Smoldering Multiple Myeloma
• Laboratory analysis
– Complete blood count and complete metabolic panel
• β2M, LDH
– M proteins
• Radiologic imaging
– Skeletal survey, MRI/CT, PET
• Bone marrow biopsy
• Specific tests to rule out other:
– Causes of anemia, renal insufficiency, hypercalcemia, etc.
Specific Diagnostic Tests
NCCN v4.2015.
a. Overall designated as best responses after a median potential follow-up of 17.3 months (patients with NDMM) or 15.9 months (patients with SMM).
b. One of 45 patients was not evaluable after 2 cycles (data not collected).
c. Three patients were not evaluable after 8 cycles (2 had not completed 8 cycles, and 1 patient’s disease had progressed prior to completion of 8 cycles).
d. One patient discontinued study participation before completing 8 cycles.
e. Twenty-nine patients were not evaluable after 20 cycles (26 patients had not completed 20 cycles, 1 patient’s disease had progressed prior to completion of 20
cycles, 1 patient’s disease had progressed just after completion of 20 cycles, and 1 patient had discontinued study participation for personal reasons).
f. Nine patients were not evaluable after 20 cycles (8 patients had not completed 20 cycles, and 1 patient had discontinued study participation before completing
8 cycles).
CRd-R in Patients with Smoldering or Newly Diagnosed Multiple Myeloma
Korde et al, JAMA Oncol 2015, doi:10.1001/jamaoncol.2015.2010
ISS or R-
ISS Stage
ISS Criteria R-ISS Criteria 5-year
OS
5-year
PFS
I Serum β2-microglobulin <
3.5 mg/L, serum albumin ≥
3.5 g/dL
ISS stage I and
standard-risk CA by
iFISH and normal LDH
82% 55%
II Not ISS stage I or III Not R-ISS stage I or III 62% 36%
III Serum β2-microglobulin ≥
5.5 mg/L
ISS stage III and either
high-risk CA by iFISH
or high LDH
40% 24%
Abbreviations: CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridization; ISS, International
Staging System; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, revised International Staging System
Revised-International Staging System for MM
Palumbo et al, J Clin Oncol 2015, doi: 10.1200/JCO.2015.61.2267
Multiple Myeloma Treatment Linesa
Induction Consolidation
Front-line treatment
Maintenance
Maintenance
Rescue
Relapsed
IMiD: Thal-Len
Proteasome Inh: Bor-Car
Steroids: Dex-Pred
Alkylator: Cyclo-Mel
Anthracycline: LipoDnr-Adr
SCT Observation
IMiD: Thal-Len
Proteasome Inh: Bor
Steroids: Dex-Pred
IMiD: Thal-Len-Pom
Proteasome Inh: Bor-Car-Ixa
Steroids: Dex-Pred
Alkylators: Mel-Cy-Benda
Investigational
HDAC Inh: Pan
MoAb: Dar-Elo
Transplant-eligible patients:
Bor/Dex; Bor/Cyclo/Dex; Bor/Dex/Dox;
Bor/Len/Dex; Bor/Thal/Dex; Len/Dex;
Thal/Dex; Dex/Vinc/LiposomalDox;
Car/Len/Dex; Dex.
NCCN v4.2015.
Is There an Optimal Bortezomib-containing
Induction Regimen?Alkylator Bor Dex vs IMID Bor Dex
(CyBORD vs VTD or RVD)
Optimal Induction Therapy in High-risk Patients
Cavo et al. Presented at: American Society of Hematology (ASH) 2015.
Optimal Induction Therapy in Low-risk Patients
Cavo et al. Presented at: American Society of Hematology (ASH) 2015.
What about CarfilzomibInduction?
Treatment Schema – 28-day Cycle
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
Patient Disposition
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
SCC and ASCT
• Stem cells were collected from patients following G-CSF plerixafor treatment
– Median 9.0 x 106 CD34+ Cells/kg (range 2.9-16.8 x 106) after a median of 2 days of collection (range 1-8)
– 6 patients collected less than 4 x 106 CD34+ cells/kg, of which 3 were re-collected for a total of 2.9, 4.2, and 9.8 x 106 total CD34+ cells/kg
• There were no unusual events during ASCT
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
Time to Response
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
MRD Evaluation
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
Treatment Outcomes
• The 3-year post-randomization PFS rate was 61% in the transplant arm vs 48% in the RVD arm.
• The PFS benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or >60 years), ISS stage (I or II or III), cytogenetics (standard or high risk), and response after the 3 first cycles of RVD (complete response or not).
• The 3-year post randomization rate of overall survival was extremely high (88%) and similar between the 2 study groups (stratified P value for log rank test = 0.25).
• The complete response rate was significantly higher in the transplant arm compared to the RVD arm: 58% vs 46%, respectively (P<0.01). Forty-one second primary malignancies among 39 patients were recorded (Transplant arm=23, RVD arm=18).
Report from ASH 2015 IFM/DFCI
Attal et al. Presented at: American Society of Hematology (ASH) 2015.
Relapsed/Refractory Multiple Myeloma
Single Agent and Doublet Efficacy
Trial Phase nIMiD
exposedPI
exposedORR
PFS (months)
OS (months)
Thalidomide 2 169 0% 0% 30% 2y : 20% 2y : 48%
BTZ vs DEX 3 669 49% 0% 38% 6.22 30
BTZ + Dox vs
BTZ3 646 41% 0% 43% 9 33
Len Dex MM009 3 177 41% 10% 61% 11.1 29.6
Len Dex MM010 3 349 30% 4.5% 60% 11.3 38
CFZ (+dex 8) 2 266 100% 99% 23.7% 3.7 15.6
Pom D vs Dex 3 302 100% 95% 31% 4.2 13.1
Barlogie B. Blood. 2001;98:492-494.
Richardson P. N Engl J Med. 2005;352:2487-2498.
Orlowski RZ. J Clin Oncol. 2007;25:3892-3901.
Weber D. N Engl J Med. 2007;357:2133-2142.
Dimopoulos M. N Engl J Med. 2007;357:2123-2132.
Siegel DS. Blood. 2012;120:2817-2825.
San Miguel J. Lancet Oncol. 2013;14:1055-1066.
Dimopoulos et al., EHA20, 2015; Abstract P273.
For phase 3 studies, data only provided for experimental arm
54.660.7
66.7
87.1
66
79
63
7771.5
78.3
611 9.3
31.8
7 4 613
6.611.7
4.3
14.1
0
10
20
30
40
50
60
70
80
90
100
Vd PanVd Rd KRd Rd EloRd Vd Kd Rd IRd
ORR
≥CR
sCR
Summary of Relapsed Refractory MM (1-3 Prior Therapies)Response Rates
Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4)
Per
cen
t
Tourmaline MM1 (5)
1. San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
2. Stewart AK et al. N Engl J Med. 2015;372:142-152.
3. Lonial S et al. Presented at: ASCO 2015. Abstract #8508.
4. Dimopoulos MA et al. Presented at: ASCO 2015. Abstract #8509.
5. Moreau P et al. Presented at: ASH 2015. Abstract #727.
8
12
18
26
15
19
9
18
14.7
20.6
0
5
10
15
20
25
30
Vd PanVd Rd KRd Rd Erd Vd Kd Rd IRd
PFS
Summary of Relapsed Refractory MM (1-3 Prior Therapies) PFS
Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4)
Mo
nth
s
Tourmaline MM1 (5)
1. San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
2. Stewart AK et al. N Engl J Med. 2015;372:142-152.
3. Lonial S et al. Presented at: ASCO 2015. Abstract #8508.
4. Dimopoulos MA et al. Presented at: ASCO 2015. Abstract #8509.
5. Moreau P et al. Presented at: ASH 2015. Abstract #727.
Clinical Trial Len
Refr
Bort
Ref
High Risk PFS
(months)
Panorama 1 0% 15.2% Vd 8
Pan-Vd 12
Aspire 0% 0% 12.6% Rd 18
KRd 26
E-Ld (Phase II) 5.5% E-Ld 33
Eloquent 2 0% 22% 30.5% Ld 15
E-Ld 19
Endeavor 25% 0% 22.6% Vd 9
Kd 18
Tourmaline MM1 0% 0% 21% IRd 20.6
Rd 14.7
Patient Populations Trials
Summary of Relapsed Refractory MM (1-3 Prior Therapies) Hazard Ratios (with 95% CI)
Mo
nth
s
8
12
18
26
15
19
9
18
14.7
20.6
0
5
10
15
20
25
30
Vd PanVd Rd KRd Rd Erd Vd Kd Rd IRd
PFS
Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4) Tourmaline MM1 (5)
HR 0.69 (0.57-0.83)
P=0.001
HR 0.70 (0.57-0.85)
P=0.0004HR 0.53 0.44-0.65)
P<0.0001
HR 0.742 (0.587-0.939)
P=0.012
HR 0.63 (0.52-0.76)
P<0.0001
1. San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.
2. Stewart AK et al. N Engl J Med. 2015;372:142-152.
3. Lonial S et al. Presented at: ASCO 2015. Abstract #8508.
4. Dimopoulos MA et al. Presented at: ASCO 2015. Abstract #8509.
5. Moreau P et al. Presented at: ASH 2015. Abstract #727.
• Consider toxicity profile of each agent – GI, cardiac, HTN, neuropathy
• Convenience – oral vs IV therapy
• Presence/absence of high molecular risk features
• Prior therapies – if PI or IMID refractory, which study outcomes are generalizable
• Sequencing issues (e.g. if elotuzumab not used with RD, then no further role based on current approval)
Given comparable hazard ratios, there is no one right answer; instead requires risk/benefit assessment for each individual patient.
Considerations in Choosing the Appropriate Evidence-based Therapy in Relapsed MM
PI + IMiD + Dex (Triplet) Efficacy
Trial Phase n IMiDexposed
IMiDrefractory
PIexposed
PIrefractory
ORR PFS(mos)
OS(mos)
Bort Thal
Dex1-2 85 74% most 0% 0% 65% 6 22
Bort Len
Dex2 64
73%T
6% L3% 53% 8% 64% 9.5 30
Bort Pom
Dex1 28 100% 100% 100% NA 71% NA NA
Car-Len-
Dex2 52 73% 44% 80% 25% 77% 15.4 NA
Car-Pom-
Dex1/2 79 100% 100% 89%
91% in
ph 170% 9.7 NR
Wang M et al. Blood. 2013;122:3122-3128.
Shah JJ et al. Presented at: ASH 2013. Abstract 690.
Pineda-Roman M. Leukemia. 2008;22:1419-1427.
Richardson PG et al. Blood. 2014;123:1461-1469.
Richardson PG et al. Presented at: ASCO 2014.
Baseline Refractory Status
Refractory to, n (%) n = 106
Last prior therapy 103 (97)
PI and IMiD 101 (95)
BORT 95 (90)
CARF 51 (48)
LEN 93 (88)
POM 67 (63)
Alkylating agent 82 (77)
BORT+LEN 87 (82)
BORT+LEN+CARF 42 (40)
BORT+LEN+POM 57 (54)
BORT+LEN+CARF+POM 33 (31)
BORT+LEN+CARF+POM+THAL 12 (11)
• Patients were heavily pretreated, and most patients were refractory to multiple lines of PI and IMiD treatment
– 97% were refractory to their last line of therapy
– 77% were refractory to alkylating agents
– 95% were double refractory
– 66% were refractory to 3 of 4 therapies (BORT, LEN, CARF, and POM)
– 63% were refractory to POM
– 48% were refractory to CARF
Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.
ORR by Subgroup
33 3330
21 20
30 29 28 2826
21
0
5
10
15
20
25
30
35
40
OR
R, %
Refractory to
Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.
Progression-free and Overall Survival
• 29 of 31 responders are still alive
• The 1-year survival rate was 65% (95% CI, 51.2–75.5)
96106 85 82 64 23 10 2 0Patients at risk
80
100
60
40
20
0
0 42 6 8 16141210
Months from start of treatmentP
atie
nts
aliv
e (%
)
Median OS = NE
(95% CI, 13.7–NE)
63106 38 32 17 5 4 1 0Patients at risk
80
100
60
40
20
0
0 42 6 8 16141210
Months from start of treatment
Pat
ient
s pr
ogre
ssio
n-fr
ee a
nd a
live
(%)
Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.
Treatment-emergent AEs >20%
Term Any Grade
n (%)
Grade 3
n (%)
Grade 4
n (%)
Fatigue 42 (40) 3 (3) -
Anemia 35 (33) 25 (24) -
Nausea 31 (29) - -
Thrombocytopenia 27 (26) 18 (17) 8 (8)
Neutropenia 24 (23) 12 (11) 3 (3)
Back pain 23 (22) 3 (3) -
Cough 22 (21) - -
• Serious treatment-emergent AEs (TEAEs)
in 32 (30%) patients and 24 (23%) had
Grade 3/4 serious TEAEs
• No discontinuations due to DARA-related
AEs
• No febrile neutropenia reported
• Few required additional supportive care
‒ Red blood cell transfusion (38%)
‒ Platelet transfusion (13%)
‒ Granulocyte colony stimulating factor
(8%)• Grade 3 or higher anemia and thrombocytopenia
occurred more frequently in nonresponders (32%
and 24%, respectively) than responders (3% and
7%, respectively)
• Grade 3 or higher neutropenia rates were similar in
nonresponders (12%) and responders (13%)
Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.
Infusion-Related Reactions (IRRs)
• Occurred in 43% of patients
• Predominantly Grade 1 or 2
– Grade 3: 5%; no Grade 4
• >90% of IRRs occurred during the first infusion
• 7% of patients had an IRR at >1 infusion
• Most common IRRs included nasal congestion (12%); throat irritation (7%); cough, dyspnea, chills, and vomiting (6% each)
• No patients discontinued treatment due to IRRs
0
5
10
15
20
25
30
35
40
45
Overall 1st infusion 2nd infusion 3rd or laterinfusion
Inci
den
ce o
f IR
R, %
Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.
MMY1001: DARA + POM-D Arm
Eligibility criteria
• Refractory to last line of therapy
• ≥2 prior lines of therapy, including 2 consecutive cycles of lenalidomide and bortezomib
• Pomalidomide naïve
• ECOG score ≤2
• Absolute neutrophil count ≥1.0×109/L, and platelet count ≥75×109/L for patients with <50% plasma cells (>50×109/L, otherwise)
• Calculated creatinine clearance ≥45 mL/min/1.73 m2
Treat 6 patients with DARA + POM-D
If ≤1 patient has DLTs
Enroll 6 additional patients
Expand up to 88 patients
DARA* IV 16 mg/kg +
Pomalidomide 4 mg (Days 1-21) +
Dexamethasone 40 mg QW
Open-label, multicenter, six-arm, Phase 1b
study (28-day cycles)
*QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond.
Chari A et al. Presented at: ASH 2015. Abstract 508.
Overall Response Rate: DARA + POM-D
• ORR = 71%
• ORR in double-refractory patients = 67%
• Clinical benefit rate (ORR + minimal response) = 73%
DARA + POM-D
(N = 75)
n (%) 95% CI
Overall response rate
(sCR+CR+VGPR+PR)53 (71) 59.0-80.6
Best response
sCR
CR
VGPR
PR
MR
SD
PD
4 (5)
3 (4)
25 (33)
21 (28)
2 (3)
17 (23)
3 (4)
1.5-13.1
0.8-11.2
22.9-45.2
18.2-39.6
0.3-9.3
13.8-33.8
0.8-11.2
VGPR or better
(sCR+CR+VGPR)32 (43) 31.3-54.6
CR or better (sCR+CR) 7 (9) 3.8-18.3
ORR = 71%
43%
VGPR or
better
9%
CR or
better
28%
33%
4%
5%
0
10
20
30
40
50
60
70
80
16 mg/kg
OR
R, %
PR VGPR CR sCR
n = 75
Chari A et al. Presented at: ASH 2015. Abstract 508.
Progression-free Survival at 6 Months: DARA + POM-D
0
Pat
ient
s pr
ogre
ssio
n-fr
ee a
nd a
live,
%
2 6Time from first dose, months
0
20
60
80
100
4
40
Patients at risk 98 67 39 19
6-month PFS rate = 66% (95% CI, 52.3-75.9)
Median follow-up of 4.2 months
Chari A et al. Presented at: ASH 2015. Abstract 508.
• FDA Approved November 16, 2015 as a single agent for >3 lines of therapy including PI, IMiD , or double refractory
• High-risk Smoldering MM
– Phase II (long intense vs intermediate vs short intense)
• Newly Diagnosed
– Phase III (SCT eligible): DVTD vs VTD
– Phase III (non-SCT eligible): DRd vs Rd
– Phase III (non-SCT eligible): DVMP vs VMP
• Relapse (1+ lines of therapy)
– Phase III: DRd vs Rd
– Phase III: DVD vs VD
• Relapsed/Refractory
– Phase II: Dara
– Phase II: Dara + [VD, VMP, VTD, PomD, Kd, KRd]
Daratumumab Status
Treatment n Eligibility ORR PFS DOR
(mos)
OS (mos)
ixazomib + dex 33 88% Lexp; B sens 34%
[78.3%]
12.4
[20.6][20.5] 96% @ 6 mo
filanesib
in low AAG
32
21
75% IMiD Ref
53% PI ref
16%
24%
3.7
5.3
8.6
8.6
19
23.3
filanesib + dex
in low AAG
55
36
100% IMiD Ref
98% PI ref
15%
19%
3.4
5.1
5.1
5.1
10.5
10.8
afuresertib 34 97% I; 88% PI 8.8%
selinexor + dex 8 Ref to all classes 50% NR NR NR
LGH 447 59 NR 10.5% NR 5.8 NR
Filanesib granted orphan drug approval by FDA in May 2014.
Kumar S et al. Presented at: ASH 2013.
Lonial S. Presented at: ASH 2013.
Voorhees et al. Presented at: ASH 2013.
Summary of Novel Agents with
Single-agent Activity
Chen C et al. Presented at: EHA 2014.
Spencer A et al. Blood. 2014.
Raab et al. Presented at: ASH 2014. Abstract 301.
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