ASH 2016; Abstract 3319.
TOURMALINE-‐MM1 Study Design
RdLenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
IRdIxazomib 4 mg Days 1, 8, 15
Lenalidomide 25 mg Days 1–21Dexamethasone 40 mg Days 1, 8, 15, 22
RandomizationN=722
Stratification:• β2-microglobulin• Prior bortezomib • Prior lenalidomide
28-day cycles
LEN NAÏVE OR LEN SENSITIVE
Moreau P et al. N Engl J Med 2016;;374(17):1621-34.
Phase III TOURMALINE-‐MM1: Progression-‐Free Survival
Moreau P et al. N Engl J Med 2016;;374(17):1621-34.
• Median overall survival: Not reached in either arm at a median follow-up of approximately 23 months
• Overall response rate: 78% (ixazomib) vs 72% (placebo)
Months since RandomizationProbability of Progression-free Survival (%)
Hazard ratio: 0.74 p = 0.01Ixazomib (n = 360)Placebo (n = 362)
Medianprogression-freesurvival (mo)
20.614.7
Placebo group
Ixazomib group
Summary of Triplet Salvage
• Multiple randomized trials in the setting of relapsed and refractory myeloma have shown
– Three drugs better overall response rates than two drugs
– Three drugs better PFS than two drug combinations
– Three drugs more toxicities BUT tolerable and similar response to treatment.
– Three drug combos have not yet shown a survival benefit but follow-‐up is still limited. However, all these studies support that DEPTH OF RESPONSE is directly related to survival and QOL.
• In the FRONTLINE setting giving the best combination upfront results in clinical benefit; why should this be different in the relapsed setting?
Safety of Treatment (Tx) with Pomalidomide (POM) and Low-‐Dose Dexamethasone (LoDEX) in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI), Including Those on Dialysis
Ramasamy K et al. Proc ASH 2015;;Abstract 374.
MM-013: Adverse Events
Grade 3-4 adverse event
Moderate RI(n = 16)
Severe RI, no dialysis (n = 21)
Severe RI + dialysis (n = 10)
Neutropenia 8 (50%) 11 (52%) 6 (60%)
Thrombocytopenia 5 (31%) 4 (19%) 4 (40%)
Leukopenia 1 (6%) 1 (5%) 4 (40%)
Febrile neutropenia 1 (6%) 0 0
Anemia 1 (6%) 7 (33%) 6 (60%)
Pneumonia 2 (13%) 1 (5%) 0
Ramasamy K et al. Proc ASH 2015;;Abstract 374.
• Grade 3 or 4 infections: 10 (21%) patients• POM + Lo-‐DEX in RRMM with RI including dialysis is generally well tolerated.
Ramasamy K et al. Proc ASH 2015; Abstract 374.
Treatment of Myeloma Cast Nephropathy (MCN): A Randomized Trial Comparing Intensive Haemodialysis(HD) with High Cut-‐Off (HCO) or Standard High-‐Flux Dialyzer in Patients Receiving a Bortezomib-‐Based Regimen (the MYRE Study, by the IntergroupeFrancophone du Myélome (IFM) and the French
Society of Nephrology (SFNDT))
Bridoux F et al.Proc ASH 2016; Abstract 978.
Press Release -‐ October 20, 2016Denosumab Non-‐Inferior to Zoledronic Acid in Delaying
Time to Skeletal-‐Related Event
“A Phase 3 study evaluating denosumab versus zoledronic acid met the
primary endpoint of non-‐inferiority (hazard ratio = 0.98, 95 percent CI,
0.85 -‐ 1.14) in delaying the time to first on-‐study skeletal-‐related event
(SRE) in patients with multiple myeloma.
“The secondary endpoints of superiority in delaying time to first SRE
and delaying time to first-‐and-‐subsequent SRE were not met. The
hazard ratio of denosumab versus zoledronic acid for overall survival
was 0.90 (95 percent CI, 0.70 -‐ 1.16)”.
http://www.prnewswire.com/news-‐releases/amgen-‐announces-‐positive-‐top-‐line-‐results-‐from-‐xgeva-‐denosumab-‐phase-‐3-‐trial-‐for-‐delay-‐of-‐bone-‐complications-‐in-‐multiple-‐myeloma-‐patients-‐300348779.html
Oprozomib: Efficacy
• Proteasome inhibition is dose dependent– >80% inhibition with 210 mg/day oprozomib
Patie
nts (n)
Savona MR et al. Blood. 2012;120. Abstract 203.
Oprozomib 210 mg/dayOprozomib 180 mg/dayOprozomib 150 mg/dayOprozomib 120 mg/day
5
4
3
2
1
0PR MR SD PD
Oprozomib and Dexamethasone in R/R Multiple Myeloma: Initial Results from the Dose Escalation
Portion of a Phase 1b/2, Multicenter Study
• R/R MM who received 1-‐5 prior lines of therapy
– At least 1 regimen including lenalidomide and/or bortezomib• Oprozomib on days 1, 2, 8, and 9 of a 14-‐day cycle (2/7 schedule) or on
days 1–5 of a 14-‐day cycle (5/14 schedule)• Oprozomib starting dose was 210 mg on both schedules
– Doses escalated in 30-‐mg increments using a standard 3+3 dose-‐escalation scheme
• 2/7 schedule (n = 12): ORR = 42%, CBR = 58%
• 5/14 Schedule (n = 7): MR = 3 pts, SD = 2 pts, CBR = 43%
• Improved GI tolerability compared to single-‐agent oprozomib
Hari PN et al. Proc ASH 2014;Abstract 3453.
Venetoclax: Bcl2 inhibition
Venetoclax (VEN) is a potent, selective, orally available small-‐molecule BCL-‐2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14).
Venetoclax in R/R Myeloma
Kumar S et al. Proc ASCO 2016; Abstract 8032.
All Patients(n=66)
T(11:14)(n=30)
No t(11;;14)(n = 36)
Venetoclax in t(11;14) MM
Therapy started
50
40
30
20mg/dL
0
10Generalized normal high
Generalized normal low
200
150
100mg/dL
0
50
Generalized normal high
Generalized normal low
Kappa FLC Kappa FLC
A.K. Stewart, unpublished
KEYNOTE-023: Change in M Protein, Free Light Chain (FLC) and Response
Mateos MV et al. Proc ASCO 2016;;Abstract 8010.
ORR (all patients) = 20/40 (50%);; len refractory = 11/29 (38%)
• Ongoing Phase III studies of pembrolizumab: KEYNOTE-185;; KEYNOTE-183
Percent change from
baseline
in M protein or FLC
35/40 (88%) of patients with a decrease
Pembrolizumab in Combination with Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple
Myeloma (RRMM)
• 28-‐day cycles of pembrolizumab (at a dose of 200 mg IV) every 2 weeks
• ORR with ≥ Partial response were observed in 27 of 48 pts (56%)
• Of 38 double refractory pts ORR was 55%
• Of 18 high-‐risk pts ORR was 33%
• Median duration of response for responding pts was 8.8 months
Badros AZ et al. Proc ASH 2016; Abstract 490.
CAR T-Cell Therapy Process
http://www.oncologynurseadvisor.com/leukemia/reprogramming-immune-system-to-target-cancer/article/461164/
T Cells Expressing an Anti-‐B-‐Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Multiple Myeloma
First-‐in-‐humans clinical trial of CAR-‐T targeting BCMA
Patient Monoclonal protein No. prior lines of therapy
CAR-‐BCMA T cells infused (per kg)
Response (duration, wks)
1 k light chain only 7 0.3 x 106 PR (2)
2 IgA-‐λ 10 0.3 x 106 SD (6)
3 k light chain only 8 0.3 x 106 SD (6)
4 λ-‐light chain only 7 1 x 106 SD (12)
5 IgG-‐k 13 1 x 106 SD (4)
6 IgG-‐λ 11 1 x 106 SD (2)
7 IgG-‐λ 6 3 x 106 SD (7)
8 k light chain only 8 3 x 106 VGPR (8)
9 k light chain only 4 3 x 106 SD (16)
10 IgA-‐k 3 9 x 106 sCR (17)
11 IgG-‐λ 5 9 x 106 VGPR (26+)
12 IgA-‐λ 5 3 x 106 SD (2)
Ali SA et al. Blood 2016;128(13):1688-‐700.
CAR-‐BCMA T-‐Cells Specifically Recognized BCMA In Vitro and Exhibited Antimyeloma Activity
Ali SA et al. Blood 2016;128(13):1688-‐700.
Pt 8: MM progressing despite 8 prior lines of therapy obtained a very good partial remission (VGPR) after infusion of CAR-‐BCMA T cells. PET–CT scans from before and after treatment show elimination of a large number of MM bone lesions.
Free k light chains level decreased after CAR T-‐cell infusion as the MM entered a VGPR and then increased with progression of the MM. The serum BCMA protein level followed a pattern similar to that of the serum free k light chains.
B-‐Cell Maturation Antigen (BCMA)-‐Specific Chimeric Antigen Receptor T Cells (CART-‐BCMA) for Multiple Myeloma (MM):
Initial Safety and Efficacy from a Phase I Study
Pt Age, Sex/Isotype
Cytogenetics # prior lines
Pre-‐treatment BM PC%
CART dose received (%of planned)
Peak CART expansion in blood:qPCR*
Best Heme
response
DoR(mos)
01 66 M/IgG k +11, -‐16q, -‐17p 11 70% 2 x 10e8 (40%)
174110 sCR 7+
02 68 M/IgA k +1q, +4p, -‐17p 9 60% 5 x 10e8(100%)
6160 MR 2
03 55 F/IgA L +1q, t(4:14), -‐16q
4 95% 2 x 10e8 (40%)
220081 VGPR 5
09 62 M/ Kappa LC
t(11;14), -‐16q, -‐17p
9 15% 5 x 10e8 (100%)
240 SD 2
10 47 M/IgG L +1q, t(11;14) 7 95% 1.8 x 10e8 (100%)
302 PD -‐-‐
11 57 F/IgG L +1q, t(4;14), -‐17p
10 90% 5 x 10e8 (100%)
5801 MR† 1+
Cohen AD et al. Proc ASH 2016; Abstract 1147.
DoR = duration of response* copies/ug genomic DNA; † follow-‐up 4 weeks, BM PC = bone marrow plasma cell