i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource. This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.

1. Optimizing Treatment Sequencing for Patients
With Relapsed/Refractory Multiple Myeloma
Shaji Kumar, MD
Mark and Judy Mullins Professor of Hematological Malignancies
Mayo Clinic Cancer Center

2. Disclosures
Advisory board/panel: AbbVie, Amgen, Antengene, AstraZeneca,
BeiGene, Bluebird Bio, Bristol Myers Squibb, Genentech/Roche,
Janssen, Kite, Oncopeptides, Takeda
Grants/research support: AbbVie, Amgen, AstraZeneca, Bristol Myers
Squibb, CARsgen, Genentech/Roche, Janssen, Kite, Merck, Novartis,
Takeda, TeneoBio
i3 Health has mitigated all relevant financial relationships

3. Learning Objectives
MM = multiple myeloma.
Determine the timing and indications for initiating therapy in relapsed
MM
Assess recent clinical trial findings on novel sequential treatment
approaches for relapsed/refractory MM
Evaluate strategies to monitor and manage adverse events associated
with novel therapies for relapsed/refractory MM

4. Defining Disease Progression: IMWG
IMWG = International Myeloma Working Group; M-protein = myeloma protein; dFLC = difference between involved minus uninvolved serum free light chains;
BMPC% = bone marrow plasma cell percentage; SPD = sum of the product of the diameters.
Kumar et al, 2016.
≥25% increase from lowest confirmed response value in ≥1 of the following:
Serum M-protein (absolute increase must be ≥0.5 g/dL; or increase ≥1 g/dL if the lowest M
spike was ≥5 g/dL)
Urine M-protein (absolute increase ≥200 mg/24 hours)
In patients without measurable serum and urine M-protein levels, dFLC levels (absolute
increase must be >10 mg/dL)
If no measurable serum/urine M-protein/FLC levels, BMPC% irrespective of baseline status
(absolute increase must be ≥10%)
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis
≥50% increase in circulating plasma cells (>200 cells per μL) if this is the only
measure of disease

5. Defining Clinical Relapse: IMWG
Kumar et al, 2016.
≥1 of the following criteria:
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic
fractures do not constitute progression)
Increase in the size of existing plasmacytomas or bone lesions (defined as 50%
and ≥1 cm increase as measured serially by the SPD) of the measurable lesion
Hypercalcemia (>11 mg/dL)
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non–
myeloma-related conditions
Rise in serum creatinine by ≥2 mg/dL from the start of therapy and attributable
to myeloma
Hyperviscosity related to serum paraprotein

6. Relapsed MM: Scope of the Problem
Kumar et al, 2014; SEER, 2021.
Median time to first relapse with current therapies: 3-4 years
>100,000 patients living
with myeloma

7. Development of Resistance
Kumar et al, 2004; Durie et al, 2012; Keats et al, 2012.

8. Case Study 1: Mr. JB
R-ISS = Revised International Staging System; IgG = immunoglobulin G; M spike = monoclonal spike; t = translocation; IFE = immunofixation;
VRD = bortezomib/lenalidomide/dexamethasone; SCT = stem cell transplant; CR = complete response; CBC = complete blood count.
74-year-old man diagnosed with MM 5 years ago
R-ISS Stage 2 disease, t(11;14), normal renal function, multiple lytic lesions
IgG kappa M spike 3.4 g/dL, kappa FLC elevated, 24-hour urine IFE–positive
Received VRd induction followed by single SCT and lenalidomide maintenance
Achieved a CR
On routine quarterly follow-up, he now has an M spike of 0.3 gm/dL
He feels fine, normal renal function, normal CBC
What would be your next step?
a) Consider a second autologous SCT
b) Increase the dose of lenalidomide and add dexamethasone
c) Perform imaging studies and observe if normal
d) Consider daratumumab, lenalidomide, and dexamethasone

9. Case Study 1: Mr. JB (cont.)
What would be your next step?
a) Consider a second autologous SCT
b) Increase the dose of lenalidomide and add dexamethasone
c) Perform imaging studies and observe if normal
d) Consider daratumumab, lenalidomide, and dexamethasone

10. Myeloma Treatment Paradigm
Mayo Clinic, 2021.
Induction
Induction followed by continuous
therapy
Consolidatio
n
Maintenance
SCT-
eligible
SCT-
ineligible
Diagnosis
and
risk
stratification
Tumor burden
Relapse
1
Relapse
2
Relapse
3
Relapse
4
Refractory
disease

11. When Should We Start Treatment for Relapse?
CRAB = hypercalcemia, renal failure, anemia, and bone disease.
Mikhael et al, 2019; Laubach et al, 2016.
Patients with clinical progression/CRAB clearly need treatment
Those with biochemical progression only (asymptomatic increase in
monoclonal protein) may not need immediate treatment
Standard-risk disease with slow trend up
Treatment indicated in the following:
High-risk disease with any progression
Presentation with renal or neurological complications
Rapid doubling of M spike

12. General Principles
dex = dexamethasone; PS = performance status.
Mikhael et al, 2019.
Duration of initial response defines biology
Triplet (2 active classes + dex) preferred over doublet
≥1 drug from a non-refractory class
Consider PS, age, and comorbidities when selecting drugs/doses
Take into account prior toxicities/residual toxicities
Treat to maximum response and maintain on 1 drug until progression
or tolerability

13. How Do We Select Treatment?
Mikhael et al, 2019.
Prior drug exposure/refractory status
High-risk vs standard-risk
Age, frailty, and comorbidity
Toxicity with prior drugs
Transplant eligibility/prior transplant
Patient preference/goals of care
Logistics of drug administration

14. KRd IRd ERd DRd DKd/Isa-Kd DVd EPd
DPd
KPd
DPd
IPd
KPd
IPd
EPd
EPd
KPd
EPd
DKd
Clinical trials OR repeat combinations of agents most remotely used
Overall, while
triplets are
preferred,
lower-dose
triplets or
doublets can
be used in
frail and
older
patients
Not Refractory to Len at First Relapse Refractory to Len at First Relapse
Rational Approach to First Relapse and Later
Len = lenalidomide; KRd = carfilzomib/lenalidomide/dexamethasone; IRd = ixazomib/lenalidomide/dexamethasone;
ERd = elotuzumab/lenalidomide/dexamethasone; DRd = daratumumab/lenalidomide/dexamethasone; DPd = daratumumab/pomalidomide/dexamethasone;
KPd = carfilzomib/pomalidomide/dexamethasone; IPd = ixazomib/pomalidomide/dexamethasone; EPd = elotuzumab/pomalidomide/dexamethasone;
DKd = carfilzomib/daratumumab/dexamethasone; Isa-Kd = isatuximab/carfilzomib/dexamethasone; DVd = daratumumab/bortezomib/dexamethasone;
Isa-Pd = isatuximab/pomalidomide/dexamethasone; KCd = carfilzomib/cyclophosphamide/dexamethasone; PVd = pomalidomide/bortezomib/dexamethasone.
Diagram courtesy of Dr. Kumar.
DPd/Isa-Pd
KCd
PVd
DKd

15. Lenalidomide-Based Combinations
PR = partial response; VGPR = very good partial response; PFS = progression-free survival; Rd = lenalidomide/dexamethasone.
Siegel et al, 2018; Stewart et al, 2015; Richardson et al, 2021; Moreau et al, 2016; Dimopoulos et al, 2016b; Lonial et al, 2015.
Trial Regimen Control N ≥PR ≥VGPR ≥CR PFS (months)
ASPIRE KRd Rd 396 87 70 32 26.3 (vs 17.6)
TOURMALINE IRd Rd 360 78 48 12 20.6 (vs 14.7)
POLLUX DRd Rd 281 93 76 43 NR (vs 18.4)
ELOQUENT ERd Rd 321 78 28 4 19.4 (vs 14.9)

16. Bortezomib-Based Combinations
EBD = elotuzumab/bortezomib/dexamethasone; Bd = bortezomib/dexamethasone.
Dimopoulos et al, 2016a; Palumbo et al, 2016; Richardson et al, 2019; Jakubowiak et al, 2016.
Trial Regimen Control N ≥PR ≥VGPR ≥CR PFS (months)
ENDEAVOR Kd Bd 464 76 54 13 18.7 (vs 9.4)
CASTOR DVd Bd 251 83 59 19 NR (vs 7.2)
OPTIMISSM PVd Bd 281 83 53 16 11.2 (vs 7.1)
Randomized
phase 2
EBd Bd 77 67 37 4 9.7 (vs 6.9)

17. CANDOR: Carfilzomib/Dexamethasone/Daratumumab (KdD)
RRMM = relapsed/refractory MM; ECOG = Eastern Oncology Cooperative Group; CrCl = creatinine clearance; LVEF = left ventricular ejection fraction;
ORR = overall response rate; MRD = minimal residual disease; OS = overall survival.
Usmani et al, 2019.
Study Design
Arm 1: KdD Carfilzomib 56 mg/m2
Dexamethasone 40 mg
Daratumumab 16 mg/kg
Arm 2: Kd Carfilzomib 56 mg/m2
Dexamethasone 40 mg
Primary
end point:
PFS
Key
secondary
end points:
ORR, MRD,
OS
28-day
cycles
0 16 24
4 8 20
12 28 32
MRD sample:
landmark analysis
Sustained MRD-
negative CR rate
Months
n=312
n=154
2:1
Patients
N=466
Key eligibility
criteria:
• RRMM
• 1-3 prior
therapies with
≥PR to ≥1
prior therapy
• ECOG PS 0-2
• CrCl
≥20mL/min
• LVEF ≥40%
MRD sample:
landmark analysis
MRD-negative CR rate
MRD sample:
baseline
Treatment
until
disease
progression

18. CANDOR: KdD Updated Analysis
Usmani et al, 2022.
KdD Significantly Prolonged PFS Compared With Kd

19. IKEMA: Isatuximab/Carfilzomib/Dexamethasone (Isa-Kd) vs Kd
IRC = independent review committee.
Moreau at al, 2020.
Relapsed MM
Primary end point:
PFS (IRC)
Key secondary end
points: ORR, ≥VGPR,
MRD negativity, CR
rate, OS
Median PFS control
arm estimated at 19
months
Prespecified interim
analysis when 65%
PFS events (103) as
per IRC
Relapsed MM
N=302 3:2 Kd (n=123)
Randomization
Stratification factors:
- Prior lines: 1 vs >1
- R-ISS: I-II vs III vs not classified
- 1-3 prior lines
- No prior therapy with carfilzomib
- Not refractory to prior anti-CD38
Treatment until PD,
unacceptable toxicities,
or patient choice
Isa-Kd (n=179)
• Isa: 10 mg/kg on D1, 8, 15, 22 in C1, then
Q2W
• K: 20 mg/m2 D1-2; 56 mg/m2 D8-9, D15-16
C1; 56 mg/m2 D1-2, D8-9, D15-16 all
subsequent cycles
• d: 20 mg D1-2, D8-9, D15-16, and
D22-23 each cycle
Kd (n=123)
• K: 20 mg/m2 D1-2; 56 mg/m2 D8-9, D15-16
C1; 56 mg/m2 D1-2, D8-9, D15-16 all
subsequent cycles
• d: 20 mg D1-2, D8-9, D15-16 and D22-23
each cycle

20. IKEMA: Isatuximab-Kd Updated Analysis (cont.)
Moreau et al, 2022.
Progression-Free Survival
Kd
mPFS: 19.2 months
(95% CI: 15.8-25.0)
Isa-Kd
mPFS: 35.7 months
(95% CI: 25.8-44.0)
HR 0.58 (95.4% CI: 0.42-0.79)
Time (months)
Kaplan-Meier
estimate
Number at risk

21. RRMM
N=300
ICARIA: Isatuximab/Pomalidomide/Dexamethasone (Isa-PD)
PI = proteasome inhibitors; PD = pomalidomide/dexamethasone; AE = adverse event.
Richardson et al, 2018.
Study Design
Isa-Pd
Pd
P: 4 mg on Days 1-21 of 28-day cycle
d: 40 mg (20 mg age ≥75) Day 1, 8, 15, 22
≥2 prior lines
with len and PI
No prior therapy
with pomalidomide
R
1:1
Primary end point:
PFS (IRC)
Key secondary
end points:
ORR, OS
Sample size calculation:
~300 patients required to
detect an HR of 0.6 with 90%
power and 1-sided
type 1 error of 2.5%
Isa: 10 mg/kg on Day 1, 8, 15, 22 in Cycle 1;
subsequently on Day 1, 15
P: 4 mg on Days 1-21 of 28-day cycle
d: 40 mg (20 mg age ≥75) on Day 1, 8, 15, 22
Treatment until progressive
disease or unacceptable AEs

22. ICARIA: Isa-Pd (cont.)
Attal et al, 2019.
Survival

23. Cycle duration: 28 days
Treatment until PD or unacceptable
toxicity
Key eligibility
criteria
• RRMM
• 1 prior line with
both lenalidomide
and a PI
• ECOG PS ≤2
• CrCl ≥30 mL/min
1:1
randomization
DPd
D: 1,800 mg SC QW Cycles 1-2,
Q2W Cycles 3-6, Q4W Cycles 7+
P: 4 mg PO Days 1-21
d: 40 mg PO Days 1, 8, 15, 22
P: 4 mg PO Days 1-21
d: 40 mg PO Days 1, 8, 15, 22
Post-
treatment
follow-up
Q4W for
patients who
discontinued
treatment
Survival
follow-up
every 12
weeks
following
PD or start
of
subsequent
therapy
Primary end point:
• PFS
Secondary end points:
• ORR, ≥VGPR, ≥CR
• MRD
• OS
• Time to response
• Duration of
response
• Time to next therapy
• Safety
• HRQOL
Stratification factors
• Number of lines of prior therapy
(1 vs 2-3 vs ≥ 4)
• ISS disease stage (I vs II vs III)
APOLLO: Daratumumab/Pomalidomide/Dexamethasone (DPd)
SC = subcutaneously; QW = once weekly; PO = orally; Q4W = every 4 weeks; ISS = International Disease Staging; HRQOL = health-related quality of life.
Dimopoulos et al, 2020.
Study Design
PD

24. %
surviving
without
progression
20
40
60
80
100
No. at risk
0
0 2 4 6 8 10 12 34
Months
14 18
Pd
DPd
153
151
121
135
93
111
79
100
52
80
36
66
5
12
0
2
0
3
0
2
16 20 22 24 26 28 30 32
0
2
61
87
46
74
12
20
1
5
27
48
17
30
5
8
Pd median: 6.9 months
12-month PFS ratea
DPd median:
12.4 months
HR, 0.63; 95% CI: 0.47-0.85;
P=0.0018
36
0
1
52%
35%
APOLLO: DPd (cont.)
aKaplan‒Meier estimate.
CI = confidence interval.
Dimopoulos et al, 2020.
Progression-Free Survival
Median PFS among patients refractory to lenalidomide was
9.9 months for DPd and 6.5 months for Pd

25. MM014: Daratumumab/Pomalidomide/Dexamethasone (DPd)
Bahlis et al, 2022.
Pom-Based Therapy After Lenalidomide in Earlier Treatment Lines

26. ELOQUENT-3: Elotuzumab/Pomalidomide/Dexamethasone (EPd)
Dimopoulos et al, 2018.

27. Carfilzomib/Pomalidomide/Dexamethasone (KPd)
Shah et al, 2015.
ORR ≥VGPR
50% 16%

28. GEM-KyCyDex: Carfilzomib/Cyclophosphamide/Dexamethasone
aDex 20 mg weekly for patients >75.
KyCyDex = carfilzomib/cyclophosphamide/dexamethasone; cyclo = cyclophosphamide.
Mateos et al, 2020.
Study Design: Multicenter, Open-Label, Randomized Phase 3 Trial
KyDex (n=101)
• Carfilzomib 70 mg/m2 IV
Days 1, 8, and 15 (20 mg/m2 day 1 cycle 1 only)
Infusion duration: 30 minutes for all doses
• Dexamethasone 40 mg weekly: 20 mg the day of Ky and 20 mg the day
after
• 28-day cycles until PD or unacceptable toxicity
KyCyDex (n=97)
• Carfilzomib 70 mg/m2 IV
Days 1, 8, and 15 (20 mg/m2 Day 1 Cycle 1 only)
Infusion duration: 30 minutes for all doses
• Dexamethasone 40 mg weekly: 20 mg the day of Ky and 20 mg the day
aftera
• Cyclophosphamide 300 mg/m2 IV Days 1, 8, and 15
28-day cycles until PD or unacceptable toxicity
Randomization 1:1
N=198
• RRMM patients after 1-3
prior lines of therapy
• Prior therapy with PIs was
allowed
• Patients refractory to PIs
were not allowed
• CrCl >30 mL/minute
• LVEF >50%
Ky and cyclo only on Days 1 and 15 since Cycle 12

29. Median follow-up: 15.6 (1.3-29)
PFS by subgroup
KyCyDex
(n=97)
KyDex
(n=101)
Len-refractory after last
line of therapy
32 (33%) 36 (36%)
Median PFS, months, 95%
95% CI
26.2
(12-39)
9.3
(5.8-12.8)
P value 0.02
After 1PL (n=11 and 10) NR 9.7
After 2PL (n=12 and 17) NR 9.3
After 3PL (n=9 and 9) 26 9.0
Len-refractory
KyCyDex
(n=35)
KyDex
(n=36)
Median PFS,
months, 95% CI
26.2
(12-39)
9.3
(5.8-12.8)
P value
HR: 0.4, 95% CI: 0.2-0.9,
P=0.02
GEM-KyCyDex (cont.)
1PL = after 1 prior line; 2PL = after 2 prior lines; 3PL = after 3 prior lines.
Mateos et al, 2020.
PFS in Len-Exposed and -Refractory Patients

30. Auto-SCT at First Relapse
IFM = Intergroupe Francophone du Myélome; RVD = lenalidomide, bortezomib, and dexamethasone; pom = pomalidomide.
Perrot et al, 2020.
Long-Term Follow-Up Analysis from IFM 2009 Trial
Median PFS2 95.3 months (RVD alone, arm A)
Median PFS2 non reached (Transplantation, arm B)
Arm A: 350 patients Arm B: 350 patients
270 PD = 77.1% 227 PD = 64.9%
Second-line: 262 Second-line: 217
105 Pom 101 Pom
201 ASCT 49 ASCT

31. MM Treatment Toxicity
IMIDs
Cytopenias
Skin rash
Risk of DVT
Proteasome inhibitors
Thrombocytopenia
Neuropathy with bortezomib
Cardiac and pulmonary toxicity with carfilzomib
Monoclonal antibodies
Infusion reactions
Increased risk of infections
IMID = immunomodulatory imide drug; DVT = deep vein thrombosis.
Asquith & Italiano, 2020; Firoozmand et al, 2020; Swan et al, 2018; Merin & Kelly, 2015; Hansel et al, 2010.

32. Case Study 2: Ms. CP
FISH = fluorescence in situ hybridization.
68-year-old woman diagnosed with MM 8 years ago
R-ISS stage 2 disease; FISH with trisomies 5, 7, 9; normal renal function; multiple lytic
lesions
IgG kappa M spike 3.4 g/dL, kappa FLC elevated, 24-hour urine IFE–positive
Received VRd induction followed by single SCT and lenalidomide maintenance
Achieved a CR
Relapsed after 4 years, received DPd and had a response lasting 2 years
Then received carfilzomib/cyclophosphamide/dex and had a response
lasting 18 months
Most recently was on EPd for 6 months

33. Case Study 2: Ms. CP (cont.)
BCMA = B-cell maturation antigen.
Now the MM is relapsing; what is the next step?
a. Teclistamab
b. Selinexor/bortezomib/dexamethasone
c. Second autologous transplant
d. Ide-cel: BCMA-targeted CAR T-cell

34. Blenrep prescribing information, 2020; Grosicki et al, 2020; NCCN, 2022.
Now the MM is relapsing, what is the next step?
a. Teclistamab
b. Selinexor/bortezomib/dexamethasone
c. Second autologous transplant
d. Ide-cel: BCMA-targeted CAR T-cell
Case Study 2: Ms. CP (cont.)

35. Myeloma Treatment Paradigm (cont.)
Induction
Induction followed by continuous
therapy
Consolidation Maintenance
SCT-
eligible
SCT-
ineligible
Diagnosis
and
risk
stratification
Tumor burden
Relapse
1
Relapse
2
Relapse
3
Relapse
4
Refractory
disease

36. What Are the Options?
ADC = antibody-drug conjugate; HDAC = histone deacetylase; CAR = chimeric antigen receptor; CELMOD = cereblon E3 ligase modulator;
BCL2 = B-cell leukemia/lymphoma-2.
Xpovio® prescribing information, 2020; Blenrep prescribing information, 2020; Farydak® prescribing information, 2015; Pepaxto® prescribing information, 2021;
NCCN, 2022; Abecma® prescribing information, 2021; Clinicaltrials.gov, 2021b.
Approved drugs
Selinexor (XPO1 inhibitor)
Belantamab mafodotin (BCMA ADC) (compassionate use program)
Panobinostat
HDAC inhibitor
Combination with bortezomib and dexamethasone for patients who have received ≥2 prior
therapies, including an immunomodulator and bortezomib
Melflufen
Ide-cel, Cilta-cel (CAR T)
BCMA bispecific (teclistamab)
Clinical trials
CAR T
T-cell engagers
CELMODs
Venetoclax (BCL2 inhibitor)

37. BOSTON: Selinexor/Bortezomib/Dexamethasone (SVd)
Grosicki et al, 2020.

38. BOSTON: SVd (cont.)
Grosicki et al, 2020.

39. Selinexor Combinations
aORR and PFS reported for pomalidomide-naive or -nonrefractory patients (patients treated with RP2D).
Cfz = carfilzomib; pom = pomalidomide; RP2D = recommended phase 2 dose.
Gasparetto et al, 2021; White et al, 2021; Gasparetto et al, 2020; NCCN, 2022.
Selinexor/
carfilzomib
Selinexor/
pomalidomide
Selinexor/
daratumumab
N 27 65 34
Median lines of
treatment
4 (1-8) 3 (1-10) 3 (1-10)
ORR 78% 57% (65%)a 73%
CR 19% 2% -
VGPR 30% 18% 37%
PR 30% 34% 37%
PFS 23.8 months 12.2 months 12.5 months
RP2D 80 mg weekly 60 mg weekly 100 mg weekly
56 mg/m2 cfz 4 mg pom 16 mg/m2 dara
40 mg dex 40 mg dex 40 mg dex
NCCN guidelines include indications for selinexor/carfilzomib/dex,
selinexor/pomalidomide/dex, and selinexor/daratumumab/dex

40. Selinexor: Toxicity Management
Mikhael et al, 2020.
Nausea and diarrhea
Nausea: recommend using 2 antiemetics in the beginning as prophylaxis
Grade 1 diarrhea: maintain dose, rule out other causes, initiate antidiarrheal treatment
Grade 2 diarrhea: rule out other causes and interrupt selinexor until resolved to grade 1
or baseline
First occurrence: restart selinexor at current dose
Second or later occurrence: reduce selinexor dose by 1 level
Grade 3 diarrhea: delay selinexor until resolved to grade 1 and the patient is clinically
stable, then reduce selinexor dose by 1 dose level
Thrombocytopenia
Dose reductions
Fatigue

41. Belantamab Mafodotin MOA
Belantamab Mafodotin
IV = intravenous.
Cho et al, 2018; Sheikh et al, 2020.
B-cell maturation antigen (BCMA)
Selectively expressed on plasmablasts and
plasma cells
Requisite for long-lived plasma cell survival
Belantamab mafodotin
Humanized afucosylated IgG1 ADC targeting
BCMA
Multimodal mechanisms of action (MOA)
Convenient IV 0.5-1–hour outpatient
infusion

42. Belantamab Toxicity Management
Blenrep prescribing information, 2020.
Ocular toxicity
Keratopathy in ~70%
Symptomatic AE in ~30%
Requires eye exam before each dose
Symptomatic eye treatments
Thrombocytopenia
Usually managed with dose interruptions/modifications
Platelet count 25,000 to <50,000 platelets/µL
Reduce dose; consider withholding
Platelet count <25,000 platelets/µL
Withhold until platelet count improves; consider resuming at reduced dose

43. Idecabtagene Vicleucel (bb2121)
Ide-cel = idecabtagene vicleucel; TM = transmembrane.
Raje et al, 2018.
BCMA CAR T cell
Targeting
domain
Anti-BCMA
CD8 hinge/TM domain
4-1BB
CD3 ζ
Hinge/
TM domain
Costimulatory
domain
T-cell
activation
domain
Intracellular domain
Extracellular domain
Ide-Cel CAR Design
SP Anti-BCMA scFv CD3 ζ
4-1BB
MND CD8
Tumor-binding
domain
Signaling domains
Linker
Promoter
Ide-cel is a second-generation CAR construct
• Autologous T cells transduced with a lentiviral
vector encoding CAR specific for BCMA
• Targeting domain: anti-BCMA
• Costimulatory domain: 4-1BB
• T-cell activation domain: CD3 ζ
4-1BB associated with less toxicity and
more durable CAR T-cell persistence than
CD28 costimulatory domain

44. Eligible
patients
Eligibility for many CAR T-cell trials generally includes
≥3 prior lines of therapy, including a proteasome inhibitor, an IMiD, and daratumumab
Refractory to last line of therapy
Adequate hematologic function, renal function
2-week hospitalization for
monitoring and managing side
effects
Hospitalization
One treatment followed by observation: “one and done”
Bridging treatment
Schema of CAR T-Cell Treatment (Ide-Cel)
Ide-cel = idecabtagene vicleucel.
Munshi et al, 2020; Munshi et al, 2021.

45. KarMMA: Best Overall Response
Munshi et al, 2020.
Primary (ORR >50%) and key secondary (CRR >10%) end points met in the ide-cel–treated
population
ORR of 73% (95% CI, 65.8-81.1; P<0.0001)
CRR (CRIsCR) of 33% (95% CI, 24.7-40.9; P<0.0001)
Median time to first response of 1.0 month (range, 0.5-8.8); median time to CR of 2.8 months
(range, 1.0-11.8)
Median follow-up of 13.3 months across target dose levels
MRD: defined as <10−5 cells by next generation sequencing
Primary (ORR >50%) and key secondary (CRR >10%) end points met in the ide-cel–treated population
ORR of 73% (95% CI, 65.8-81.1; P<0.0001)
CRR (CRIsCR) of 33% (95% CI, 24.7-40.9; P<0.0001)
Median time to first response of 1.0 month (range, 0.5-8.8); median time to CR of 2.8 months (range,
1.0-11.8)
Median follow-up of 13.3 months across target dose levels

46. Progression-Free Survival in Ide-Cel
Munshi et al, 2020; Munshi et al, 2021.

47. Idecabtagene Vicleucel (cont.)
Munshi et al, 2021; NCCN, 2022.
KarMMa trial
73% of patients had a response
33% of patients had a complete response or better
Median progression-free survival was 8.8 months
Common adverse events:
Neutropenia (91%)
Anemia (70%)
Thrombocytopenia (63%)
Cytokine release syndrome (84%)
Neurotoxic effects (18%)
NCCN guidelines
Indicated for patients who have had ≥4 prior therapies, including the following:
Anti-CD38 monoclonal antibody
Proteasome inhibitor
Immunomodulatory agent

48. CARTITUDE-1: Cilta-Cel, Phase 1b/2
Clita-cel = ciltacabtagene autoleucel; cy = cyclophosphamide; flu = fludarabine; PK = pharmacokinetics; PD = pharmacodynamics.
Martin et al, 2021; Karlin, 2021; Berdeja et al, 2020.
Median administered dose:
0.71x106 (range 0.51–0.95x106) CAR+ viable T cells/kg Follow-up
Posttreatment assessments
(Day 101 up to end of cohort)
Safety, efficacy, PK, PD, biomarker
Post-infusion assessments (Day 1 to 100)
Safety, efficacy, PK, PD, biomarker
Cilta-cel infusion
Target: 0.75×106 (0.5–1.0×106)
CAR+ viable T cells/kg (Day 1)
Cy (300 mg/m2) + Flu (30 mg/m2)
(day -5 to -3)
Bridging therapy (as needed)
Apheresis
Screening (1 to ≤28 days)
VHH
VHH
Binding domains
CD3z
4-1BB
Cilta-cel
2 BCMA-targeting single-domain
antibodies designed to confer avidity

49. CARTITUDE-1: Efficacy Response
Martin et al, 2022.
Median time to first response was 1 month (range,
0.9–10.7)
Median time to best response was 2.6 months
(range, 0.9–17.8)
Median time to CR or better was 2.9 months
(range, 0.9–17.8)
Median duration of response was not estimable
(21.8 months–NE)
3.1%
12.4%
82.5%
0%
20%
40%
60%
80%
100%
Patients,
%
ORRa: 97.9% (95/97)
sCR VGP
R
PR
Best response =
≥VGPR:
94.9%
sCR:
82.5%
Responses deepened over time from the 1-year follow-up
Best response
at any time
Median–1 year
follow-up
Median–2 years
follow-up
sCR, % 67 83

50. CARTITUDE-1: PFS and OS
Martin et al, 2022; Martin et al, 2021.
80 80 78 73 71 64 61 35 19 4 1 1
2-year PFS: 71.0% (95% CI, 57.6–80.9)
Median PFS not reached (95% CI, 25.2–NE)
0
sCR patients
All patients sCR patients
Patients
(%)
100
80
60
40
20
0
0 3 6 9 12 15 18
Months
21 24 27 30 33 36
Progression-Free Survival
Patients at risk
All patients 97 95 85 77 74 67 63 36 19 4 1 1 0
2-year PFS: 60.5% (95% CI, 48.5–70.4)
Median PFS not reached (95% CI, 22.8 months–NE)
100
80
60
40
Patients
(%)
20
0
0 3 6 9 12 15 18
Months
21 24 27 30 33 36
Overall Survival
Patients at risk
All patients 97 96 91 88 85 81 78 46 23 8 2 1 0
2-year OS: 74.0% (95% CI, 61.9–82.7)
Median OS not reached (95% CI, 27.2 months–NE)

51. CAR-T Toxicity
Bonifant et al, 2016.

52. Managing CAR-T Toxicity: CRS
ICU = intensive care unit.
Schubert et al, 2020.
Grade 1: supportive management
Antipyretics, IV hydration
Infection diagnostic workup; initiate anti-infective treatment
Grade 2: continue grade 1 strategies plus…
IV fluid boluses
Supplemental oxygen
Tocilizumab ± corticosteroid
Grade 3: continue grade 1 strategies plus…
Consider ICU management
Vasopressor support and/or supplemental oxygen
Tocilizumab + corticosteroid
Grade 4: continue grade 1 strategies plus….
ICU management
Vasopressor support and/or supplemental oxygen via positive pressure
Tocilizumab + dexamethasone/methylprednisolone

53. Teclistamab: BCMA × CD3 T-Cell Redirecting Bispecific Antibody
Usmani et al, 2021; Moreau et al, 2021; Tecvayli® prescribing information, 2022.
T-cell redirecting bispecific antibody that binds to
CD3 on T cells and BCMA on plasma cells
The phase 1 portion of the MajesTEC-1 study
identified the RP2D for teclistamab monotherapy:
1.5 mg/kg subcutaneous (SC) QW with step-up
doses of 0.06 and 0.3 mg/kg

54. MajesTEC-1: Overall Response Rate
Moreau et al, 2021.
ORR of 62.0% (95% CI: 53.7–69.8)
represents a substantial benefit for
patients with triple-class–exposed
disease
Median time to first response: 1.2
months (range: 0.2–5.5)
MRD negativity rate
24.7% at a threshold of 10-5
16.7% at a threshold of 10-6
In patients who achieved ≥CR, the MRD-
negativity rate was 41.9%

55. MajesTEC-1: Overall Safety Profile
Moreau et al, 2021.
Teclistamab was well tolerated; no patients required dose reduction
Only 1 patient discontinued due to an AE (adenoviral
pneumonia)
Serious AEs occurred in 88 patients (53.3%)
Teclistamab-related serious AEs occurred in 33 patients
Injection-site reactions occurred in 58 patients (35.2%; all grade
1/2)
Infections occurred in 104 (63%) patients (grade 3/4: 35.2%)
9 (5.5%) patients had opportunistic infections
119 patients (72.1%) had evidence of hypogammaglobulinemia
41 of these patients received IVIG at any time during the study (at
physician discretion)
There were 9 deaths due to AEs; none were related to
teclistamab
COVID-19 (n=7)
Pneumonia (n=1)
Hemoperitoneum (n=1)
Safety Analysis Set
N=165
AEs ≥20%, n (%) Any Grade Grade 3/4
Hematologic
Neutropenia 108 (65.5) 94 (57.0)
Anemia 82 (49.7) 57 (34.5)
Thrombocytopenia 63 (38.2) 35 (21.2)
Lymphopenia 56 (33.9) 53 (32.1)
Nonhematologic
CRS 118 (71.5) 1 (0.6)
Injection site erythema
42 (25.5) 0 (0)
Fatigue 41 (24.8) 3 (1.8)
Nausea 40 (24.2) 1 (0.6)
Headache 36 (21.8) 1 (0.6)
Diarrhea 34 (20.6) 4 (2.4)

56. Talquetamab: GPRC5D × CD3 Bispecific Antibody
Krishnan et al, 2021.
GPRC5D is highly expressed on
MM plasma cells
Talquetamab binds to GPRC5D
and CD3 receptors, mediating T-
cell recruitment, activation, and
subsequent lysis of MM cells
In the ongoing phase 1, RP2D was
identified as a weekly SC dose of
405 µg/kg

57. MonumenTAL-1: Overall Response Rate
Krishnan et al, 2021
16.7% 14.3%
40%
33.3%
3.3%
9.5%
10%
9.5%
0
10
20
30
40
50
60
70
80
sCR
CR
VGPR
PR
Response
405 µg/kg
SC QW
n=30
800 µg/kg
SC Q2W
n=25
Median follow-up (months), median
median (range)
9.0 (0.9–17.1) 4.8 (0.4–11.1)
Response-evaluable patients, n 30 21
ORR, n (%) 21 (70.0) 14 (66.7)
ORR in triple-class–refractory
patients, n/N (%)
15/23 (65.2) 12/18 (66.7)
ORR in penta-drug–refractory
patients, n/N (%)
5/6 (83.3) 5/6 (83.3)
Median time to first confirmed
response (months), median (range) 0.9 (0.2–3.8) 1.2 (0.2–6.8)
70.0%
(21/30)
66.7%
(14/21)
≥VGPR:
52.4%
≥VGPR:
53.3%
405 µg/kg SC QW 800 µg/kg SC Q2W
ORRa
Patients
(%)
ORR appears to be comparable across both RP2Ds

58. Cevostamab: FcRH5 x CD3 Bispecific Antibody
Li et al, 2017; Sumiyoshi et al, 2021; Cohen et al, 2020; Trudel et al, 2021.
Fc receptor-homolog 5 (FcRH5)
Expressed exclusively in B-cell lineage
(myeloma cells > normal B cells)
Near ubiquitous expression on myeloma cells
Cevostamab bispecific antibody
Targets membrane-proximal domain of FcRH5
on myeloma cells and epsilon domain of CD3 on
T cells
Dual binding results in T-cell directed killing of
myeloma cells
Anti-CD3
Fab region
Anti-FcRH5
Fab region
T cell
CD3
FcRH5
Activation
Apoptosis
Myeloma
cell

59. Cevostamab Response
Trudel et al, 2021.
Response observed at the 20mg target dose level
and above (N=143 patients)
ORR increases with target dose
ORR in C1 single step-up expansion (3.6/90mg):
29.0%
ORR in C1 double step-up expansion
(0.3/3.6/160mg): 54.8%
Response occurs early
Median time to first response: 1.0 mo (range:
0.7–5.9)
Response deepens over time
Median time to best response: 2.1 mo (range:
0.7–11.4)
MRD negativity by NGS (<10–5) detected in 7/10
evaluable patients with ≥VGPR
15.7%
23.3%
10.8%
25.0%
8.4%
6.7%
0
20
40
60
80
100
Patients
(%)
PR VGPR CR sCR
Best response rates in efficacy-evaluable patients by dose level
20–90mg
dose level
N=83
ORR: 36.1%
132–198mg
dose level
N=60
ORR: 56.7%
≥VGPR:
20.5%
≥VGPR:
33.3%
1.7%
1.2%

60. Summary of Trials With T-Cell Engagers
Harrison et al, 2020; Garfall et al, 2020; Rodriguez et al, 2020; Madduri et al, 2020; Chari et al, 2020; Cohen et al, 2020.
AMG701 Teclistamab TNB038B REGN5458 Talquetamab Cevostamab
Target BCMA BCMA BCMA BCMA GPCR5D FcHR5
N 75 84 38 45 137 51
P2D 18 mg 1,500 ug/kg NA NA 405 ug/kg -
Median lines of
treatment
6 (1-25) 6 (2-14) 7 (4-13) 5 (2-17) 6 (2-20) 6 (2-15)
Triple refractory 68% 95% NA 6.7% 79% 67%
Penta refractory NA 70% NA 53% 31% NA
Overall response 36% 64% 37% 35.6% 73% 53%
Complete
response
7% 19% 8% 31% NA 12%
Infection 17% 15% NA 47% 37% NA
CRS 9% 53% 21% 38% 47% 75%
Neurotoxicity 8% 5% NA 2% 5% NA

61. Bispecific Antibody Toxicity
Sedykh et al, 2018; Zhou et al, 2020; Suurs et al, 2019.
Cytokine release syndrome is fairly common, usually low grade
Neurotoxicity usually uncommon
Infusion reactions
Persistent cytopenias
Increased risk of infections

62. Combination Chemotherapy: VDT PACE
VDT PACE = bortezomib/dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide; MR = minimal response.
Lakshman et al, 2018.
Response category Response after first cycle, n Best response, n
CR + VGPR 10 (7.3%) 14 (10.3%)
CR + VGPR + PR 69 (50.7%) 74 (54.4%)
CR + VGPR + PR + MR 88 (64.7%) 93 (68.4%)

63. 0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
P
e
r
c
e
n
t
a
g
e
o
f
P
a
t
ie
n
t
s
sC R C R V G P R PR
F a v o r a b le
n = 9
O R R 8 8 %
O R R 2 0 %
13%
7%
11%
N o n -fa v o r a b le
n = 1 5
B C L 2 :B C L 2 L 1 ra tio fo r P a tie n ts w ith t(1 1 ;1 4 )
33%
33%
11%
(n=9) (n=15)
BCL2:BCL2L1 BCL2:BCL2L1
High Low
BCL2 and BCL2L1 (BCL-XL) quantitation using droplet
digital PCR performed on CD138-selected bone
marrow mononuclear cells collected at baseline
Inhibiting BCL2: Venetoclax
Kumar et al, 2017.
0
1 0
2 0
3 0
4 0
5 0
P
e
r
c
e
n
t
a
g
e
o
f
P
a
t
ie
n
t
s
sC R C R V G P R PR
A ll P a tie n ts
N = 6 6
t(1 1 ;1 4 )
n = 3 0
O R R 2 1 %
O R R 4 0 %
n o n -t(1 1 ;1 4 )
n = 3 6
O R R 6 %
6%
8%
13%
4%
10%
13%
3%
3%
3%
4%

64. Venetoclax: BCL2 Inhibitor
Kumar et al, 2020b.
Cycles 1–8: 21-day cycle, bortezomib 1.3 mg/m2 Days 1, 4, 8, 11 and dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12
Cycles 9+: 35-day cycle, bortezomib 1.3 mg/m2 Days 1, 8, 15, 22 and dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23
Randomization PD
PD
Venetoclax (800 mg qd) +
Bortezomib +
Dexamethasone
Placebo +
Bortezomib +
Dexamethasone
2:1
N=291
Key eligibility:
• RRMM
• 1–3 prior lines of therapy
• PI nonrefractory
Primary Endpoint:
• PFS (per IRC)
Key Secondary End points:
• ORR
• ≥VGPR
• OS
• QoL/PRO parameters
n=194
n=97
PFS was investigator assessed
in the final OS analysis

65. BELLINI Subgroups
Ven = venetoclax; Pbo = placebo..
Kumar et al, 2021
Patients PFS OS
Ven +
Bd
(n)
Pbo +
Bd
(n)
HR
(95% CI) P value
HR
(95% CI) P value
t(11;14) or BCL2high 74 40
0.32
(0.20–0.53)
<0.0001
0.82
(0.40–1.70)
NS
t(11;14) 20 15
0.12
(0.03–0.44)
0.0014
0.61
(0.16–2.32)
NS
BCL2high 66 32
0.37
(0.21–0.64)
0.0005
0.70
(0.32–1.51)
NS
Non-t(11;14) and 51 24
0.48
(0.26–0.90)
0.0215
0.86
(0.35–2.12)
NS
Hazard Ratios for PFS and OS by BCL2 Expression and t(11;14)
BCL2high
31%
8%
t(11;14)
7% 8%
7% 31%
8%
t(11;14) or BCL2high
Non-t(11;14) and BCL2high
31%
t(11;14)
BCL2high
7% 31%
8%
n=114
BELLINI Biomarker Subgroups
(n=240)

66. Iberdomide
IBER is an oral, potent novel CRBN E3 ligase modulator (CELMoD)
compound that co-opts CRBN to enable enhanced degradation of target proteins,
including Ikaros and Aiolos
IBER induces potent direct antimyeloma and immune-stimulatory activity in preclinical models
IBER is active in LEN- and POM-resistant myeloma cell lines and enhances cell-mediated killing
through immune stimulation
IBER = iberdomide.
Matyskiela et al, 2018; Bjorklund et al, 2020; van de Donk et al, 2020.

67. Iberdomide-Dexamethasone
Lonial et al, 2022.
Maximum tolerated dose was not
reached
Most common grade ≥3 adverse
events:
Neutropenia (45%)
Anemia (28%),
Infection (27%)
Thrombocytopenia (22%)
Serious adverse events occurred in 57
(53%) patients.
One (1%) treatment- related death
(sepsis) and five (5%) patients
discontinued iberdomide due to
adverse
In the dose-escalation cohort

68. Iberdomide Combinations
van de Donk et al, 2020.

69. Salvage High-Dose Therapy (HDT)
Cook et al, 2014.

70. ReLAPSE: Len-Dexamethasone ± Salvage ASCT
ASCT = autologous SCT; ITT = intention to treat;
PD = progressive disease; PBSC = peripheral blood stem cell;
HDCT = high-dose chemotherapy.
Goldschmidt et al, 2021.

71. ReLAPSE: PFS/OS
Goldschmidt et al, 2021.

72. Role of MRD in Relapse Setting
POLLUX = daratumumab/lenalidomide/dexamethasone; CASTOR = daratumumab/bortezomib/dexamethasone
Avet-Loiseau et al, 2021.

73. CLINICAL TRIALS!

74. The Future? MyDRUG
RAS = rat sarcoma; IDH = isocitrate dehydrogenase; CDK = cyclin-dependent kinase; FGFR3 = fibroblast growth factor receptor 3.
Clinicaltrials.gov, 2021a.
Other
No detectable actionable
alterations
Daratumumab
+ IPd
RAF/RAS
mutations
Cobimetinib
+ dex
Cobimetinib
+ IPd
IDH activating
mutations
Enasidenib
+ dex
Enasidenib
+ IPd
CDK pathway
activating
alterations
Abemaciclib
+ dex
Abemaciclib
+ IPd
FGFR3
activating
alterations
Erdafitinib
+ dex
Erdafitinib
+ IPd
t(11;14)
Venetoclax
+ IPd
Other
activating
alterations
Other
inhibitor
Other inhibitor
+ IPd
Profiling for alterations (NCT02884102)
Genetic abnormality
Therapeutic regimen
Functional high-risk patients
Other
+ IPd
NCT03732703

75. Key Takeaways
Therapeutic advances have led to prolonged survival in MM, but it remains a
chronic disease
Treatment of MM requires a long-term strategy
The key is delivering the best “package” of treatment at a given stage
Optimal combinations and sequencing are key
Switching to regimens with new drug classes offers best outcomes
The future will be developing more individualized approaches

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77. References (cont.)
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78. References (cont.)
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