Management of Relapsed/Refractory Multiple Myeloma Morie A Gertz, MD, MACP Consultant Division of Hematology Roland Seidler Jr Professor and Chair Department of Medicine College of Medicine Mayo Distinguished Clinician Mayo Clinic Rochester, Minnesota
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Management of Relapsed/Refractory Multiple Myeloma
Morie A Gertz, MD, MACPConsultant
Division of HematologyRoland Seidler Jr Professor and Chair
• 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
• 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
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