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Understanding the Latest Clinical

Data to Optimize the Care of


Patients With Multiple Myeloma

Supported by educational grants from Amgen, Celgene Corporation,


and Takeda Oncology.
Core Faculty

Carol Ann Huff, MD



Medical Director, Department of Oncology 

Associate Professor of Medicine and Oncology 

Johns Hopkins University 

Baltimore, Maryland
Shaji Kumar, MD

Department of Hematology

Mayo Clinic 

Rochester, Minnesota
Agenda

▪Diagnosis and Staging


▪Selecting Appropriate Induction Therapy
▪Autologous Stem Cell Transplantation
▪Duration of Therapy in Multiple Myeloma
▪Optimal Therapy for Transplantation-Ineligible Patients
▪Treatment Options in Relapsed/Refractory Multiple
Myeloma
Diagnosis and Staging
Updated IMWG Criteria for Diagnosis of
Multiple Myeloma
• MGUS • Smoldering Myeloma • Multiple Myeloma
▪ M protein < 3 g/dL ▪ M protein ≥ 3 g/dL (serum) ▪ Underlying plasma cell
or ≥ 500 mg/24 hrs (urine) proliferative disorder
▪ Clonal plasma cells in BM
< 10% ▪ Clonal plasma cells in BM 
 ▪ AND 1 or more myeloma-
≥ 10% to 60% defining events
▪ No myeloma-defining
events ▪ No myeloma-defining ▪ ≥ 1 CRAB* feature
events ▪ Clonal plasma cells in BM 

≥ 60%
▪ Serum free light-chain
ratio ≥ 100
▪ > 1 MRI focal lesion

*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)

R: Renal insufficiency (CrCl < 40 mL/min or serum creatinine > 2 mg/dL)

A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)

B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET/CT)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. Slide credit: clinicaloptions.com


Progression to Symptomatic MM

100
Smoldering MM
MGUS
80 27% will convert in 15 years
Roughly 2% per year 78
73
Progression (%)

66
60
15% more will convert over next 5 yrs 

51 and then 1% per yr thereafter
40
51% will convert in first 5 yrs
~ 10% per yr
20 21
4 16
10
0
0 5 10 15 20 25
Yrs Since Diagnosis

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Slide credit: clinicaloptions.com


Risk Factors for Progression

2-Yr
Factor, % Progression
High levels of circulating plasma cells 80
High bone marrow plasma cell proliferative rate 80
Evolution of smoldering multiple myeloma 65
Abnormal plasma cell immunophenotype ≥ 95%
plus immunoparesis 50
Cytogenetic subtypes: t(4;14), 1q amp, or del(17p) 50
Unexplained decrease in creatinine clearance by 

≥ 25% accompanied by a rise in urinary monoclonal
protein or serum free light-chain concentrations NA

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. Slide credit: clinicaloptions.com


MGUS-SMM: Management

▪Observation is the standard of care


▪Regular follow-up
▪MGUS
– Typically annual
– IgG, < 1 g/L can be followed every 2-3 yrs
▪SMM
– Every 3-6 mos, depending on risk
– Consider bisphosphonates with decreased BMD

Slide credit: clinicaloptions.com


Newly Diagnosed MM: Why Risk Stratify?

▪2 important goals
– Counsel: Need to provide pt with realistic expectations
based on currently available treatments
– Therapy: Choose specific therapies based on their
differential effects on high-risk vs standard-risk disease

Slide credit: clinicaloptions.com


Are There High-Risk Features?

▪International Staging System stage


▪Cytogenetic abnormalities
– del(13), hypodiploidy
– t(4;14), t(14;16), or del(17p) (by FISH)
▪Poor performance status
▪Circulating myeloma cells
▪High serum LDH

Slide credit: clinicaloptions.com


Revised ISS Staging System

1.0
Stage Definition
▪ Serum albumin ≥ 3.5 g/dL 0.8

Probability of OS
AND β2-M ≤ 3.5 mg/L
1 ▪ Normal LDH
▪ No t(4;14), t(14;16), or 0.6
del(17p)
2 ▪ Not stage I or III 0.4
▪ β2-M ≥ 5.5 mg/dL PLUS
Median OS, Mos
3 ▪ High LDH, OR
0.2 R-ISS I NR

▪ t(4;14), t(14;16), or del(17p) R-ISS II 83

R-ISS III 43
0
0 12 24 36 48 60 72
Mos

Palumbo A, et al. J Clin Oncol. 2015;33:2863-2869. Slide credit: clinicaloptions.com


mSMART: Classification of Active MM

High Risk Intermediate Risk* Standard Risk*†

▪ FISH‡ ▪ FISH All others including:


‒ del(17p) ‒ t(4;14)§ ▪ Trisomies
‒ 1q gain ▪ t(11;14)ǁ
‒ t(14;16)
‒ t(14;20) ▪ Complex karyotype ▪ t(6;14)
▪ Metaphase
▪ GEP del(13q) or
‒ High-risk hypodiploidy
signature ▪ High PC S-phase¶

*A subset will be classified as high-risk by GEP.


†LDH > ULN and β -M > 5.5 mg/L may indicate worse prognosis.
2
‡Trisomies may ameliorate.
§Prognosis is worse when associated with high β -M and anemia.
2
ǁt(11;14) may be associated with plasma cell leukemia.
¶Cutoffs vary.

Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al.


Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc.
2013;88:360-376. Slide credit: clinicaloptions.com
Selecting Appropriate 

Induction Therapy
Goals of Induction Therapy

▪High response rate; rapid/deep response


▪Improve performance status and quality of life
▪Not limit PBSC mobilization (for younger pts)
▪Current issues
– Optimal regimen
– Optimal duration of therapy
– Role of transplantation
How deep of a response should we aim for?

Slide credit: clinicaloptions.com


Achieving ≥ VGPR or CR Should Be the
Goal of Therapy
Achieving ≥ VGPR[1] Achieving CR[2]
1.00 1.00
Probability of OS

Probability of OS
0.8
0.75
0.6
0.50 P = .0017
0.4
0.25 CR + VGPR (n = 445) 0.2 CR or better PR PD
PR (n = 288) VGPR SD
0 0
0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7
Yrs Since Transplantation Yrs Since Transplantation
▪ Pts with sCR have a significantly better
outcome: estimated 5-yr OS 80% with sCR vs
53% with CR or 47% with nCR

1. Harousseau JL, et al. J Clin Oncol. 2009;27:5720-5726. 



2. Kapoor P, et al. J Clin Oncol. 2013;31:4529-4535. Slide credit: clinicaloptions.com
Initial Management of MM in
Transplantation-Eligible Pts
Adult with
symptomatic MM

Yes Continue therapy and


Is this pt a workup for SCT
transplantation
candidate?
≥ PR after 

Yes 4 cycles? No
Secondary induction
therapy and discussion
with a SCT specialist
Select treatment with Start initial
considerations of therapy
comorbidities

VHA clinical guidance for the initial management of adults with 



multiple myeloma. 2009. Slide credit: clinicaloptions.com
Factors Affecting Transplantation
Eligibility
▪ Age
– Older than 70 yrs of age may not be eligible
– Older pts more sensitive to toxicity; less physical reserve
▪ Performance status
▪ Comorbidities
– Renal impairment
– Cardiovascular disease
– Pulmonary disease
– Hepatic disease (chronic hepatitis or cirrhosis)

Slide credit: clinicaloptions.com


Current Considerations for Initial
Treatment of MM
▪Induction for younger pts
– 3-drug induction followed by autologous
transplantation[1]
– Maintenance therapy post autologous transplantation[2]
– Maximize duration of first response[3,4]
– Assessing depth of response and understanding
implications for pt outcome[5]

1. Cavo M, et al. Lancet. 2010;376:2075-2085. 



2. McCarthy PL, et al. Expert Rev Hematol. 2014;7:55-66. 

3. Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. 

4. Lenhers N, et al. ASH 2013. Abstract 3183. 

5. Paiva B, et al. Blood. 2012;119:687-691. Slide credit: clinicaloptions.com
Induction Therapy for Pts With
Transplantation-Eligible MM
Preferred Regimens Other Regimens

Category 1 Category 2A
▪ Bort/dox/dex ▪ IRd
Initial therapy (induction) ▪ Rd ▪ KRd
for transplantation-eligible ▪ RVd Category 2B
pts (response assessment ▪ VD ▪ Dexamethasone
after cycle 2) ▪ VTD ▪ Liposomal dox/vin/dex
Category 2A ▪ Thal/dex
▪ CyBorD

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.


3.2016. Slide credit: clinicaloptions.com
Earlier Phase Studies: Induction Regimens
for Transplantation-Eligible Pts

Pts Achieving ≥ VGPR (%)


Regimen Median Total Survival, % 100
Cycles, n 89
RVd[1] 10* 18-mo PFS: 75 80
18-mo OS: 97 67
60 58
12-mo PFS: 95 60
18-mo PFS: 92
KRd[2,3] 12 3-yr PFS: 79
3-yr OS: 96 40
5-yr PFS: 42
CyBorD[4] 4† 5-yr OS: 70 20
12-mo PFS: 88 0
IRd[5] 7 12-mo OS: 94 ] ] ]
[1 [2 [4 ]
[5
*Induction and maintenance; any drug. 
 V d Rd o r D d
†Median not reported; response after 4 cycles R K B IR
stated as primary goal of study. Cy

1. Richardson, PG et al. Blood. 2010;116:679-686. 2. Jakubowiak A, et


al. Blood. 2012;120:1801-1809. 3. Jasielec J, et al. ASH 2013. Abstract
3220. 4. Reeder CB, et al. Br J Haematol. 2014.167;563-564. 5. Kumar
SK, et al. Lancet Oncol. 2014;15:1503-1512. Slide credit: clinicaloptions.com
Autologous Stem Cell
Transplantation
Phase III Trial: High-Dose Mel + ASCT vs
MPR in Newly Diagnosed MM
▪ Randomized, controlled phase III trial exploring utility of high-dose melphalan +
ASCT consolidation ± lenalidomide maintenance vs MPR consolidation ±
lenalidomide maintenance in newly diagnosed MM
PFS, OS From Time of Diagnosis
(N = 273) Mel + ASCT + len maintenance
Mel + ASCT with no maintenance
100 MPR + len maintenance
 100
MPR with no maintenance
75 75
PFS (%)

OS (%)
50 50

25 25
37.4 54.7
21.8 34.2
0 0
0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66
Mos Mos

Palumbo A, et al. N Engl J Med. 2014;371:895-905. Slide credit: clinicaloptions.com


Phase III Trial: Rd Induction and ASCT vs
Cyclophosphamide + Rd Consolidation
▪ A randomized, controlled phase III trial comparing high-dose melphalan
+ ASCT vs cyclophosphamide + Rd consolidation in newly diagnosed
MM
Median PFS, Mos
ASCT (n = 127) 43.3

100 CRd (n = 129) 28.6 100
80 HR: 0.40 (95% CI: 0.25-0.63; 80
P < .001) 4-Yr OS, %
PFS (%)

60 60 ASCT

OS (%)
86

40 40 CRd 71
HR: 0.42 (95% CI: 0.23-0.76;
20 20 P < .004)
Median f/u: 55 mos Median f/u: 55 mos
▪0 Increased grade 3/4 AEs with ASCT vs0 CRd, but similar serious
0hematologic
10 20 (0%
30 vs 2%;
40 50 P60
= .49)
70 and nonhematologic
0 10 20 30 (7%
40 vs5010%;
60 
 70
P = .393) AEs Mos Mos

Gay F, et al. Lancet Oncol. 2015;16:1617-1629. Slide credit: clinicaloptions.com


Phase III IFM/DFCI 2009: Frontline RVd ±
ASCT in Younger Pts (< 65 Yrs) With MM
N = 700 previously untreated patients younger than 65 yrs of age
Outcome, % RVd + ASCT RVd Only HR (95% CI)
(n = 350) (n = 350)
4-yr PFS 47 35 0.69 (0.56-0.84; P < .001)
4-yr OS 81 83 1.2 (0.7-1.8; P = NS)
SPM 5 3
ORR 99 98
≥ VGPR 88 78 P = .001

PFS benefit in ASCT arm uniform across subgroups


Age (≤ or > 60 yrs), sex, Ig isotype (IgG or others), ISS stage (I or II or III),
cytogenetics (standard or high risk), and response after the 3 first cycles of
RVd (CR or not)

Attal M, et al. ASH 2015. Abstract 391. Slide credit: clinicaloptions.com


Phase III EMN02/HO95 Trial: Upfront ASCT
vs VMP in Newly Diagnosed MM: Efficacy
HR (95% CI;
Outcome VMP ASCT
P Value)
PFS
Overall population, n 497 695
▪ Median, mos 44 NR 0.73 (0.59-0.90; .
▪ 3 yr, % 57.5 66.1 003)
Standard-risk cytogenetics, n 220 290
▪ Median, mos 46 NR 0.68 (0.47-0.98;
▪ 3 yr, % 69.6 76.6 .034)
High-risk cytogenetics, n 181 292
▪ Median, mos 32 42 0.69 (0.52-0.92;
▪ 3 yr, % 43.2 55.2 .010)

Response (n = 451) (n = 641) --


▪ VGPR or better, % 73.8 85.5 < .001

▪ Median follow-up: 26 mos (range: 19-37 mos)


Cavo M, et al. ASCO 2016. Abstract 8000. Slide credit: clinicaloptions.com
MMRC: Extended KRd Treatment With
ASCT in NDMM
▪ An open-label, single-arm phase II trial exploring utility of extended
KRd treatment with transplantation in NDMM (N = 62)
– Treatment: KRd induction (4 cycles) → ASCT and KRd consolidation and
maintenance (cycles 5-18); further R maintenance off protocol


100 97 100 100100


85 87 87 87 ≥ VGPR
80
Response (%)

75 71 ≥ nCR
60 ≥ CR
sCR
40 32
21 24 22
20 12 8
0
▪ KRd + ASCT produced higher
Induction
 ASCT
 sCR rate at 8 cycles
Consolidation
 End vs historical
of KRd

(n = 48)
controls without (n = 37)
ASCT (71% vs 30%);(nAEs
= 24)similar (n
to =historical
8) controls

Zimmerman TM, et al. ASCO 2015. Abstract 8510. Slide credit: clinicaloptions.com
Duration of Therapy in 

Multiple Myeloma
Maintenance Therapy for Pts With
Transplantation-Eligible MM
Preferred Regimens Other Regimens
Category 1 Category 2B
▪ Lenalidomide ▪ VP
▪ Thalidomide ▪ VT
Maintenance therapy
Category 2A ▪ Interferon
▪ Bortezomib ▪ Steroids
▪ Thal + pred

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.


3.2016. Slide credit: clinicaloptions.com
IFM 2005-02: Lenalidomide vs Placebo
Maintenance After ASCT for Myeloma
▪ Phase III study in pts < 65 yrs of age after ASCT in first line (N = 459)*
– Consolidation: Len 25 mg/day PO Days 1-21 every 28 days for 2 mos;
maintenance: randomize to Len 10-15 mg/day or placebo until relapse

PFS
100 ▪ 5-yr PFS (primary endpoint)
superior with Len vs placebo:
75 Len 42% vs 18%, respectively 

Placebo (P < .0001)
Pts (%)

50
– PFS benefit independent of
subgroup (eg, β2-M, ORR)
20
HR
 ▪ Median EFS: 40 mos with Len vs
Len vs placebo: 0.50; P < .001 23 mos for placebo
0
0 6 12 18 24 30 36 42 48 54 60 ▪ Median OS: similar (> 80 mos)
Mos
*Induction with VD or VAD; consolidation with
▪ Grade 3/4 PN: similar in both
lenalidomide. groups
Attal M, et al. ASH 2013. Abstract 406. Slide credit: clinicaloptions.com
CALGB 100104: Lenalidomide vs Placebo
Maintenance Following ASCT for Myeloma
▪ Phase III trial with D-S stage I-III pts; < 71 yrs of age and > 2 cycles of induction with SD
or better (N = 460)
▪ PFS: ITT analysis with median 

follow-up from transplant of 34 mos ▪ OS: 35 deaths with lenalidomide and 

53 deaths with placebo
– Estimated HR: 0.48 (95% CI: 0.36- 0.63); 

– 3-yr OS: 88% vs 80%; HR: 0.62 or a 38%
median TTP: 46 vs 27 mos
reduction in death with the cross over

1.0 1.0
2-sided P < .001
Probability of PFS

0.8 0.8 Lenalidomide

Probability of OS
0.6 Lenalidomide 0.6 Placebo

0.4 0.4
2-sided P = .03
0.2 86 of 128 placebo pts Placebo 0.2
crossed over to lenalidomide Median follow-up: 45 mos
0 0
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
Mos Since ASCT Mos Since ASCT

McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. Slide credit: clinicaloptions.com


Cumulative Incidence of Second Primary
Malignancies by Treatment
Solid SPMs Hematological SPMs
Len + mel Len + mel
10 10
Cumulative incidence (%)

Cumulative incidence (%)


Len + cyclo Len + cyclo
Len + dex Len + dex
No len (mel regimens) No len (mel regimens)

5 5

0 0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7

Cum Incidence, % Solids SPM Hematological SPM


3 Yrs 5 Yrs 3 Yrs 5 Yrs
Len + mel 2.7 4.4 1.8 3.9
Len + cyclo 3.5 NE 0.3 NE
Len + dex 2.2 2.6 0.3 1.3
No len 2.9 3.4 0.4 1.4

Palumbo A, et al. Lancet Oncol. 2014;15:333-342. Slide credit: clinicaloptions.com


Lenalidomide Maintenance After ASCT in
MM: Overall Survival
▪ Lenalidomide maintenance significantly improved survival after ASCT
from pooled data analysis
– 7-yr OS: 62% vs 50% in the control arm
– Median OS: not estimable* vs 86.0 mos in control arm (median follow-up:
80 mos)
– Overall HR: 0.74 (95% CI: 0.62-0.89; P = .001)

▪ All studies showed lenalidomide benefit, but results were


heterogeneous (P = .047)
– CALGB HR: 0.56 (95% CI: 0.42-0.76)
– IFM HR: 0.91 (95% CI: 0.72-1.15)
– GIMEMA HR: 0.66 (95% CI: 0.34-1.26)

*Median OS for lenalidomide arm extrapolated to be 116 mos based on median of control arm and HR of 0.74.

Attal M, et al. ASCO 2016. Abstract 8001. Slide credit: clinicaloptions.com


Lenalidomide Maintenance After ASCT in
MM: Other Outcomes
▪Lenalidomide maintenance benefit seen in most
subgroups except high-risk cytogenetics
– HR: 1.18 (95% CI: 0.66-2.10)
▪Mean duration of maintenance treatment: 25 mos in
IFM trial, 30 mos in CALGB trial
▪Incidence of second primary malignancies significantly
higher with lenalidomide maintenance
– Hematologic: HR: 2.03 (95% CI: 1.14-3.61; P = .015)
– Solid tumor: HR: 1.71 (95% CI: 1.04-2.79; P = .032)

Attal M, et al. ASCO 2016. Abstract 8001. Slide credit: clinicaloptions.com


Lenalidomide Maintenance Therapy: 

Meta-analysis of Randomized Trials
▪In a study of 4 RCTs (N = 1935), lenalidomide
maintenance vs no maintenance or placebo
associated with:
– Improved PFS (overall HR: 0.49; P < .001)
– Trend toward improved OS (overall HR: 0.77; P = .071)
– Significantly higher risk of grade 3/4 neutropenia, VTE,
thrombocytopenia, fatigue
– Significantly higher risk of second primary malignancies
(OR: 1.62; P = .006)

Singh PP, et al. ASH 2013. Abstract 407. Slide credit: clinicaloptions.com
HOVON-65: Bortezomib in Induction and
Maintenance for Newly Diagnosed MM
▪ CR/nCR superior with PAD induction (30% vs 15% with VAD) and by best
response (35% vs 49% with VAD) (P < .001 for both)[1]
▪ PFS and OS superior with bortezomib-based treatment regimen[1]


PFS, Censored at AlloSCT OS


100 100
Cumulative Percentage

Cumulative Percentage
HR: 0.76 (95% CI: 0.64-0.90; HR: 0.78 (95% CI: 0.64-0.90;
P = .001) P = .01)
75 75

50 50
N F N D
VAD 414 311
 VAD 414 182

25 PAD 413 284
 25
PAD 413 155

Cox LR stratified P = .002 Cox LR stratified P = .05
0 0
▪ Bortezomib
0 12 significantly improved
24 36 48 60 72 84 OS for pts presenting
0 12 24 with
36 renal
48 60failure
72 84

(P < .001)[2] Mos Mos

1. Sonneveld P, et al. ASH 2013. Abstract 404. 



2. Sonneveld P, et al. J Clin Oncol. 2012;24:2946-2955. Slide credit: clinicaloptions.com
Maintenance in Myeloma

▪PFS advantage[1-3] ▪Unclear whether all pts


▪OS improvements?[2] benefit from
maintenance
▪Toxicities of treatment
▪Unclear which agent(s)
– Myelosuppression[3]
and duration of therapy
– Second primary
malignancies[3,4]
– Quality of life

1. Attal M, et al. ASH 2013. Abstract 406. 



2. McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
3. Attal M, et al. N Engl J Med. 2012;366:1782-1791. 

4. Palumbo A, et al. Lancet Oncol. 2014;15:333-342. Slide credit: clinicaloptions.com
Optimal Therapy for
Transplantation-Ineligible Patients
Myeloma in the Elderly: Considerations

▪Is the disease different?


– Comorbidities raise risk of toxicity
– Frailty score (from 0-5)—based on age, comorbidities,
and cognitive and physical conditions—can predict
mortality and the risk of toxicity[1]
▪What are the goals of therapy?
– 2-drug vs 3-drug induction: patient preference?
– Duration of therapy important even in elderly

Palumbo A, et al. Blood. 2015;125:2068-2074. Slide credit: clinicaloptions.com


Effect of Pt Fitness on Myeloma Treatment
Outcomes
▪ Pooled analysis of data on 869 newly diagnosed elderly pts from 3 trials
3-Yr OS Discontinuation at 12 Mos
1.00 1.00
Fit

Intermediate fitness


Discontinuation (%)
Frail
0.75 0.75
OS (%)

0.50 0.50

0.25 Fit
 0.25


Intermediate fitness

Frail
0 0
0 6 12 18 24 30 36 0 6 12 18 24
Mos Mos

OS: fit (0) 84%, intermediate (1) 76% 
 Fit 17%, intermediate 21% (HR: 1.41; 

(HR: 1.61; P = .42), frail (≥ 2) 57% 
 P = .052), frail (≥ 2) 31% (HR: 2.21; 

(HR: 3.57; P < .001) P < .001)

Palumbo A, et al. Blood. 2015;125:2068-2074. Slide credit: clinicaloptions.com


Myeloma in Octogenarians: The Era of
Modern Myeloma Therapy
▪ More moderate to severe renal impairment
▪ Worsening PS (≥ 2)
▪ More frequent ISS 3 disease
▪ Cytogenetics different; less frequently del(17p) and t(4;14)
▪ Efficacy comparisons between those < 65 vs ≥ 80 yrs of age

Outcome Pts < 65 Yrs of Age Pts ≥ 80 Yrs of Age


Response to therapy, % 85 63
Median PFS, mos 31 11
OS 66% at 5 yrs Median 19.5 mos
Early mortality at 2 mos, % 3 14

Dimopoulos M, et al. ASH 2014. Abstract 4738. Slide credit: clinicaloptions.com


CR Correlates With Long-term Survival in
Elderly Pts Treated With Novel Agents
▪ Retrospective analysis: 3 randomized trials of GIMEMA and HOVON (N = 1175)
– First-line treatment: MP (n = 332), MPT (n = 332), VMP (n = 257), VMPT-VT (n = 254)

1.0 PFS 1.0 OS


Probability of 


CR
 CR

0.8 0.8

Probability

VGPR
 VGPR

0.6

of OS
All 
 PR 0.6 PR
PFS

Pts 0.4 0.4


0.2 0.2
P < .001 P < .001
0 0
0 24 48 72 0 24 48 72
1.0 1.0
Probability of 


CR
 0.8 CR



0.8

Probability

Pts Older VGPR
 VGPR


of OS
0.6 PR 0.6 PR
PFS

Than 75 Yrs
of Age 0.4 0.4
0.2 0.2 P = .004
P = .001
0 0
0 24 48 72 0 24 48 72
Mos Mos

Gay F, et al. Blood. 2011;117:3025-3031. Slide credit: clinicaloptions.com


Induction and Maintenance Therapy for Pts
With Transplantation-Ineligible MM
Preferred Regimens Other Regimens
Category 1 Category 2A
▪ Rd ▪ IRd
▪ RVd ▪ MP
Initial therapy (induction) ▪ MPR Category 2B
for transplantation-ineligible ▪ MPT ▪ Dexamethasone
pts (response assessment ▪ MPV ▪ Liposomal dox/vin/dex
after cycle 2) Category 2A ▪ Thal/dex
▪ VD ▪ Vin/dox/dex
▪ CyBorD

Category 1 Category 2B
▪ Lenalidomide ▪ VP
▪ Thalidomide ▪ VT
Maintenance therapy Category 2A ▪ Interferon
▪ Bortezomib ▪ Steroids
▪ Thalidomide + prednisone

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.


3.2016. Slide credit: clinicaloptions.com
FIRST Trial: Efficacy Analysis of Len/Dex
vs MPT in SCT-Ineligible Pts With MM
Median PFS, Mos HR (P Value) 4-Yr OS, % HR (P Value)
Rd vs MPT: 0.72 (.00006)
Rd (n = 535) 25.5 Rd (n = 535) 59.4 Rd vs MPT: 0.78 (.0168)
Rd vs Rd18: 0.70 (.00001) Rd vs Rd18: 0.90 (.307)
Rd18 (n = 541) 20.7 Rd18 vs MPT: 1.03 (.70349) Rd18 (n = 541) 55.7 Rd18 vs MPT: 0.88 (.184)
100 MPT (n = 547) 21.2 100 MPT (n = 547) 51.4

80 80

60
PFS (%)

60

OS (%)
40 40
72 wks

20 20

0 0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Mos Mos

▪ Overall response (continuous Rd vs MPT): 75% vs 62% (P < .00001)


▪ Similar, tolerable safety profiles between treatment groups
▪ Incidence of second primary malignancies: 3% with continuous Rd vs 6% with Rd18 vs
5% with MPT

Benboubker L, et al. N Engl J Med. 2014;371:906-917. Slide credit: clinicaloptions.com


SWOG S0777: RVd vs Rd in Pts With Newly
Diagnosed MM
RVd Rd
Confirmed Response, % (n = 216*) (n = 214*)
ORR (PR or better) 81.5 71.5
▪ CR 15.7 8.4
▪ VGPR 27.8 23.4
▪ PR 38.0 39.7
SD or better 97.2 95.8
▪ SD 15.7 24.3
PD or death 2.8 4.2
RVd Rd
Survival, Mos HR P Value
(n = 242) (n = 229)
0.712
Median PFS 43 30 .0018
(0.560-0.906)
0.709
Median OS 75 64 .025
(0.516-0.973)
*Assessable.
Durie B, et al. ASH 2015. Abstract 25. Slide credit: clinicaloptions.com
Modified Lenalidomide, Bortezomib, and
Dexamethasone in ASCT-Ineligible Pts
▪ Phase II trial exploring utility of modified RVd (RVd lite); N = 53
– Lenalidomide: single daily oral dose of 15 mg on Days 1-21
– Bortezomib: 1.3 mg/m2 SC once weekly on Days 1, 8, 15, 22
– Dexamethasone: 20 mg twice weekly if ≤ 75 yrs or once weekly if > 75 yrs
▪ RVd lite resulted in 90% ORR (≥ PR), ≥ VGPR: 43%
– 5 pts discontinued study after < 4 cycles; reasons included worsening
adrenal insufficiency, rash attributed to lenalidomide, travel distance
▪ AEs manageable and well tolerated in an older population
– Grade ≥ 3 AEs: hypophosphatemia (31%), rash (10%)

O’Donnell E, et al. ASH 2015. Abstract 4217. Slide credit: clinicaloptions.com


Suggested Empiric Age-Adjusted Dose
Reduction in Pts With Myeloma
Agent Younger Than 65 Yrs 65-75 Yrs Older Than 75 Yrs
40 mg/day on Days 1-4, 40 mg/day on Days 1, 8,1 20 mg/day on Days 1, 8,
Dexamethasone 15-18 q4w or Days 1, 8, 5, 22 q4w 15, 22 q4w
15, 22 q4w
0.25 mg/kg on Days 1-4 0.25 mg/kg on Days 1-4 0.18 mg/kg on Days 1-4
Melphalan q6w q6w or 0.18 mg/kg on q6w or 0.13 mg/kg on Days
Days 1-4 q4w 1-4 q4w
300 mg/day on Days 1, 8, 300 mg/day on Days 1, 8, 50 mg/day on Days 1-21
Cyclophosphamide 15, 22 q4w 15 q4w or 50 mg/day on
 q4w or 50 mg/day QOD on
Days 1-21 q4w Days 1-21 q4w
100 mg/day or 

Thalidomide 200 mg/day 50 mg/day to 100 mg/day
200 mg/day
25 mg/day on Days 1-21 15-25 mg/day on Days 10-25 mg/day on Days 1-21
Lenalidomide
q4w 1-21 q4w q4w
1.3 mg/m2 bolus on
1.3 mg/m2 bolus on 
 1.0- 1.3 mg/m2 bolus on

Bortezomib Days 1, 4, 8, 11 q3w or
Days 1, 4, 8, 11 q3w Days 1, 8, 15, 22 q5w
on Days 1, 8, 15, 22 q5w

Palumbo A, et al. N Engl J Med. 2011;364:1046-1060. Slide credit: clinicaloptions.com


Induction Therapy in Myeloma: Summary

▪Melphalan therapy a less frequent choice


▪Novel therapies and 3-drug regimens increasingly
preferred treatment approach in newly diagnosed pts
with myeloma
▪Treatment regimens of longer duration may yield
greater efficacy than shorter treatment regimens
▪In general, deeper responses to treatment translate to
longer response duration

Slide credit: clinicaloptions.com


Treatment Options in Relapsed/
Refractory 

Multiple Myeloma
Definition of Relapsed and Refractory
Myeloma
▪ Relapsed and refractory myeloma[1] • IMWG Criteria for PD
– Meets IMWG criteria for PD[2]
– RR MM: progression on therapy in ▪ ≥ 25% increase in serum or urine
paraprotein from nadir (absolute
pts who obtain ≥ minor response or increase ≥ 0.5 g/dL and ≥ 200 mg/
progress within 60 days of most 24 hrs, respectively), or
recent therapy
– Primary refractory MM: progression ▪ Involved-to-uninvolved serum FLC
ratio > 100 mg/L, or
on therapy without having achieved
at least minor response ▪ ≥ 10% increase in bone marrow
– Relapsed MM: meets IMWG criteria plasma cells, or
for PD but does not fit definition of ▪ New bone or soft tissue lesions, or
RR or primary refractory MM[3] ▪ Increasing size of existing bone or
soft tissue lesions, or
▪ Serum calcium > 11.5 mg/dL

1. Nooka AK, et al. Blood. 2015;125:3085-3099. 2. Durie BG, et al.


Leukemia. 2006;20:1467-1473. 3. Rajkumar SV, et al. Blood.
2011;117:4691-4695. Slide credit: clinicaloptions.com
Myeloma: Scope of the Problem
▪ Median time to first relapse with current therapies: 3-4 yrs
1.0

0.9
0.8
0.7 2006-2010
OS (%)

0.6
> 100,000 pts living
0.5 with myeloma
0.4
2001-2005
0.3
0.2
0.1
0
0 1 2 3 4 5 6
Yrs
Kumar SK, et al. Leukemia. 2014;28:1122-1128. Slide credit: clinicaloptions.com
Confronting Disease Relapse in Myeloma

Median, Mos
Median Response Duration (Mos)

Events, n/N
 (Range)



12 100
OS
 170/286
 9 (7-11)

EFS 217/286 5 (4-6)
10 80
8
60

Pts (%)
6
40
4

2 20

0 0
First Second Third Fourth Fifth Sixth 0 12 24 36 48 60
Treatment Regimen Mos

Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.


Kumar SK, et al. Leukemia. 2012;26:149-157. Slide credit: clinicaloptions.com
Questions to Ask

1. Do I really need to treat this pt?


2. Does the pt have new high-risk features?
3. What drugs have been used so far?
4. Response to previous treatments (eg, efficacy,
duration of response, toxicity)?
5. How well is the pt (PS, marrow reserve)?
6. What are the pt’s goals/preferences?

Slide credit: clinicaloptions.com


Recommended Regimens for Pts With
Relapsed/Refractory MM
Preferred Regimens Other Regimens
Category 1 Category 2A
▪ Bortezomib ▪ Bendamustine
▪ Bortezomib/liposomal doxorubicin ▪ Bortezomib/vorinostat
▪ Elotuzumab/len/dex ▪ Bendamustine/len/dex

▪ Ixazomib/len/dex
▪ KRd
▪ Rd
▪ Pan/bort/dex
▪ Pom/dex

Category 2A
▪ CyBorD, RVd, VD, VCD, VTD
▪ Carfilzomib, KD
▪ Cyclo/len/dex
▪ Daratumumab
▪ DCEP
▪ DT-PACE ± bortezomib
▪ High-dose cyclophosphamide
▪ Thalidomide/dexamethasone
▪ Repeat primary induction Tx if relapse at > 6 mos

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.


3.2016. Slide credit: clinicaloptions.com
Five New Approvals for RRMM in 2015

▪Panobinostat (HDAC inhibitor) + bort/dex


▪Carfilzomib (proteasome inhibitor) + len/dex
▪Daratumumab (CD38-targeted monoclonal antibody)
as single agent
▪Ixazomib (oral proteasome inhibitor) + len/dex
▪Elotuzumab (anti-SLAMF7 monoclonal antibody) + len/
dex

Slide credit: clinicaloptions.com


PANORAMA 1: Bort/Dex ± Panobinostat in
R/R Myeloma
▪Subgroup analysis of phase III trial of pts who received
≥ 2 previous treatments, including bortezomib and an
IMiD
– FDA approved indication based on subgroup analysis

Outcome Pan/Bort/Dex
 Bort/Dex
 Significance


(n = 73) (n = 74)
ORR, %[1] 58.9 39.2 P = .017
Median PFS, mo[1] 12.5 4.7 HR: 0.47
Median OS, mo[2] 25.5 19.5 Not significant

1. Richardson PG, et al. Blood. 2016;127:713-721.



2. San Miguel J, et al. ASH 2015. Abstract 3026. Slide credit: clinicaloptions.com
ASPIRE: KRd vs Rd in R/R Myeloma

Phase III trial


Outcome KRd
 Rd 
 Significance
(n = 396) (n = 396)
ORR, % 87.1 66.7 P < .001
Median PFS, mo 26.3 17.6 HR: 0.69; P = .0001
2-yr OS, % 73.3 65.0 HR: 0.79; P = .04

▪ Interim OS results did not meet prespecified statistical boundary


(P = .005)
▪ AEs consistent with previous studies; no unexpected toxicities
observed
– Grade ≥ 3 cardiac failure and ischemic heart disease: 3.8% and
3.3% in KRd arm vs 1.8% and 2.1% in Rd arm, respectively

Stewart AK, et al. N Engl J Med. 2015;372:142-152. Slide credit: clinicaloptions.com


Carfilzomib/Pomalidomide/
Dexamethasone in R/R MM: Response
Phase I/II trial
ITT Response, % All Evaluable Pts Primary Study Population*
After 4 KPd cycles (n = 54) (n = 44)
▪ CR/nCR 4 2
▪ ≥ VGPR 30 23
▪ ≥ PR 72 73
▪ ≥ MR 80 82
Best response (n = 55) (n = 45)
▪ CR/nCR 16 13
▪ ≥ VGPR 47 44
▪ ≥ PR 84 84
▪ ≥ MR 93 96
*PI sensitive/naive and lenalidomide refractory (second line) and/or prior lenalidomide (third+ line).

▪ ≥ PR after 1 treatment cycle


– 65% among all evaluable pts (n = 54)
– 61% among primary study population (n = 44)

Rosenbaum CA, et al. ASCO 2016. Abstract 8007. Slide credit: clinicaloptions.com
SIRIUS: Daratumumab in R/R Myeloma

▪ Phase II trial; patients were heavily pretreated


▪ Reductions in paraprotein occurred in majority of pts
▪ Responses observed across subgroups
▪ Deepening of responses with continued treatment
– Median time to response: 1 mo

Outcome Daratumumab
 95% CI


(n = 106)
ORR, % 29.2 20.8 – 38.9
Median PFS, mo 3.7 2.8 - 4.6
1-year* OS, % 65 51.2 - 75.5
Median DoR, mo 7.4 5.5 - NE
*Median OS not reached

Lonial S, et al. Lancet. 2016;Jan 6:[E-pub ahead of print]. Slide credit: clinicaloptions.com
CASTOR: Daratumumab/Bortezomib/
Dexamethasone in R/R MM: Efficacy
DVd
 Vd
 HR 

Efficacy Outcome P Value
(n = 251) (n = 247) (95% CI)
Median PFS following 1
NR 7.5 0.31 

prior treatment, mos < .0001
77.5 29.4 (0.18-0.52)
▪ 1-yr PFS, %
Median TTP, mos NR 7.3 0.30 

< .0001
▪ 1-yr PFS, % 65.4 28.8 (0.21-0.43)
ORR, % 83 63 < .0001
▪ ≥ VGPR 59 29 < .0001
▪ ≥ CR 19 9 .0012
▪ Time
MRD to PR
negative, % occurred 14
early in pts (~2
3 mos), but CR took longer to
develop in many pts (≥ 8 mos)

Palumbo A, et al. ASCO 2016. Abstract LBA4. Slide credit: clinicaloptions.com


TOURMALINE-MM1: Ixazomib Efficacy

Ixazomib + Rd Placebo + Rd
Characteristic P Value
(n = 360) (n = 362)
Median PFS, mos 20.6 14.7 .012*
ORR, % 78.3 71.5 .035
▪ CR 11.7 6.6 .019
▪ VGPR 36.4 32.3
▪ PR 66.7 64.9
Median time to response, mos 1.1 1.9
Median DoR, mos 20.5 15.0
Median TTP, mos 21.4 15.7 .007†
*HR: 0.742. †HR: 0.712.

▪ PFS benefit with ixazomib seen in all prespecified subgroups,


including cytogenetic high risk, PI and IMiD exposed

Moreau P, et al. ASH 2015. Abstract 727. Slide credit: clinicaloptions.com


ELOQUENT-2: Anti-SLAMF7 Monoclonal
Antibody Elotuzumab + Rd vs Rd—Efficacy
Elotuzumab + Rd Rd
Outcome HR (95% CI)
(n = 321) (n = 325)
PFS
▪ Median, mos 19.4 14.9 0.73 (0.60-0.89;
▪ 1 yr, % 68 57 P = .0014)
▪ 2 yrs, % 41 27
▪ 3 yrs, % 26 18
Median time to next
33 21 0.62 (0.50-0.77)
treatment, mos
ORR, % 79 66
0.77 (0.61-0.97;
Interim OS, mos 43.7 39.6
P = .0257)

▪ PFS benefit seen with elotuzumab in all predefined subgroups

Dimopoulos MA, et al. ASH 2015. Abstract 28. Slide credit: clinicaloptions.com
KEYNOTE-023: Pembrolizumab/
Lenalidomide/Dexamethasone: Response
Len-Refractory
Efficacy Population
Best Overall Response, % Population
(n = 40)
(n = 29)
ORR 50 38
▪ Stringent CR 3 3
▪ VGPR 13 10
▪ PR 35 24
SD 48 59
Disease control rate 

98 97
(CR + PR + SD)
▪ 88% of pts showed some decrease in M protein or free light
PD chains from baseline 3 3

Mateos MV, et al. ASCO 2016. Abstract 8010. Slide credit: clinicaloptions.com
Promising Agents in Clinical Trial

▪ Proteasome inhibitors
– Marizomib (NPI0052): orally available, irreversible nonpeptide PI
– Oprozomib (ONX0912): orally available, irreversible carfilzomib derivative
▪ HDAC inhibitors
– Vorinostat + bortezomib
– Rocilinostat (ACY1215): selective HDAC-6 inhibitor
▪ KSP inhibitors
– Filanesib (ARRY-520): inhibits spindle formation during mitosis, inducing
cell death
▪ Monoclonal antibodies
– Isatuximab (SAR650984): humanized anti-CD38 antibody

Nooka AK, et al. Blood. 2015;125:3085-3099. Slide credit: clinicaloptions.com


Salvage ASCT in the Relapsed Setting:
Reasonable Option?
▪ Data from Mayo Clinic Transplant Center suggests that ASCT2
appears safe and effective treatment for relapsed MM (N = 98)
– ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos
– Rate of TRM: 4%, suggesting a favorable benefit-to-risk ratio
▪ Shorter TTP after ASCT1 predicts shorter OS post–ASCT2

TTP After ASCT1 Median From ASCT2, Mos (Range)


PFS OS
< 12 mos 5.6 (3-8) 12.6 (4-23)
< 18 mos 7.1 (6-8) 19.4 (10-42)
< 24 mos 7.3 (6-10) 22.7 (13-62)
< 36 mos 7.6 (7-12) 30.5 (19-62)

Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573. Slide credit: clinicaloptions.com
ASCT: Timing of Transplantation

100

80
Survival (%)

60

40

20 Delayed ASCT (n = 118)



Early ASCT (n = 174)
0
0 20 40 60 80 100 120
Mos From Diagnosis
▪ Median OS not significantly different at 4 yrs (P = .3)
– Early ASCT: 86 mos (95% CI: 80-98); delayed ASCT: NR (95% CI: 54-NR)

Kumar S, et al. Cancer. 2012;118:1585-1592. Slide credit: clinicaloptions.com


Allogeneic SCT

▪Graft-vs-myeloma effect
▪Can potentially provide sustained disease control (aka,
cure)
▪High treatment-related mortality
▪Morbidity from GVHD
▪No definite OS advantage vs autologous SCT
▪Should be offered to high-risk pts in trials

Slide credit: clinicaloptions.com


Adverse Event Management
Peripheral Neuropathy: Risk Factors and
General Considerations
General Considerations Disease- and Treatment-Related
▪ Endocrine disorders Factors
– Hypothyroidism ▪ Hyperviscosity syndrome
– Diabetes ▪ Hypergammaglobulinemia
▪ Nutritional disease ▪ Incidence of peripheral neuropathy in
untreated pts: 39%
▪ Connective tissue disease
▪ Vascular disease ▪ Incidence of grade 3/4 CIPN with
novel agents
▪ Medications – Bortezomib: 6% to 22%
▪ Herpes zoster – ↓ with wkly vs twice-weekly dosing
▪ Most common symptoms – ↓ with SC administration
– Sensory deficits – Thalidomide: 3% to 23%
– Neuropathic pain – ↑ with higher doses and prolonged
therapy
– Carfilzomib: < 2%
Gleason C, et al. J Natl Compr Cancer Netw. 2009;7:971-979.
Palumbo A, et al. J Clin Oncol. 2014;32:587-600. Kurtin S, et al. 

J Adv Pract Oncol. 2013;4:307-321. Siegel D, et al. Haematologica.
2013;98:1753-1761. Slide credit: clinicaloptions.com
Risk Assessment for VTEs in Pts
Receiving IMiD-based Therapy
▪ VTE prophylaxis for individual risk factors (eg, age or obesity) or
myeloma-related risk factors (eg, immobilization or
hyperviscosity)
– If ≤ 1 risk factor present, aspirin 81-325 mg/day
– If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 

40 mg/day) or full-dose warfarin (target INR: 2-3)
▪ VTE prophylaxis for myeloma therapy–related risk factors (eg,
high-dose dexamethasone, IMiDs, doxorubicin, multiagent
chemotherapy)
– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin
(target INR: 2-3)

Palumbo A, et al J Clin Oncol. 2014;32:587-600. 



Palumbo A, et al. Leukemia. 2008;22:414-423. Slide credit: clinicaloptions.com
Myelosuppression and Infection

▪ Myelosuppression is associated with myeloma and 



the drugs used to treat it
– Increased risk of infection due to hypogammaglobulinemia
– Dose-modification guidelines are available in package inserts
▪ Infection prophylaxis
– Pts should remain up to date on appropriate vaccinations
– VZV prophylaxis when receiving PIs
– Use of IVIG or prophylactic antibiotics is controversial and should
only be used when warranted
– Pt education emphasizing importance of alerting treating clinicians
of potential infection can reduce unnecessary antibiotics

Slide credit: clinicaloptions.com


Current Management of Bone Disease

▪ Effective antimyeloma therapy ▪ Radiotherapy (low dose)


– Impending fracture
▪ Novel therapies have benefits – Cord compression
– Direct effect on inflammatory – Plasmacytomas
cytokines
– Inhibition of bone resorption ▪ Vertebroplasty/kyphoplasty
– Osteoclast stimulation
▪ Orthopedic consultation
▪ Bisphosphonates – Impending or actual long-bone
– Pamidronate fractures
– Zoledronic acid – Bony compression of spinal cord
▪ Supplement with calcium and – Vertebral column instability
vitamin D3 to maintain calcium
homeostasis

Niesvizky R, et al. J Natl Compr Canc Netw. 2010;8(suppl 1):S13-S20.


Christoulas D, et al. Expert Rev Hematol. 2009;2:385-398. Drake MT.
Oncology (Williston Park). 2009;23(14 suppl 5):28-32. Terpos E, et al. 

J Clin Oncol. 2013;31:2347-2357. Webb SL, et al. Br J Pharmacol.
2014;171:3765-3776. Slide credit: clinicaloptions.com
Conclusions: Myeloma Treatment

▪Approaches that have worked before, to which pts


were not refractory, should be tried
▪Since no therapy is curative, all options need to be
tried sequentially
▪No good data on optimum sequence or regimen
▪Encourage pts to participate in ongoing clinical trials
▪New challenges in relapsed disease
– Nonsecretory disease, extramedullary relapses, poor
marrow reserve limiting drug therapy

Slide credit: clinicaloptions.com


Conclusions, cont’d

▪In general, deeper responses translate to longer


response duration
▪Treat to maximum response, balancing toxicity
▪Even minor responses have clinical value in relapsed
disease
▪Duration of therapy not clear, but “drug holidays” help
with toxicity, quality of life

Slide credit: clinicaloptions.com


Future of Myeloma Therapy

▪New drugs with different mechanisms of action


▪Heterogeneous disease: have to match the
mechanism with the biologic abnormality
▪Combination regimens may provide possible cure
– Combinations of agents effective against myeloma in
general with targeted agent for the specific subtype
▪Effective combinations have to move to upfront setting
▪Early intervention may be the key for cure

Slide credit: clinicaloptions.com


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