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Current management of
multiple myeloma
Jorge J. Castillo, MD Assistant Professor of Medicine
Harvard Medical School [email protected]
Multiple myeloma
• MM is a plasma cell
neoplasm characterized
by the accumulation of
malignant plasma cells
in the bone marrow
producing a monoclonal
paraprotein.
• MM accounts for 10%
of all hematologic
malignancies.
• Risk factors
– MGUS (1% per year)
– Age: median 66 years
– Sex: Male > female
– Race: blacks > whites >
Asians/Hispanics
– Obesity
Myeloma subtypes
Castillo. CPPOP 2016
Diagnosis of myeloma
• Clonal bone marrow
plasma cells greater
than or equal to 10%
OR
• Biopsy-proven bone or
soft tissue
plasmacytoma
• Hypercalcemia: serum calcium
>11 mg/dL
• Renal insufficiency: creatinine
clearance <40 mL/min or
serum creatinine >2 mg/dL
• Anemia: hemoglobin <10 g/dL
• Bone lesions: osteolytic
lesions on radiographs, CT,
PET/CT, or MRI
Rajkumar et al. Lancet Oncol 2014
Diagnosis of myeloma
Diagnostic update
• The following represent an 80% risk of developing
active MM within 2 years and should be considered
active MM:
– Clonal bone marrow plasma cell involvement greater than or
equal to 60%
– Serum FLC ratio greater than or equal to 100; kappa:lambda
in kappa-restricted myeloma or lambda:kappa in lambda-
restricted myeloma
– Greater than 1 focal lesion on MRI
Rajkumar et al. Lancet Oncol 2014
Improved survival in patients with myeloma
Kumar et al. Blood 2008
Kumar et al. Leukemia 2014
Greipp et al. J Clin Oncol 2005
Palumbo et al. J Clin Oncol 2015
10
Timeline of Advances in Multiple Myeloma Through 2015
Mechanism of action of proteasome inhibitors
Mechanism of action of immunomodulators
Van de Donk et al. Cancer Managem Res 2012
Mechanism of action of monoclonal antibodies
Van de Donk et al. Blood 2016
Treatment for myeloma - frontline
Treatment for myeloma - frontline
Attal et al. N Engl J Med 2017
Moreau et al. Blood 2016
Lenalidomide (n=306)
Placebo (n=302)
Hematologic cancers
13 (4%) 5 (2%)
Solid tumors 10 (3%) 4 (1%) Nonmelanoma skin cancers
5 (2%) 3 (1%)
Total 32 (9%) 12 (4%) Attal et al. N Engl J Med 2012
Lenalidomide (n=231)
Placebo (n=229)
Hematologic cancers
8 (3%) 1 (0.4%)
Solid tumors 10 (4%) 5 (2%) Nonmelanoma skin cancers
4 (2%) 3 (1.3%)
Total 22 (9%) 12 (5%)
McCarthy et al. N Engl J Med 2012
Treatment for myeloma - relapsed
Dimopoulos et al. Lancet Oncol 2016
Stewart et al. N Engl J Med 2015
Moreau et al. N Engl J Med 2016
Dimopoulos et al. N Engl J Med 2016
17.3
31.5
30.1
24.7
23.5 11.9
22.6
9.1
0.
25.
50.
75.
100.
DRd… Rd…
sCRCRVGPRPR
≥VGPR:
76%c
ORR = 77%b
≥VGPR: 46%
≥CR:
46%c ≥CR:
21%
ORR = 93%b
P <0.0001
OR
R, %
Palumbo et al. N Engl J Med 2016
Lonial et al. N Engl J Med 2016
Pomalidomide plus low-dose dexamethasone versus high-dose
dexamethasone alone for patients with relapsed and refractory
multiple myeloma (MM-003): a randomised, open-label, phase 3 trial
San Miguel et al. Lancet Oncol 2013
28
Selected Phase III Trials in Relapsed Disease
Name of trial No. prior lines Arm N PFS (months)
ORR ≥VGPR ≥CR
ENDEAVOR 1-3 Kd 464 18.7 77% 54% 13%
Vd 465 9.4 63% 29% 6%
TOURMALINE-MM1 1-3 IRd 360 20.6 78% 48% 12%
Rd 362 14.7 72% 39% 7%
ELOQUENT-2 1-3 Elo-Rd 321 19.4 79% 33% 4%
Rd 325 14.9 66% 28% 7%
ASPIRE 1-3 KRd 396 26.3 87% 70% 32%
Rd 396 17.6 67% 40% 9%
PANORAMA 1 1-3 Pano-Vd 387 12.0 61% 11%
Vd 381 8.0 55% 6%
NIMBUS (MM-003) ≥2§ Pd 302 4.0 31% 6% 1%
D 153 1.9 10% 1% 0%
CASTOR ≥1 Vd-dara 251 NE 83% 59% 19%
Vd 247 7.2 63% 29% 9%
POLLUX ≥1 Rd-dara 286 NE 93% 76% 43%
Rd 283 18.4 76% 44% 19%
Management issues
Proteasome inhibitors Immunomodulators
• Full-dose aspirin for
thrombosis prophylaxis
• Risk of secondary cancers
Daratumumab
• Zoster prophylaxis
• False positive Coombs
• SPEP interference
• Flow interference
• Zoster prophylaxis
• Subcutaneous bortezomib
is preferred
• Carfilzomib can cause
cardiac and pulmonary
toxicity in elderly patients
Elotuzumab
• SPEP interference
La Huerta et al. J Clin Oncol 2017
PFS According to MRD Status at 10–5
CASTOR POLLUX
Patients
pro
gre
ssio
n fre
e a
nd a
live
(%)
0
20
40
60
80
100
0 3 6 9 12 15 18 24
Vd MRD negative
DVd MRD negative
Vd MRD positive
DVd MRD positive
Patients at risk
Months
21
6
26
241
225
6
26
176
189
6
26
123
172
5
26
68
134
3
15
20
76
2
7
7
26
0
1
0
4
0
0
0
1
0
0
0
0
Patients
pro
gre
ssio
n fre
e a
nd a
live
(%)
0
20
40
60
80
100
0 3 6 9 12 15 21 27
Rd MRD negative
DRd MRD negative
Rd MRD positive
DRd MRD positive
Patients at risk
Months
24
16
71
267
215
16
71
233
195
16
71
190
178
15
70
166
167
15
66
144
161
12
57
120
137
0
6
5
9
0
0
0
1
0
0
0
0
18
10
28
38
54
Rd MRD–
DRd MRD–
DRd MRD+
Rd MRD+
Vd MRD–
DVd MRD–
DVd MRD+
Vd MRD+
Usmani, et al. ASH 2016; 653:1151
Mateos, et al. ASH 2016; 653:1150
Barlogie et al. Blood 2014
Venetoclax – Mechanism of Action
Roberts et al. N Engl J Med 2015
Punnoose et al. Mol Cancer Ther 2016
• Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival
• Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1 and bortezomib can indirectly inhibit MCL-1
• Venetoclax enhanced bortezomib activity in vitro and in vivo2
• N = 66
• Median age: 64 y
• Median of 3 prior lines of therapy
All patients 66 67
Not refractory to bortezomib 39 90
Bortezomib-refractory 26 31
1 to 3 prior therapies 37 89
4 to 6 prior therapies 29 38
Bcl-2 high 18 94
Bcl-2 low 27 59
ORR, %
Moreau et al. ASH 2016
n
• Venetoclax/bortezomib/dexamethasone was well tolerated, no MTD
• Clinical benefit was higher in patients with fewer lines of therapy,
patients who were not bortezomib-refractory, and patients who had high
Bcl-2 expression
Venetoclax + Bortezomib + Dexamethasone
Selinexor: A new class of drug
Selinexor – STORM Trial Quad and Penta Refractory
Vogl et al. ASH 2016
STORM Trial
N=78
Response
VGPR 5 %
PR 15 %
MR 13 %
Patient
Characteristics
Sel Dex
Quad Refr
Sel Dex
Penta Refr Sel VD Sel KD Sel PomD
Patients Enrolled 48 31 33 22 20
Median Priors
(range) 7 (3 – 16) 7 (5 – 17) 4 (1 – 11) 4 (2 – 10) 5 (2 – 9)
ORR 21% 20% 77% 63% 60%
CBR 29% 40% 91% 84% 73%
Antigen Presenting Cell
MHC
CTL
A-4
CD
80
C
D8
6
T cell
TCR CD
28
Ipilimumab* Tremelimumab
CD
27
C
D7
0
PD
L1
PD
L2
Nivolumab* Pembrolizumab* Pidilizumab
Durvalumab Atezolizumab* MSB0010718C BMS-936559
*US Food and Drug Administration
(FDA) Approved
Predictors of Clinical Activity
(based on solid tumor
experience)
• Tumor antigen–specific T cells
• Neoantigens
• Shared antigens
• Antigen presentation
• Evidence of immune
recognition
• Adaptive resistance
• “Target expression”
Checkpoint inhibitors
Leshokin et al. IMW New Delhi 2017
Pembrolizumab + RD for Relapsed/ Refractory MM
Best Overall Response n (%)
Efficacy Population†
(n = 40)
Lenalidomide
Refractory
(n = 29)
ORR 20 (50) 11 (38)
Stringent CR (sCR) 1 (3) 1 (3)
Very good PR (VGPR) 5 (13) 3 (10)
PR 14 (35) 7 (24)
SD 19 (48) 17 (59)
Disease control rate (CR + PR + SD) 39 (98) 28 (97)
Progressive disease (PD) 1 (3) 1 (3)
Mateos et al. J Clin Oncol 2016
• 11 patients NE by central review
• 3 discontinued within cycle 1 for reasons other than PD (2 no
treatment assessments and 1 SD by investigator)
• 8 inadequate myeloma data for response assessment (5 PD
and 3 SD by investigator)
Future: CAR T-cells
Autologous T-cells engineered to express a T-cell receptor that specifically
targets an antigen (BCMA, CD38) on the myeloma cells
Future: CAR-T Cell for Refractory MM
Lin et al. EORTC-NCI-AACR 2016
Conclusions
• The survival of patients with myeloma is
improving.
• Primary treatment should include RVD followed by
ASCT, if appropriate, and maintenance.
• Multiple treatment options for relapsed and/or
refractory myeloma patients.
• Venetoclax, selinexor, checkpoint inhibitors are
undergoing clinical trials.
Current management of
multiple myeloma
Jorge J. Castillo, MD Assistant Professor of Medicine
Harvard Medical School [email protected]
