1. 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.

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3. 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
This slide lists the faculty who were involved in the production of these slides.

4. 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

5. Diagnosis and Staging

6. Updated IMWG Criteria for Diagnosis of Multiple Myeloma
MGUS
M protein < 3 g/dL
Clonal plasma cells in BM < 10%
No myeloma-defining events
Smoldering Myeloma
M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine)
Clonal plasma cells in BM ≥ 10% to 60%
Multiple Myeloma
Underlying plasma cell proliferative disorder
AND 1 or more myeloma- defining events
≥ 1 CRAB* feature
Clonal plasma cells in BM ≥ 60%
Serum free light-chain ratio ≥ 100
> 1 MRI focal lesion
BM, bone marrow; CrCl, creatinine clearance; CT, computed tomography; Hb, hemoglobin; MGUS, monoclonal gammopathy of undetermined significance; M-protein, monoclonal protein; MRI, magnetic resonance imaging; PET-CT, positron-emission tomography / computed tomography; ULN, upper limit of normal.
*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)
Slide credit: clinicaloptions.com
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

7. Progression to Symptomatic MM
100 80 60 40 20
Smoldering MM
MGUS
27% will convert in 15 years
Roughly 2% per year 78 73 66
15% more will convert over next 5 yrs and then 1% per yr thereafter
Progression (%) 51
51% will convert in first 5 yrs
~ 10% per yr
MGUS; monoclonal gammopathy of unknown significance; MM, multiple myeloma. 21 16 4 10 5 10 15 20 25
Yrs Since Diagnosis
Slide credit: clinicaloptions.com
Kyle RA, et al. N Engl J Med. 2007;356:

8. Risk Factors for Progression
2-Yr Progression
High levels of circulating plasma cells 80
High bone marrow plasma cell proliferative rate
Evolution of smoldering multiple myeloma 65
Abnormal plasma cell immunophenotype ≥ 95% plus immunoparesis 50
Cytogenetic subtypes: t(4;14), 1q amp, or del(17p)
Unexplained decrease in creatinine clearance by ≥ 25% accompanied by a rise in urinary monoclonal protein or serum free light-chain concentrations NA
Slide credit: clinicaloptions.com
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

9. 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
BMD, bone mineral density; MGUS; monoclonal gammopathy of unknown significance; SMM, smoldering multiple myeloma.
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10. 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
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11. 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
FISH, fluorescent in-situ hybridization; LDH, lactate dehydrogenase.
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12. Revised ISS Staging System
1.0
Stage
Definition 1
Serum albumin ≥ 3.5 g/dL AND β2-M ≤ 3.5 mg/L
Normal LDH
No t(4;14), t(14;16), or del(17p) 2
Not stage I or III 3
β2-M ≥ 5.5 mg/dL PLUS
High LDH, OR
t(4;14), t(14;16), or del(17p)
0.8
0.6
Probability of OS
0.4
Median OS, Mos
0.2
R-ISS I NR R-ISS II 83 R-ISS III 43
β2-M, beta2-microglobulin; LDH, lactate dehydrogenase; NR, no response; OS, overall survival; R-ISS, Revised International Staging System. 12 24 36 48 60 72
Mos
Slide credit: clinicaloptions.com
Palumbo A, et al. J Clin Oncol. 2015;33:

13. mSMART: Classification of Active MM
High Risk
Intermediate Risk*
Standard Risk*†
FISH‡
del(17p)
t(14;16)
t(14;20)
GEP
High-risk signature
FISH
t(4;14)§
1q gain
Complex karyotype
Metaphase del(13q) or hypodiploidy
High PC S-phase¶
All others including:
Trisomies
t(11;14)ǁ
t(6;14)
FISH, fluorescent in-situ hybridization; GEP, gene-expression profiling; LDH, lactate dehydrogenase; MM, multiple myeloma.
*A subset will be classified as high-risk by GEP.
†LDH > ULN and β2-M > 5.5 mg/L may indicate worse prognosis.
‡Trisomies may ameliorate.
§Prognosis is worse when associated with high β2-M and anemia.
ǁt(11;14) may be associated with plasma cell leukemia.
¶Cutoffs vary.
Dispenzieri A, et al. Mayo Clin Proc. 2007;82: Kumar SK, et al. Mayo Clin Proc. 2009;84: Mikhael JR, et al. Mayo Clin Proc. 2013;88:
Slide credit: clinicaloptions.com

14. Selecting Appropriate Induction Therapy

15. 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?
MRD, minimal residual disease; PBSC, peripheral blood stem cells.
Slide credit: clinicaloptions.com

16. Achieving ≥ VGPR or CR Should Be the Goal of Therapy
Pts with sCR have a significantly better outcome: estimated 5-yr OS 80% with sCR vs 53% with CR or 47% with nCR
Achieving CR[2]
1.00
0.75
0.50
0.25
1.00
0.8
0.6
Probability of OS
Probability of OS
P = .0017
0.4
CR + VGPR (n = 445)
0.2
CR or better PR PD
PR (n = 288)
VGPR SD 4 5 6 7 8 1 2 3 1 2 3 4 5 6 7
CR, complete response; nCR, near complete response; OS, overall survival; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response
Yrs Since Transplantation
Yrs Since Transplantation
1. Harousseau JL, et al. J Clin Oncol. 2009;27: Kapoor P, et al. J Clin Oncol. 2013;31:
Slide credit: clinicaloptions.com 16

17. Initial Management of MM in Transplantation-Eligible Pts
Adult with symptomatic MM
Continue therapy and workup for SCT
Yes
Is this pt a transplantation candidate?
≥ PR after 4 cycles?
Yes No
Secondary induction therapy and discussion with a SCT specialist
MM, multiple myeloma; PR, partial response; SCT, stem cell transplantation; VHA, Veterans Health Administration.
Select treatment with considerations of comorbidities
Start initial therapy
VHA clinical guidance for the initial management of adults with multiple myeloma
Slide credit: clinicaloptions.com

18. 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

19. 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: McCarthy PL, et al. Expert Rev Hematol. 2014;7: Palumbo A, et al. N Engl J Med. 2011;364: Lenhers N, et al. ASH Abstract Paiva B, et al. Blood. 2012;119:
Slide credit: clinicaloptions.com

20. Induction Therapy for Pts With Transplantation-Eligible MM
Preferred Regimens
Other Regimens
Initial therapy (induction) for transplantation-eligible pts (response assessment after cycle 2)
Category 1
Bort/dox/dex Rd
RVd VD
VTD
Category 2A
CyBorD
IRd
KRd
Category 2B
Dexamethasone
Liposomal dox/vin/dex
Thal/dex
Bort, bortezomib; CyBorD, cyclophosphamide/bortezomib/dexamethasone; dex, dexamethasone; dox, doxorubicin; IRd, ixazomib, lenalidomide, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; len, lenalidomide; MM, multiple myeloma; pred, prednisone; Rd, lenalidomide/low-dose dexamethasone; RVd, bortezomib/lenalidomide/dexamethasone; thal, thalidomide; VD, bortezomib/dexamethasone; vin, vincristine; VP, bortezomib/prednisone; VT, bortezomib/thalidomide; VTD, bortezomib/thalidomide/dexamethasone.
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v
Slide credit: clinicaloptions.com

21. Pts Achieving ≥ VGPR (%)
Earlier Phase Studies: Induction Regimens for Transplantation-Eligible Pts
Regimen
Median Total Cycles, n
Survival, %
RVd[1]
10*
18-mo PFS: 75
18-mo OS: 97
KRd[2,3] 12
12-mo PFS: 95
18-mo PFS: 92
3-yr PFS: 79
3-yr OS: 96
CyBorD[4] 4†
5-yr PFS: 42
5-yr OS: 70
IRd[5] 7
12-mo PFS: 88
12-mo OS: 94
100 80 60 40 20 89 67 60 58
Pts Achieving ≥ VGPR (%)
RVd[1]
KRd[2]
*Induction and maintenance; any drug. †Median not reported; response after 4 cycles stated as primary goal of study.
CyBorD, bortezomib/cyclophosphamide/dexamethasone; IRd, ixazomib/lenalidomide/dexamethasone; KRd, carfilzomib/lenalidomide/dexamethasone; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival; RVd, bortezomib/lenalidomide/dexamethasone; VGPR, very good partial response.
IRd[5]
CyBorD[4]
1. Richardson, PG et al. Blood. 2010;116: Jakubowiak A, et al. Blood. 2012;120: Jasielec J, et al. ASH Abstract Reeder CB, et al. Br J Haematol ; Kumar SK, et al. Lancet Oncol. 2014;15:
Slide credit: clinicaloptions.com

22. Autologous Stem Cell Transplantation

23. 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 MPR with no maintenance
100 75 75
PFS (%) 50
OS (%) 50
ASCT, autologous stem cell transplantation; Len, lenalidomide; MPR, melphalan, prednisone, lenalidomide; NDMM, newly diagnosed MM. 25 25
37.4
54.7
21.8
34.2 6 12 18 24 30 36 42 48 54 60 66 6 12 18 24 30 36 42 48 54 60 66
Mos
Mos
Slide credit: clinicaloptions.com
Palumbo A, et al. N Engl J Med. 2014;371:

24. 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
Increased grade 3/4 AEs with ASCT vs CRd, but similar serious hematologic (0% vs 2%; P = .49) and nonhematologic (7% vs 10%; P = .393) AEs
Median PFS, Mos
ASCT (n = 127) CRd (n = 129)
100 80 60 40 20
100 80 60 40 20
HR: 0.40 (95% CI: ;
P < .001)
4-Yr OS, %
ASCT CRd
PFS (%)
OS (%)
HR: 0.42 (95% CI: ;
P < .004)
Median f/u: 55 mos
Median f/u: 55 mos
ASCT, autologous stem cell transplantation; C, cyclophosphamide; D, dexamethasone; NDMM, newly diagnosed multiple myeloma; R, lenalidomide. 10 20 30 40 50 60 70 10 20 30 40 50 60 70
Mos
Mos
Slide credit: clinicaloptions.com
Gay F, et al. Lancet Oncol. 2015;16:

25. 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
(n = 350)
RVd Only
HR (95% CI)
4-yr PFS 47 35
0.69 ( ; P < .001)
4-yr OS 81 83
1.2 ( ; P = NS)
SPM 5 3
ORR 99 98
≥ VGPR 88 78
P = .001
ASCT, autologous stem cell transplantation; ISS, International Staging System; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RVd, lenalidomide, bortezomib, dexamethasone.
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)
Slide credit: clinicaloptions.com
Attal M, et al. ASH Abstract 391.

26. Phase III EMN02/HO95 Trial: Upfront ASCT vs VMP in Newly Diagnosed MM: Efficacy
Outcome
VMP
ASCT
HR (95% CI;
P Value)
PFS
Overall population, n
Median, mos
3 yr, %
497 44
57.5
695 NR
66.1
0.73 ( ; .003)
Standard-risk cytogenetics, n
220 46
69.6
290
76.6
0.68 ( ;
.034)
High-risk cytogenetics, n
181 32
43.2
292 42
55.2
0.69 ( ;
.010)
Response
(n = 451)
(n = 641) --
VGPR or better, %
73.8
85.5
< .001
ASCT, autologous stem cell transplantation; MM, multiple myeloma; NR, not reached; VGPR, very good partial response; VMP, bortezomib/melphalan/prednisone.
Median follow-up: 26 mos (range: mos)
Slide credit: clinicaloptions.com
Cavo M, et al. ASCO Abstract 8000.

27. 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
KRd + ASCT produced higher sCR rate at 8 cycles vs historical controls without ASCT (71% vs 30%); AEs similar to historical controls
100 80 60 40 20 97
100
100
100 85 87 87 87
≥ VGPR
≥ nCR
≥ CR
sCR 75 71
Response (%) 32 21 24 22
AE, adverse event; ASCT, autologous stem cell transplantation; CR, complete response; KRd, carfilzomib, lenalidomide, dexamethasone; nCR, near complete response; NDMM, newly diagnosed multiple myeloma; R, lenalidomide; sCR, serum complete response; VGPR, very good partial response. 12 8
Induction (n = 48)
ASCT (n = 37)
Consolidation (n = 24)
End of KRd (n = 8)
Slide credit: clinicaloptions.com
Zimmerman TM, et al. ASCO Abstract 8510.

28. Duration of Therapy in Multiple Myeloma

29. Maintenance Therapy for Pts With Transplantation-Eligible MM
Preferred Regimens
Other Regimens
Maintenance therapy
Category 1
Lenalidomide
Thalidomide
Category 2A
Bortezomib
Category 2B VP VT
Interferon
Steroids
Thal + pred
CyBorD, cyclophosphamide/bortezomib/dexamethasone; dex, dexamethasone; dox, doxorubicin; len, lenalidomide; MM, multiple myeloma; pred, prednisone; Rd, lenalidomide/low-dose dexamethasone; RVd, bortezomib/lenalidomide/dexamethasone; thal, thalidomide; VD, bortezomib/dexamethasone; vin, vincristine; VP, bortezomib/prednisone; VT, bortezomib/thalidomide; VTD, bortezomib/thalidomide/dexamethasone.
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v
Slide credit: clinicaloptions.com

30. 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 mg/day or placebo until relapse
PFS
5-yr PFS (primary endpoint) superior with Len vs placebo: 42% vs 18%, respectively (P < .0001)
PFS benefit independent of subgroup (eg, β2-M, ORR)
Median EFS: 40 mos with Len vs 23 mos for placebo
Median OS: similar (> 80 mos)
Grade 3/4 PN: similar in both groups
100 75 50 20
Len
Placebo
Pts (%)
ASCT, autologous stem cell transplantation; β2-M, beta2-microglobulin; EFS, event-free survival; Len, lenalidomide; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PN, peripheral neuropathy.
HR Len vs placebo: 0.50; P < .001 6 18 12 30 24 42 36 48 60 54
Mos
*Induction with VD or VAD; consolidation with lenalidomide.
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Attal M, et al. ASH Abstract 406.

31. 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
Estimated HR: 0.48 (95% CI: ); median TTP: 46 vs 27 mos
OS: 35 deaths with lenalidomide and deaths with placebo
3-yr OS: 88% vs 80%; HR: 0.62 or a 38% reduction in death with the cross over
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
2-sided P < .001
Lenalidomide
Lenalidomide
Placebo
Probability of PFS
ASCT, autologous stem cell transplantation; D-S, Durie-Salmon; HSCT, hematopoietic stem cell transplantation; ITT, intent to treat; OS overall survival; PFS, progression-free survival; SD, stable disease; TTP, time to progression.
Probability of OS
2-sided P = .03
Placebo
86 of 128 placebo pts
crossed over to lenalidomide
Median follow-up: 45 mos 10 20 30 40 50 60 70 10 20 30 40 50 60 70
Mos Since ASCT
Mos Since ASCT
Slide credit: clinicaloptions.com
McCarthy PL, et al. N Engl J Med. 2012;366:

32. Cumulative Incidence of Second Primary Malignancies by Treatment
Solid SPMs
Hematological SPMs
Len + mel
Len + cyclo
Len + dex
No len (mel regimens)
Len + mel
Len + cyclo
Len + dex
No len (mel regimens) 10 10 1 2 3 4 5 6 1 2 3 4 5 6 7
Cumulative incidence (%) 5
Cumulative incidence (%) 5 7
Cum Incidence, %
Solids SPM
Hematological SPM
3 Yrs
5 Yrs
Len + mel
2.7
4.4
1.8
3.9
Len + cyclo
3.5 NE
0.3
Len + dex
2.2
2.6
1.3
No len
2.9
3.4
0.4
1.4
Cyclo, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide; Mel, melphalan; SPM, second primary malignancy.
Slide credit: clinicaloptions.com
Palumbo A, et al. Lancet Oncol. 2014;15:

33. 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: ; P = .001)
All studies showed lenalidomide benefit, but results were heterogeneous (P = .047)
CALGB HR: 0.56 (95% CI: )
IFM HR: 0.91 (95% CI: )
GIMEMA HR: 0.66 (95% CI: )
ASCT, autologous stem cell transplantation; MM, multiple myeloma.
*Median OS for lenalidomide arm extrapolated to be 116 mos based on median of control arm and HR of 0.74.
Slide credit: clinicaloptions.com
Attal M, et al. ASCO Abstract 8001.

34. Lenalidomide Maintenance After ASCT in MM: Other Outcomes
Lenalidomide maintenance benefit seen in most subgroups except high-risk cytogenetics
HR: 1.18 (95% CI: )
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: ; P = .015)
Solid tumor: HR: 1.71 (95% CI: ; P = .032)
ASCT, autologous stem cell transplantation; MM, multiple myeloma.
Slide credit: clinicaloptions.com
Attal M, et al. ASCO Abstract 8001.

35. 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)
OR, overall response; OS, overall survival; PFS, progression-free survival; RCTs, randomized controlled trials; VTE, venous thromboembolism.
Slide credit: clinicaloptions.com
Singh PP, et al. ASH Abstract 407.

36. PFS, Censored at AlloSCT Cumulative Percentage Cumulative Percentage
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]
Bortezomib significantly improved OS for pts presenting with renal failure (P < .001)[2]
PFS, Censored at AlloSCT OS
100 75 50 25
100 75 50 25
HR: 0.78 (95% CI: ;
P = .01)
HR: 0.76 (95% CI: ;
P = .001)
Cumulative Percentage
Cumulative Percentage
N F
VAD PAD Cox LR stratified P = .002
N D
VAD PAD Cox LR stratified P = .05
Allo, allogeneic; D, number of patient deaths; F, number of treatment failures; LR, likelihood ratio; N, number of patients; nCR, near complete response; PAD, bortezomib/doxorubicin/dexamethasone; SCT, stem cell transplantation; VAD, vincristine/doxorubicin/dexamethasone. 12 24 36 48 60 72 84 12 24 36 48 60 72 84
Mos
Mos
1. Sonneveld P, et al. ASH Abstract Sonneveld P, et al. J Clin Oncol. 2012;24:
Slide credit: clinicaloptions.com 36 36

37. Maintenance in Myeloma
PFS advantage[1-3]
OS improvements?[2]
Toxicities of treatment
Myelosuppression[3]
Second primary malignancies[3,4]
Quality of life
Unclear whether all pts benefit from maintenance
Unclear which agent(s) and duration of therapy
PFS, progression-free survival.
1. Attal M, et al. ASH Abstract McCarthy PL, et al. N Engl J Med. 2012;366:
3. Attal M, et al. N Engl J Med. 2012;366: Palumbo A, et al. Lancet Oncol. 2014;15:
Slide credit: clinicaloptions.com

38. Optimal Therapy for Transplantation-Ineligible Patients

39. 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
Slide credit: clinicaloptions.com
Palumbo A, et al. Blood. 2015;125:

40. 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 Frail
0.75
0.75
0.50
0.50
OS (%)
Discontinuation (%)
Fit Intermediate fitness Frail
0.25
0.25 6 12 18 24 30 36 6 12 18 24
Mos
Mos
OS: fit (0) 84%, intermediate (1) 76% (HR: 1.61; P = .42), frail (≥ 2) 57% (HR: 3.57; P < .001)
Fit 17%, intermediate 21% (HR: 1.41; P = .052), frail (≥ 2) 31% (HR: 2.21; P < .001)
Slide credit: clinicaloptions.com
Palumbo A, et al. Blood. 2015;125:

41. 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
ISS, International Staging System; OS< overall survival; PFS, progression-free survival.
Slide credit: clinicaloptions.com
Dimopoulos M, et al. ASH Abstract 4738.

42. Pts Older Than 75 Yrs of Age
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
CR VGPR PR
CR VGPR PR
0.8
0.8
Probability of PFS
0.6
All Pts
Probability of OS
0.6
0.4
0.4
0.2
0.2
P < .001
P < .001 24 48 72 24 48 72
1.0
1.0
CR, complete response; MP, melphalan, prednisone; MPT, melphalan, prednisone, thalidomide; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; VMP, bortezomib, myeloma, prednisone; VMPT-VT, bortezomib, melphalan, prednisone, thalidomide plus maintenance bortezomib/thalidomide.
CR VGPR PR
CR VGPR PR
0.8
0.8
Pts Older Than 75 Yrs of Age
Probability of PFS
0.6
Probability of OS
0.6
0.4
0.4
0.2
0.2
P = .001
P = .004 24 48 72 24 48 72
Mos
Mos
Slide credit: clinicaloptions.com
Gay F, et al. Blood. 2011;117:

43. Induction and Maintenance Therapy for Pts With Transplantation-Ineligible MM
Preferred Regimens
Other Regimens
Initial therapy (induction) for transplantation-ineligible pts (response assessment after cycle 2)
Category 1 Rd
RVd
MPR
MPT
MPV
Category 2A VD
CyBorD
IRd MP
Category 2B
Dexamethasone
Liposomal dox/vin/dex
Thal/dex
Vin/dox/dex
Maintenance therapy
Lenalidomide
Thalidomide
Bortezomib VP VT
Interferon
Steroids
Thalidomide + prednisone
CyBorD, cyclophosphamide/bortezomib/dexamethasone; dex, dexamethasone; dox, doxorubicin; IRd, ixazomib, lenalidomide, dexamethasone; MP, melphalan/prednisone; MPR, melphalan/prednisone/lenalidomide; MPT, melphalan/prednisone/thalidomide; MPV, melphalan/prednisone/bortezomib; Rd, lenalidomide/low-dose dexamethasone; RVd, bortezomib/lenalidomide/dexamethasone; thal/dex, thalidomide/dexamethasone; vin, vincristine; VD, bortezomib/dexamethasone; VP, bortezomib/prednisone; VT, bortezomib/thalidomide.
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v
Slide credit: clinicaloptions.com

44. FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Pts With MM
Median PFS, Mos
Rd (n = 535)
25.5
Rd18 (n = 541)
20.7
MPT (n = 547)
21.2
HR (P Value)
Rd vs MPT: 0.72 (.00006)
Rd vs Rd18: 0.70 (.00001)
Rd18 vs MPT: 1.03 (.70349)
4-Yr OS, %
Rd (n = 535)
59.4
Rd18 (n = 541)
55.7
MPT (n = 547)
51.4
HR (P Value)
Rd vs MPT: 0.78 (.0168)
Rd vs Rd18: 0.90 (.307)
Rd18 vs MPT: 0.88 (.184)
100 80 60 40 20
100 80 60 40 20
PFS (%)
OS (%)
72 wks
Len/Dex, lenalidomide, dexamethasone; MM, multiple myeloma; MPT, melphalan, prednisone, thalidomide; OS, overall survival; PFS, progression-free survival; Rd, continuous lenalidomide, low-dose dexamethasone; Rd18, 18 weeks of lenalidomide, low-dose dexamethasone; SCT, stem cell transplantation. 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60
Mos
Mos
Overall response (continuous Rd vs MPT): 75% vs 62% (P < )
Similar, tolerable safety profiles between treatment groups
Incidence of second primary malignancies: 3% with continuous Rd vs 6% with Rd18 vs 5% with MPT
Slide credit: clinicaloptions.com
Benboubker L, et al. N Engl J Med. 2014;371:

45. SWOG S0777: RVd vs Rd in Pts With Newly Diagnosed MM
Confirmed Response, %
RVd
(n = 216*) Rd
(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
24.3
PD or death
2.8
4.2
Survival, Mos
RVd
(n = 242) Rd
(n = 229) HR
P Value
Median PFS 43 30
0.712
( )
.0018
Median OS 75 64
0.709
( )
.025
CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide, dexamethasone; SD, stable disease; VGPR, very good partial response; RVd, bortezomib, lenalidomide, dexamethasone.
*Assessable.
Slide credit: clinicaloptions.com
Durie B, et al. ASH Abstract 25.

46. 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%)
AEs, adverse events; ASCT, autologous stem cell transplantation; ORR, overall response rate; PR, partial response; RVd, lenalidomide/bortezomib/dexamethasone; SC, subcutaneous; VGPR, very good partial response.
Slide credit: clinicaloptions.com
O’Donnell E, et al. ASH Abstract 4217.

47. Suggested Empiric Age-Adjusted Dose Reduction in Pts With Myeloma
Agent
Younger Than 65 Yrs
65-75 Yrs
Older Than 75 Yrs
Dexamethasone
40 mg/day on Days 1-4, q4w or Days 1, 8, 15, 22 q4w
40 mg/day on Days 1, 8,1 5, 22 q4w
20 mg/day on Days 1, 8, 15, 22 q4w
Melphalan
0.25 mg/kg on Days 1-4 q6w
0.25 mg/kg on Days 1-4 q6w or 0.18 mg/kg on Days 1-4 q4w
0.18 mg/kg on Days 1-4 q6w or 0.13 mg/kg on Days 1-4 q4w
Cyclophosphamide
300 mg/day on Days 1, 8, 15, 22 q4w
300 mg/day on Days 1, 8, 15 q4w or 50 mg/day on Days 1-21 q4w
50 mg/day on Days 1-21 q4w or 50 mg/day QOD on Days 1-21 q4w
Thalidomide
200 mg/day
100 mg/day or 200 mg/day
50 mg/day to 100 mg/day
Lenalidomide
25 mg/day on Days 1-21 q4w
15-25 mg/day on Days 1-21 q4w
10-25 mg/day on Days 1-21 q4w
Bortezomib
1.3 mg/m2 bolus on Days 1, 4, 8, 11 q3w
1.3 mg/m2 bolus on
Days 1, 4, 8, 11 q3w or
on Days 1, 8, 15, 22 q5w
mg/m2 bolus on Days 1, 8, 15, 22 q5w
Slide credit: clinicaloptions.com
Palumbo A, et al. N Engl J Med. 2011;364:

48. 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

49. Treatment Options in Relapsed/Refractory Multiple Myeloma

50. Definition of Relapsed and Refractory Myeloma
Meets IMWG criteria for PD[2]
RR MM: progression on therapy in pts who obtain ≥ minor response or progress within 60 days of most recent therapy
Primary refractory MM: progression on therapy without having achieved at least minor response
Relapsed MM: meets IMWG criteria for PD but does not fit definition of RR or primary refractory MM[3]
IMWG Criteria for PD
≥ 25% increase in serum or urine paraprotein from nadir (absolute increase ≥ 0.5 g/dL and ≥ 200 mg/ 24 hrs, respectively), or
Involved-to-uninvolved serum FLC ratio > 100 mg/L, or
≥ 10% increase in bone marrow plasma cells, or
New bone or soft tissue lesions, or
Increasing size of existing bone or soft tissue lesions, or
Serum calcium > 11.5 mg/dL
FLC, free light chain; IMWG, International Myeloma Working Group; PD, progressive disease; RR, relapsed/refractory; RRMM, relapsed/refractory multiple myeloma.
1. Nooka AK, et al. Blood. 2015;125: Durie BG, et al. Leukemia. 2006;20: Rajkumar SV, et al. Blood. 2011;117:
Slide credit: clinicaloptions.com

51. Myeloma: Scope of the Problem
Median time to first relapse with current therapies: 3-4 yrs
1.0
0.9
0.8
0.7
0.6
OS (%)
> 100,000 pts living with myeloma
0.5
0.4
0.3
0.2
0.1 1 2 3 4 5 6
Yrs
Slide credit: clinicaloptions.com
Kumar SK, et al. Leukemia. 2014;28: 51 51

52. Confronting Disease Relapse in Myeloma
Median, Mos (Range) 9 (7-11) 5 (4-6)
Events, n/N 170/ /286 12
100
OS EFS 10 80 8 60
Median Response Duration (Mos) 6
Pts (%) 40 4 20 2
EFS, event-free survival.
First
Second
Third
Fourth
Fifth
Sixth 12 24 36 48 60
Treatment Regimen
Mos
Kumar SK, et al. Mayo Clin Proc. 2004;79:
Kumar SK, et al. Leukemia. 2012;26:
Slide credit: clinicaloptions.com

53. Questions to Ask Do I really need to treat this pt?
Does the pt have new high-risk features?
What drugs have been used so far?
Response to previous treatments (eg, efficacy, duration of response, toxicity)?
How well is the pt (PS, marrow reserve)?
What are the pt’s goals/preferences?
PS, performance status.
Slide credit: clinicaloptions.com

54. Recommended Regimens for Pts With Relapsed/Refractory MM
Preferred Regimens
Other Regimens
Category 1
Bortezomib
Bortezomib/liposomal doxorubicin
Elotuzumab/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
Bendamustine
Bortezomib/vorinostat
Bendamustine/len/dex
CyBorD, cyclophosphamide/bortezomib/dexamethasone; Cyclo, cyclophosphamide; DCEP, dexamethasone, cyclophosphamide, etoposide, and cisplatin; dex, dexamethasone; DT-PACE, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; KD, carfilzomib/dexamethasone; KRd, carfilzomib/lenalidomide/dexamethasone; len, lenalidomide; pan/bort/dex, panobinostat/bortezomib/dexamethasone; Pom/dex, pomalidomide/dexamethasone; Rd, lenalidomide/low-dose dexamethasone; Tx, treatment; VD, bortezomib/dexamethasone; RVd, bortezomib/lenalidomide/dexamethasone; VTD, bortezomib, dexamethasone, thalidomide; VTD-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide.
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v
Slide credit: clinicaloptions.com

55. 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
Bort/dex, bortezomib plus dexamethasone; HDAC, histone deacetylase; Len/dex, lenalidomide plus dexamethasone;
Slide credit: clinicaloptions.com

56. 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 (n = 73)
Bort/Dex (n = 74)
Significance
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
Bort/dex, bortezomib, dexamethasone; IMiD, immunomodulatory agent; Pan, panobinostat; RR, relapsed/refractory.
1. Richardson PG, et al. Blood. 2016;127: San Miguel J, et al. ASH Abstract 3026.
Slide credit: clinicaloptions.com

57. ASPIRE: KRd vs Rd in R/R Myeloma
Phase III trial
Outcome
KRd (n = 396)
Rd (n = 396)
Significance
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
KRd, carfilzomib/lenalidomide/low-dose dexamethasone; NR, not reached; Rd, lenalidomide/low-dose dexamethasone; R/R, relapsed/refractory.
Slide credit: clinicaloptions.com
Stewart AK, et al. N Engl J Med. 2015;372:

58. Carfilzomib/Pomalidomide/ Dexamethasone in R/R MM: Response
Phase I/II trial
ITT Response, %
All Evaluable Pts
Primary Study Population*
After 4 KPd cycles
CR/nCR
≥ VGPR
≥ PR
≥ MR
(n = 54) 4 30 72 80
(n = 44) 2 23 73 82
Best response
(n = 55) 16 47 84 93
(n = 45) 13 44 96
KPd, carfilzomib/pomalidomide/dexamethasone; MM, multiple myeloma; MR, minimal response; nCR, near CR; PI, proteasome inhibitor; R/R, relapsed/refractory; VGPR, very good partial response.
*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)
Slide credit: clinicaloptions.com
Rosenbaum CA, et al. ASCO Abstract 8007.

59. 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 (n = 106)
95% CI
ORR, %
29.2
20.8 – 38.9
Median PFS, mo
3.7
1-year* OS, % 65
Median DoR, mo
7.4
5.5 - NE
CBR, clinical benefit rate; DoR, duration of response; MR, minor response; NE, not estimable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RR, relapsed/refractory; sCR, stringent complete response; VGPR, very good partial response.
*Median OS not reached
Slide credit: clinicaloptions.com
Lonial S, et al. Lancet. 2016;Jan 6:[E-pub ahead of print].

60. CASTOR: Daratumumab/Bortezomib/ Dexamethasone in R/R MM: Efficacy
Time to PR occurred early in pts (~2 mos), but CR took longer to develop in many pts (≥ 8 mos)
Efficacy Outcome
DVd (n = 251)
Vd (n = 247)
HR (95% CI)
P Value
Median PFS following 1 prior treatment, mos
1-yr PFS, % NR
77.5
7.5
29.4
0.31 ( )
< .0001
Median TTP, mos
65.4
7.3
28.8
0.30 ( )
ORR, %
≥ VGPR
≥ CR 83 59 19 63 29 9
.0012
MRD negative, % 14 3
DVd, daratumumab/bortezomib/dexamethasone; MRD, minimal residual disease; NR, not reached; TTP, time to progression; Vd, bortezomib/dexamethasone; VGPR, very good PR.
Slide credit: clinicaloptions.com
Palumbo A, et al. ASCO Abstract LBA4.

61. TOURMALINE-MM1: Ixazomib Efficacy
Characteristic
Ixazomib + Rd
(n = 360)
Placebo + Rd
(n = 362)
P Value
Median PFS, mos
20.6
14.7
.012*
ORR, % CR
VGPR PR
78.3
11.7
36.4
66.7
71.5
6.6
32.3
64.9
.035
.019
Median time to response, mos
1.1
1.9
Median DoR, mos
20.5
15.0
Median TTP, mos
21.4
15.7
.007†
DoR, duration of response; IMiD, immunomodulatory drug; PI, proteasome inhibitor; Rd, dexamethasone/lenalidomide; TTP, time to progression; VGPR, very good PR.
*HR: †HR:
PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed
Slide credit: clinicaloptions.com
Moreau P, et al. ASH Abstract 727.

62. ELOQUENT-2: Anti-SLAMF7 Monoclonal Antibody Elotuzumab + Rd vs Rd—Efficacy
Outcome
Elotuzumab + Rd
(n = 321) Rd
(n = 325)
HR (95% CI)
PFS
Median, mos
1 yr, %
2 yrs, %
3 yrs, %
19.4 68 41 26
14.9 57 27 18
0.73 ( ;
P = .0014)
Median time to next treatment, mos 33 21
0.62 ( )
ORR, % 79 66
Interim OS, mos
43.7
39.6
0.77 ( ;
P = .0257)
Rd, lenalidomide plus low-dose dexamethasone.
PFS benefit seen with elotuzumab in all predefined subgroups
Slide credit: clinicaloptions.com
Dimopoulos MA, et al. ASH Abstract 28.

63. KEYNOTE-023: Pembrolizumab/ Lenalidomide/Dexamethasone: Response
88% of pts showed some decrease in M protein or free light chains from baseline
Best Overall Response, %
Efficacy Population
(n = 40)
Len-Refractory Population
(n = 29)
ORR
Stringent CR
VGPR PR 50 3 13 35 38 10 24 SD 48 59
Disease control rate (CR + PR + SD) 98 97 PD
Len, lenalidomide; PD, progressive disease; SD, stable disease; VGPR, very good PR.
Slide credit: clinicaloptions.com
Mateos MV, et al. ASCO Abstract 8010.

64. 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
HDAC, histone deacetylase; KSP, kinesin spindle protein; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma.
Slide credit: clinicaloptions.com
Nooka AK, et al. Blood. 2015;125:

65. 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)
ASCT, autologous stem cell transplantation; TRM, treatment-related mortality; TTP, time to progression.
Slide credit: clinicaloptions.com
Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:

66. ASCT: Timing of Transplantation
100 80 60 40 20
Survival (%)
Delayed ASCT (n = 118) Early ASCT (n = 174)
ASCT, autologous stem cell transplantation; NR, no response. 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)
Slide credit: clinicaloptions.com
Kumar S, et al. Cancer. 2012;118:

67. 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
GVHD, graft-vs-host disease; SCT, stem cell transplantation.
Slide credit: clinicaloptions.com

68. Adverse Event Management

69. Peripheral Neuropathy: Risk Factors and General Considerations
Endocrine disorders
Hypothyroidism
Diabetes
Nutritional disease
Connective tissue disease
Vascular disease
Medications
Herpes zoster
Most common symptoms
Sensory deficits
Neuropathic pain
Disease- and Treatment-Related Factors
Hyperviscosity syndrome
Hypergammaglobulinemia
Incidence of peripheral neuropathy in untreated pts: 39%
Incidence of grade 3/4 CIPN with novel agents
Bortezomib: 6% to 22%
↓ with wkly vs twice-weekly dosing
↓ with SC administration
Thalidomide: 3% to 23%
↑ with higher doses and prolonged therapy
Carfilzomib: < 2%
CIPN, chemotherapy-induced peripheral neuropathy.
Gleason C, et al. J Natl Compr Cancer Netw. 2009;7: Palumbo A, et al. J Clin Oncol. 2014;32: Kurtin S, et al. J Adv Pract Oncol. 2013;4: Siegel D, et al. Haematologica. 2013;98:
Slide credit: clinicaloptions.com

70. 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 mg/day
If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 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)
IMiD, immunomodulatory agent; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.
Palumbo A, et al J Clin Oncol. 2014;32: Palumbo A, et al. Leukemia. 2008;22:
Slide credit: clinicaloptions.com

71. 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

72. Current Management of Bone Disease
Effective antimyeloma therapy
Novel therapies have benefits
Direct effect on inflammatory cytokines
Inhibition of bone resorption
Osteoclast stimulation
Bisphosphonates
Pamidronate
Zoledronic acid
Supplement with calcium and vitamin D3 to maintain calcium homeostasis
Radiotherapy (low dose)
Impending fracture
Cord compression
Plasmacytomas
Vertebroplasty/kyphoplasty
Orthopedic consultation
Impending or actual long-bone fractures
Bony compression of spinal cord
Vertebral column instability
Niesvizky R, et al. J Natl Compr Canc Netw. 2010;8(suppl 1):S13-S20. Christoulas D, et al. Expert Rev Hematol. 2009;2: Drake MT. Oncology (Williston Park). 2009;23(14 suppl 5): Terpos E, et al. J Clin Oncol. 2013;31: Webb SL, et al. Br J Pharmacol. 2014;171:
Slide credit: clinicaloptions.com

73. 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

74. 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

75. 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

76. Go Online for More CCO Coverage of Multiple Myeloma!
ClinicalQuiz™ testing your knowledge of multiple myeloma Journal Club slidesets and modules of key myeloma articles Interactive case studies of myeloma management Additional CME-certified slidesets on multiple myeloma with expert faculty commentary on all the key studies
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