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 Dr. Rahul Banerjee, Assistant Professor at the University of Washington and Fred Hutchinson Cancer Center, will provide a case-based discussion on leveraging BCMA-directed antibody-drug conjugates, CAR T-cell therapies, and bispecific T-cell engagers to improve outcomes for patients with multiple myeloma in need of additional treatment options. STATEMENT OF NEED Multiple myeloma is a disease that remains incurable for most patients, many of whom become refractory to the majority of available treatments (Kumar et al, 2022). It is estimated that 35,730 new cases of multiple myeloma are diagnosed in the United States annually, and 12,590 people die of the disease (Siegel et al, 2023). Agents targeting B-cell maturation antigen (BCMA), including antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers, represent a promising therapy class for patients in need of additional treatment options, including those with higher genetic risk and heterogeneity (Kumar et al, 2022). This activity led by Rahul Banerjee, MD, FACP, Assistant Professor in the Division of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Center, will provide strategies for leveraging BCMA-directed therapies for improved patient outcomes in relapsed/refractory multiple myeloma. TARGET AUDIENCE Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with multiple myeloma (MM). LEARNING OBJECTIVES Upon completion of this activity, participants should be able to: Evaluate the mechanisms of action, efficacy, and safety of BCMA-directed therapies in relapsed/refractory MM Assess guideline-recommended combination and sequential treatment strategies for relapsed/refractory MM Identify risk factors for the development of treatment-specific adverse events with different classes of BCMA-directed therapies Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies Examine the roles of gene expression profiling, soluble BCMA, and measurable residual disease (MRD) in clinical practice.

1. Leveraging BCMA-Directed Therapies to Improve
Patient Outcomes in Relapsed/Refractory Multiple
Myeloma
Rahul Banerjee, MD, FACP
Assistant Professor, Division of Medical Oncology
University of Washington
Fred Hutchinson Cancer Center

2. Disclosures
Consultant: BMS, Caribou Biosciences, Genentech, Janssen, Sanofi,
SparkCures
Grants/research support: Pack Health
i3 Health has mitigated all relevant financial relationships

3. Learning Objectives
BCMA = B-cell maturation antigen; MM = multiple myeloma.
Evaluate the mechanisms of action, efficacy, and safety of BCMA-directed
therapies in relapsed/refractory MM
Assess guideline-recommended combination and sequential treatment
strategies for relapsed/refractory MM
Identify risk factors for the development of treatment-specific adverse events
with different classes of BCMA-directed therapies
Describe mechanisms of drug resistance/loss of response to BCMA-directed
therapies
Examine the roles of gene expression profiling, soluble BCMA, and
measurable residual disease (MRD) in clinical practice

4. Classifying Relapsed or
Refractory MM

5. Case Study 1
CT = computed tomography; SPEP = serum protein electrophoresis; IgG = immunoglobulin G; ISS = International Staging System;
GERD= gastroesophageal reflux disease; PC = plasma cell; FISH = fluorescence in situ hybridization.
65-year-old woman with incidentally-noted lytic lesions on a CT scan
obtained after a minor motor vehicle accident
Further workup:
Calcium, creatinine, hemoglobin normal
SPEP: M-spike 2.3 g/dL (IgG kappa), kappa 430.0 mg/L, lambda 35.0 mg/L
Whole-body CT: multiple lytic lesions with no fractures
ISS stage I disease (albumin 4.0 g/dL, beta-2 microglobulin 1.6 mg/L)
Past medical history:
Hypertension, on lisinopril; GERD, on as-needed pantoprazole
Bone marrow biopsy:
25%-30% PCs on core biopsy
FISH: t(4;14) noted on CD138-enriched FISH
Newly Diagnosed Multiple Myeloma

6. Helpful Diagnostic Tests in MM: Part 1
IFE = immunofixation; CBC = complete blood count; CMP = complete metabolic panel; B2 = beta-2; LDH = lactate dehydrogenase; IgA = immunoglobulin A;
IgM = immunoglobulin M; UPEP = urine protein electrophoresis; IMWG = International Myeloma Working Group.
Blood testing:
Helpful: SPEP, serum IFE, free light chains
Helpful: CBC, CMP
Helpful: B2 microglobulin, LDH, albumin as above (for staging)
Sometimes helpful: IgG, IgA, IgM
IgA levels sometimes easier to track than M-spikes for IgA myeloma
Unhelpful: B2 glycoprotein antibody (that’s for anti-phospholipid syndrome!)
Urine testing:
Sometimes helpful: 24-hour urine total protein, UPEP, urine IFE
Note that UPEP’s “total protein” assay not considered to be as accurate
Not helpful: urine free light chains
Unclear how to use these in clinical practice, since not in IMWG guidelines

7. Helpful Diagnostic Tests in MM: Part 2
MRD = measurable residual disease; AL = amyloid light chain; PET-CT = positron emission tomography/CT; MRI = magnetic resonance imaging.
Bone marrow biopsy:
Helpful: PC percentage by immunohistochemical staining of core biopsy
Aspirate generally not considered to be as accurate
If “patchy” but areas above >60%, reasonable to consider as MM-defining
Unhelpful (at diagnosis): PC percentage by flow cytometry
Plasma cells often die or inaccurately labeled on flow cytometry
Flow is more useful to identify MRD (more on this in next section)
Helpful only if positive: Congo Red staining of blood vessels in marrow
Yield of separate fat pad biopsy much higher if AL amyloidosis suspected
Cross-sectional imaging:
Helpful: PET-CT, whole-body CT, or whole-body MRI
CT focuses on bone, while MRI focuses on marrow (complementary)
Not helpful: skeletal surveys
X-ray survey can miss certain bones and early bone damage from myeloma

8. Case Study 1 (cont.)
Dara-VRd = daratumumab/bortezomib/lenalidomide/dexamethasone; VZV = varicella zoster virus; VTE = venous thromboembolism;
VGPR = very good partial response; ASCT = autologous stem cell transplantation.
Treated with first-line Dara-VRd:
Daratumumab subcutaneously
Bortezomib subcutaneously
Lenalidomide orally
Dexamethasone 40 mg  20 mg once per week
Supportive care: acyclovir (VZV), apixaban (VTE), vitamin D (bone strength)
Also started on zoledronic acid for bone strength
Best response to induction therapy: VGPR
Serum M-spike (IgG kappa) decreases from 2.3 g/dL to 0.1 g/dL
Bone marrow biopsy with <5% PCs; conventional flow negative as well
Note: daratumumab and isatuximab are themselves IgG kappa antibodies!
Proceeds to ASCT with melphalan 200 mg/m2
Treatment Course

9. Case Study 1 (cont.)
VRd = bortezomib/lenalidomide/dexamethasone.
What post-ASCT strategy would you recommend?
a. Lenalidomide maintenance for 1 year, then stop
b. Lenalidomide maintenance indefinitely
c. Bortezomib/lenalidomide (VR) doublet with bortezomib every 1-2 weeks
d. Bortezomib/lenalidomide/dex (VRd) with twice-weekly bortezomib
Question 1

10. Case Study 1 (cont.)
Question 1
What post-ASCT strategy would you recommend?
a. Lenalidomide maintenance for 1 year, then stop
b. Lenalidomide maintenance indefinitely
c. Bortezomib/lenalidomide (VR) doublet with bortezomib every 1-2
weeks
d. Bortezomib/lenalidomide/dex (VRd) with twice-weekly bortezomib

11. Case Study 1 (cont.)
Nooka et al, 2014; Gay et al, 2021.
Given her high-risk cytogenetics with t(4;14), she receives doublet
maintenance with bortezomib and lenalidomide
Rationale: the “Emory paper” where patients with high-risk cytogenetics
received VRd consolidation after ASCT until progression
Caveat #1: single-arm trial with no control group
Caveat #2: in real-world practice, I often drop the dexamethasone and space
the bortezomib out to once every 2 weeks
More recent example from FORTE trial of carfilzomib and lenalidomide (KR)
maintenance versus lenalidomide (R) alone:
No high-risk features: 3-year PFS 90% (KR) vs 73% (len alone)
1+ high-risk features: 3-year PFS 69% (KR) vs 56% (len alone)
Interestingly: KR outperformed R in all high-risk subgroups except amp(1q)
Post-ASCT Maintenance

12. Case Study 1 (cont.)
BMBx = bone marrow biopsy; CR = complete response; VR = bortezomib/lenalidomide; PD = progressive disease.
Month Serum M-Spike Notes or Actions
1/2022 2.3 g/dL First cycle of Dara-VRd
5/2022 0.1 g/dL Fifth cycle of Dara-VRd. VGPR as best response
6/2022 N/A ASCT with melphalan 200 mg/m2
9/2022 0 BMBx with stringent CR. MRD not assessed
10/2022 0 Initiation of VR maintenance (note: GRIFFIN used consolidation)
1/2023 0 -
4/2023 0.2 g/dL -
5/2023 0.3 g/dL -
6/2023 0.6 g/dL Unconfirmed PD (M-spike rise by ≥25% and ≥0.5 g/dL)
6/2023 0.6 g/dL Confirmed PD
6/2023 0.6 g/dL BMBx with 20% PCs. No anemia, renal insufficiency, or bone lesions
Biochemical Progression

13. How Do We Define Relapsed/Refractory MM?
FLC = free light chain; LC = light chain; CRAB = hypercalcemia/renal insufficiency/anemia/bone lesions; EMD = extramedullary disease.
Kumar et al, 2016; Zamir et al, 2021.
Most commonly: biochemical progression
Serum M-spike rise by ≥25% (and ≥0.5 g/dL)
Difference in FLC rise by ≥25% (and ≥100 mg/L, ie ≥10 mg/dL)
Only for LC-only disease, eg if M-spike was never ≥1 g/dL
25% increase in bone marrow PC burden (and ≥10% absolute increase)
Only for oligosecretory disease, eg if M-spike and LC never really measurable
Blood tests require confirmation on repeat draw
Less commonly: new CRAB criterion
“Oligosecretory relapse” or “EMD relapse”: blood tests remain normal, but new
lytic lesion/fracture
~10%-15% of relapses are oligosecretory, and these become more common
with later lines of therapy

14. How Many Lines of Therapy Has She Received?
aA discontinued regimen restarted at a later date will be counted as a new line of therapy if there were ≥1 other regimens administered in between. Restarting
the same regimen (even with dose modifications) without any other intervening regimen is not considered a new line.
SCT = stem cell transplant.
Rajkumar et al, 2015.
Counting isn’t easy in MM!
She has received 1 line of therapy because
everything, including the ASCT and
doublet maintenance, was planned
If she had received chemomobilization with
stem cell collection, this still would be 1 line
of therapy
General rules of thumb:
Any unplanned addition or substitution of
therapy is considered a new line
Switching therapies due to toxicities does
count as a new line even if in remission
Why do lines of therapy matter?
Guidelines for Counting Lines of Therapy in Myeloma
Definition of a new
line of therapy
Comment
Discontinuation of 1
treatment regimen
and start of anothera
The reasons for discontinuation, addition,
substitution, or SCT do not influence how lines
lines are counted. It is recognized that reasons
reasons for change may include end of
planned therapy, toxicity, progression, lack of
of response, inadequate response, etc
Unplanned addition of
of substitution of ≥1
≥1 drugs in a regimen
regimen
-
In patients
undergoing >1 SCT,
each SCT
(autologous or
allogeneic) is
considered a new line
line of therapy
Note that a planned tandem SCT is an
exception and is considered 1 line. Planned
induction and/or consolidation, maintenance
maintenance with any SCT (frontline, relapse,
relapse, autologous, or allogeneic) is
considered 1 line

15. Relapsed/Refractory MM: the Numbers
Nikolau et al, 2022; Giri et al, 2022.
In the year 2020:
127,000 patients with MM in the US
106,000 on any type of treatment
57,000 currently on first-line
27,000 currently on second-line
5,000 currently on ≥fifth-line
Currently: CAR T and bsAbs are only
approved as fifth or later line
Real-world analysis: patients almost
twice as likely to die as they are to receive
a fifth line of therapy

16. What About Triple-Class–Refractory Status?
PI = proteasome inhibitor; IMID = immunomodulatory imide; MAb = monoclonal antibody; Isa-Kd = isatuximab/carfilzomib/dexamethasone;
KRd = carfilzomib/lenalidomide/dexamethasone; Dara-Pd = daratumumab/pomalidomide/dexamethasone.
Costa et al, 2023.
Triple-class refractory (TCR): refractory to
≥1 PI, ≥IMID, and ≥CD38 Mab
For example, PD after:
Dara-VRd  ASCT  len, (1 prior line)
VRd  ASCT  len, then Isa-Kd (2 prior lines)
VRd  ASCT  observation historically, then KRd,
then Dara-Pd thereafter (3 prior lines)
Advantages of TCR nomenclature:
Better reflects disease biology and treatment
Doesn’t “disadvantage” patients who received
quadruplet induction therapy upfront
In 1 study, TCR status outperformed number of
lines of therapy as negative prognostic indicator Odds ratio for overall response
to current therapy

17. Noteworthy Chromosomal Aberrations in RRMM
RRMM = relapsed/refractory MM; R2-ISS = second revision of the International Staging System.
Abdallah et al, 2020; D’Agostino et al, 2022; Lannes et al, 2023; Schmidt et al, 2021.
Established FISH risk factors with negative prognosis:
del(17p) [carries p53 gene]
t(4;14), t(14;16), or t(14;20)
In general, any chromosome 14 translocation apart from t(11;14)
Note: R2-ISS doesn’t include t(14;16) as high risk. Most of us still do
What about copy number gains of 1q (CKS1B gene)?
Unequivocally more common in RRMM than newly diagnosed MM
Nomenclature: gain(1q) = 3 copies or amp(1q) = ≥4 copies
amp(1q) generally thought of as bad, eg FORTE study previously
gain(1q) more controversial. Driver aberration or passenger aberration?
New research: gain(1q) & amp(1q) probably there since diagnosis in very small
clones, and evolutionary pressure leads to their amplification

18. Gene Expression Profiling (GEP) in RRMM
MGUS = monoclonal gammopathy of uncertain significance.
Shah et al, 2020; Heuck et al, 2014; Zhan et al, 2007.
2 commercially available tests
SKY92
GEP70 (the “Arkansas” model)
Similar principle to 21-gene breast cancer testing
Also commercially available, also with concerns about insurance reimbursement
However, these tests are not yet routinely used to change management as they are in
patients with hormone receptor–positive breast cancer
In post hoc analysis of Myeloma XI, SKY92 high-risk patients:
Comprised 12% of patients (n=161) with no high-risk FISH findings
Had shorter PFS in regression even after adjusting for high-risk FISH
Did no better with post-ASCT lenalidomide than with observation
Conversely, “MGUS-like” GEP pattern has better prognosis

19. Other Noteworthy RRMM Abnormalities
OS = overall survival.
Davies et al, 2022; Rodríguez-Otero et al, 2019.
Bad: specific gene mutations
Eg, deletion or knockout mutation of TP53 gene
Previously called “double hit” if patient also has del(17p) [other copy missing]
MYC pathway dysregulation more often in RRMM than newly diagnosed MM
Bad: chromothripsis (chromosomal “shattering”)
Bad: proliferative indices such as S-phase ≥2%
Good: “MGUS-like” phenotype based on flow cytometry
Algorithm of total, total clonal, and total non-clonal PCs in bone marrow
10-year OS in 1 study: 41% in patients with “MGUS-like” phenotype, versus 20%
in patients with “MM-like” phenotype
Similar to findings from “MGUS-like” GEP signature mentioned previously

20. What About “Functional High-Risk” RRMM?
PFS = progression-free survival.
Kansagra et al, 2021; Facon et al, 2022.
In my opinion, the most anxiety-provoking type of RRMM!
Varying definitions, but normally either:
Relapse within 18 months of initiation of first-line therapy
Relapse within 12 months of ASCT
Why is this type of myeloma so concerning?
We don’t always know who these patients are a priori!
Anywhere from 20%-60% of functional high-risk patients have high-risk FISH
Does the lack of durable response to first line recur?
Yes, in the IKEMA study of Isa-Kd in patients with 1-3 prior lines
PFS 24.7 months in patients who were functional high-risk (based on last line)
Versus PFS 35.7 months (ie, a full year shorter) in all-comers receiving Isa-Kd

21. Miscellaneous High-Risk Features in RRMM
Goldman-Mazur et al, 2023; Jiménez-Segura et al, 2022; Sidana et al, 2019; Fernández de Larrea et al, 2021.
Clinical progression instead of biochemical
progression
Eg, oligosecretory relapse with new lytic lesions
In retrospective analyses, patients who are treated for
biochemical progression rather than clinical progression
(eg, new CRAB) have better outcomes
Caveat: perhaps related to early treatment being associated
with better outcomes
EMD in general
True soft-tissue plasmacytomas are worse
than paraskeletal EMD originating in a bone
Circulating PCs at any point
Reminder: cutoff for PC leukemia now ≥5% circulating
PCs, not ≥20%
Types of EMD
Soft-
tissue
Para-
skeletal

22. Case Study 1 (cont.)
High-risk cytogenetics: t(4;14) at diagnosis
Functional high-risk: relapse ≤18 months of starting
Triple-class-exposed: received Dara-VRd with first cycle
Note: not triple-class-refractory yet, since dara not part of maintenance
CD38 retreatment very reasonable, but response likely won’t last as long
What are our options now?
Clinical trial (perhaps of a bsAb or CAR T therapy?)
Dara-Kd, Isa-Kd, Dara-Pd, Isa-Pd, KPd, or Elo-Pd
Main components here: carfilzomib or pomalidomide
For aggressive relapses: inpatient chemotherapy, eg VD-PACE, DCEP, hCVAD
What will be our options once at 4+ prior lines?
How Does Our Patient Fit in?
KPd = carfilzomib/pomalidomide/dexamethasone; elo = elotuzumab;
VD-PACE = bortezomib/dexamethasone/cisplatin/doxorubicin/cyclophosphamide/etoposide; DCEP = dexamethasone/cyclophosphamide/etoposide/cisplatin;
hCVAD = cyclophosphamide/vincristine/doxorubicin/dexamethasone.

23. BCMA as a Diagnostic and
Therapeutic Target

24. What is BCMA?
TNF = tumor necrosis factor; APC = antigen-presenting cell; APRIL = A proliferation–inducing ligand; BAFF = B cell–activating factor.
Yang et al, 2005; Jiang et al, 2011.
B-cell maturation antigen (BCMA):
Part of the TNF superfamily, found on B cells and plasma cells
Used for immune cell activation, including activation of APC functionality
Natural ligands: proteins like APRIL and BAFF, also found on B cells
Help B cells to signal each other to survive and to produce antibodies
In contrast: GPRC5D (target of talquetamab) is an “orphan” with no known ligand
What happens to BCMA knockout mice?
Expected: fewer and shorter-lived plasma cells
Unexpected: worsened lupus and autoimmune manifestations
Perhaps a different repertoire of B cells if long-lived cells knocked out

25. What Is Soluble BCMA?
Visram et al, 2021; Salazar-Camarena et al, 2020.
Soluble BCMA (sBCMA):
Also called serum BCMA, since found in blood
Naturally cleaved at low levels by B cells and
plasma cells themselves
Responsible enzyme: gamma secretase (more
on this later)
Can soluble BCMA predict B-cell immunity?
To an extent, yes. Higher sBCMA levels shown
to correlate with lupus activity
Can soluble BCMA differentiate “good”
MGUS from “bad” MGUS?
Likely yes! sBCMA starts higher and rises faster
in patients who go on to develop MM
Patients with
MGUS who did
not develop MM
Patients with
MGUS who did
later develop MM

26. Can sBCMA Be a Prognostic Marker?
Jew et al, 2021; Bujarski et al, 2021.
Pros of using sBCMA as a prognostic marker
Newly diagnosed MM patients with “elevated” baseline sBCMA have worsened
outcomes versus those with “normal” sBCMA at diagnosis
Among patients with “elevated” sBCMA at baseline, those with subsequent
normalization have better survival than those who don’t
sBCMA is elevated even in patients with otherwise non-secretory MM
Cons of using sBCMA as a prognostic marker
Not routinely available in CLIA-certified labs yet
We don’t know what the true cutoff of normal versus elevated is
Not yet ready to guide treatment decision making

27. Does sBCMA Go Down With Treatment?
Bujarski et al, 2021; Girgis et al, 2023.
In general, yes!
sBCMA is thought to be a reliable marker
of total in vivo plasma cell burden
sBCMA half-life approximately 24-36
hours, so much more reactive to changes
than M-spike
Are sBCMA kinetics different with BCMA-
targeting versus non–BCMA-targeting
therapies?
No, in at least 1 study of teclistamab
(BCMA bsAb) versus talquetamab
(GPRC5D bsAb)
sBCMA likely does not “distract” BCMA-
directed therapies like we once thought

28. Does sBCMA Go All the Way to Zero?
ide-cel = idecabtagene vicleucel.
Usmani et al, 2022.
Not quite, but perhaps below our
detectable limit
In the KarMMa-2 trial of ide-cel (more
on this in a few slides), 68% of patients
“cleared” sBCMA
Caveat #1: lower detectable limit
depends on assay
Caveat #2: no clear consensus on
what defines “clearance”
Interesting tidbit:
sBCMA eventually recovers (normal
plasma cell reconstitution once BCMA
CAR T cells disappear?)

29. How Can BCMA on Myeloma Cells Be Targeted?
axi-cel = axicabtagene ciloleucel; cilta-cel = ciltacabtagene autoleucel; NK = natural killer.
Romano et al, 2021; Hoffman et al, 2022; Drago et al, 2021; IMF, 2022; Ordóñez-Reyes et al, 2022; Cancer.org, 2022; Zhang et al, 2022.
Class of Drug Noteworthy Mechanism Examples
“Naked” antibody
(Eg, daratumumab but with BCMA)
Antibody-dependent cellular
cytotoxicity
SEA-BCMA
Antibody-drug conjugate
(Eg, gemtuzumab ozogamicin but
with BCMA)
Direct cell death using lethal
“warhead” on antibody
Belantamab mafodotin, removed from
from US market in 2022
Bispecific antibodies
(Eg, blinatumomab but with BCMA)
Direct cytotoxicity from native T
T cells
Teclistamab. Many more in
development (more soon)
CAR T cell therapies
(Eg, axi-cel but with BCMA)
Direct cytotoxicity from
engineered T cells, either
autologous or allogeneic
Ide-cel and cilta-cel. Many more in
development (more soon)
CAR-NK cell therapies
Direct cytotoxicity from
engineered NK cells, generally
allogeneic
Several in early-phase development
development

30. Focus on Ide-Cel (CAR-T) in 3+ Prior Lines
CRS = cytokine release syndrome; ICANS = immune effector cell–associated neurotoxicity syndrome.
USFDA, 2021; Abecma prescribing information, 2021; Munshi et al, 2021.
Idecabtagene vicleucel (ide-cel):
First BCMA CAR T therapy to gain FDA
approval, March 2021
Mouse-derived CAR
Seminal KarMMa-1 trial:
Median of 6 prior lines of therapy
ORR 73%, median PFS 8.8 months
Toxicities: 84% CRS, 18% ICANS
Pearls to remember:
BCMA CAR-T isn’t curative, unlike
with CD19 CAR T in lymphoma
Perhaps higher dose (closer to 450
million CAR-positive T cells) matters!

31. Focus on Ide-Cel (CAR-T) in 2-4 Prior Lines
Rodríguez-Otero et al, 2023.
KarMMa-3 trial:
First published randomized controlled
trial of CAR-T in myeloma
Population: 95% daratumumab-
refractory, 66% triple-class–refractory
Results:
Median PFS 13.3 months with ide-cel
versus only 4.4 months with control
(several triplet options)
Pearls to remember:
Using CAR T in earlier lines (ostensibly,
healthier T cells collected) does not
necessarily equate to better outcomes!

32. Focus on Ide-Cel (CAR-T) in Functional High Risk
Usmani et al, 2022.
KarMMa-2 cohort A:
Study specifically of ide-cel CAR-T in
functional high-risk (remember me?)
Results:
Median PFS 11.4 months
Pearls to remember:
IKEMA sub-analysis of “functional high-
risk” patients: median PFS of 24.7 months
with Isa-Kd
Big caveats: cross-trial comparison,
differences in how “functional” defined
Perhaps continued pressure with ongoing
Isa-Kd more helpful than “1 and done”
CAR-T therapy?
Progression-Free Survival
Median PFS was 11.4 months
(95% CI 5.6-19.6)
Median follow-up was 21.5 months
(range: 2-31 months)

33. Focus on Cilta-Cel (CAR-T) in 3+ Prior Lines
USFDA, 2022b; Jin et al, 2023; Berdeja et al, 2021; Martin et al, 2023.
Ciltacabtagene autoleucel (cilta-cel):
Second BCMA CAR-T therapy to gain FDA
approval in February 2022
Llama-derived “nanobody” CAR
Each individual CAR in cilta-cel has 2 heavy chains,
hence “bi-epitopic” BCMA binding
Seminal CARTITUDE-1 trial:
Median of 6 prior lines
ORR 98%, 27-month PFS 55%
Toxicities: 95% CRS, 21% ICANS
Rare cases of Parkinsonian symptoms that didn’t
resolve with steroids or levodopa
Pearls to remember:
Parkinsonian symptoms are possible

34. Focus on Cilta-Cel (CAR-T) After Prior BCMA
Cohen et al, 2023.
CARTITUDE-2 Cohort C:
Eligibility: triple-class–exposed and prior BCMA
ADC or BCMA bsAb
Small study (n=20), ORR 60%
Median PFS 9.1 months
Responders more likely to have been further
away from prior BCMA than non-responders
Pearls to remember:
How to sequence BCMA therapy comes up ALL
the time, including on the assessment
Bottom line: BCMA CAR-T might work after
prior BCMA, but (for many reasons) not as well
as it does in BCMA-naive patients

35. Investigational BCMA CAR-T Therapies
Zevor-cel = zevorcabtagene autoleucel; TCR = T-cell receptor; CMV = cytomegalovirus; GVHD = graft-versus-host disease; HLA = human leukocyte antigen.
Chen et al, 2022; Frigault et al, 2023; Martínez Bedoya et al, 2021; Mailankody et al, 2023.
Class: less immunogenic CAR Ts
Claim to fame: less immunogenic CARs are less likely to trigger “anti-drug antibodies”
(ADAs), eg native B cells attacking the CAR T cells
This is generally why CAR T reinfusions don’t work!
Examples:
Zevor-cel (CT0153), which is fully humanized
CART-ddBCMA, a synthetic molecule designed to lower ADA formation
Class: allogeneic CAR T cells
Claim to fame: “off-the-shelf” infusions from healthy donors
Healthier T cells with no risk of “out of specification” products
Minimal “brain to vein” time, hence no bridging required
Native TCR knocked out, so no need for HLA matching and no risk of GVHD
Cons: higher risk of infections from stronger lymphodepletion to promote T-cell
persistence, eg CMV reactivation as seen with ALLO-715

36. Focus on Teclistamab (BCMA bsAb)
US FDA, 2022a; Moreau et al, 2022.
Teclistamab:
First bsAb (CD3 and BCMA) approved in
myeloma, October 2022
“Off the shelf” similar to allo-CAR-T
Results:
Median 5 prior lines of therapy (78% had triple-
class-refractory disease)
Median PFS 11.3 months
CRS in 72%, neurotoxicity in 14%
Infections in 77% of patients; Grade 3+
infections in 45% of patients
Pearls to remember:
First cycle still generally requires hospitalization
for CRS monitoring
Infections are a big deal with bsAbs!
Worse than with
BCMA CAR-T!

37. Investigational BCMA BsAbs
Bumma et al, 2022; Sebag et al, 2021; Abdallah et al, 2022; Wong et al, 2022; D’Souza et al, 2022.
Class: bsAbs with potentially longer half-life
Claim to fame: longer persistence means less frequent dosing
Example #1: linvoseltamab (REGN5458), with humanized epitopes
Example #2: elranatamab (PF-06863135), with humanized epitopes
Example #3: HPN217, which also binds albumin to prolong half-life
Class: bsAbs with potentially improved binding
Claim to fame: better myeloma cell binding and T-cell activation
Example #1: alnuctamab (CC-93269), with 2 BCMA binding sites
Example #2: ABBV-383 (TNB-383B), with low-affinity T-cell binding to promote
a healthier T-cell response and fewer side effects
Are these hypotheses true? Time will tell!

38. How Will We Choose Between So Many Options?
orva-cel = orvacabtagene autoleucel.
Colonna et al, 2020; Harrison et al, 2020; Mailankody et al, 2022; Chari et al, 2022; Trudel et al, 2021.
Short answer: time
Many more products (eg, JCARH125/ orva-cel CAR-T and AMG 701/pavurutamab)
were once under investigation as well
FDA approval is appropriately a high bar in this crowded marketplace
Convenience for patients:
Within CAR T space: manufacturing interval, durations of response
Within bsAb space: subcutaneous dosing, less frequent dosing
What about non–BCMA-targeted approaches?
Not covered here for time reasons
May have different side effect profiles:
Eg, GPRC5D-targeted approaches have fewer infections but more dysgeusia
Examples:
MCARH109 CAR-T: binds GPRC5D
Talquetamab bsAb: binds GPRC5D
Cevostamab bsAb: binds FcRH5

39. What Are Toxicities To Look Out For? Part 1
aEnhanced bridging, which in large part lifted restrictions on what bridging could be used, likely helped lower the rates of Parkinsonism with CARTITUDE-1.
PLT = platelets; WBC = white blood cell count; PRN = as needed.
Yan et al, 2021; Banerjee et al, 2021; Cohen et al, 2022; Siegler & Kenderian, 2020; Asawa et al, 2022; Jain et al, 2023.
Toxicity Potential Risk Factors Established What’s on the Horizon
CRS: fevers,
less commonly hypoxia
hypoxia
Higher tumor burden,
higher CAR T-cell or
bsAb dose
Tocilizumab for
persistent grade 1 or
grade 2+, ± steroids
Prophylactic tocilizumab
tocilizumab to facilitate
outpatient bsAbs?
ICANS: delirium,
(other neuro deficits can
can occur)
Particular construct (eg,
(eg, CD28 costimulatory
costimulatory domain)
Corticosteroids, in rare
cases intrathecal
chemotherapy
“Smarter” bridging and
lymphodepletion
regimensa
Cytopenias: often
and PLTs. Can be
prolonged!
Tumor burden in bone
marrow, pre-therapy
cytopenias
Growth factors generally
generally fine after first
first week; PRN
transfusions
“Just-in-time” stem cell
collection and boost for
high-risk patients?

40. What Are Toxicities To Look Out For? Part 2
aFor example, monthly IVIG whenever IgG <400 mg/dL.
HLH = hemophagocytic lymphohistiocytosis; IEC-HS = immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome;
IVIG = intravenous immunoglobulin; LFT = liver function tests.
Kambhampati et al, 2022; NCCN, 2022; Hines et al, 2023.
Toxicity Potential Risk Factors Established What’s on the Horizon
Infections: particularly
relevant with continued
continued bsAb
treatment
Cytopenias, use of
tocilizumab or
corticosteroids
Antiviral prophylaxis,
perhaps levofloxacin in
first 3 months
Standardized IVIG
thresholdsa. CMV
monitoring?
IEC-HS: formerly called
“CAR-HLH.” LFTs and
coagulopathy
??? We’re still figuring
this out!
Anakinra alongside
concurrent CRS
management
??? We’re still figuring
this out!

41. Why Does BCMA Therapy Fail? Part 1
TME = tumor microenvironment.
Banerjee et al, 2022; Ahn et al, 2021.
Myeloma cells become resistant:
Shedding of BCMA (eg, as sBCMA)
Downregulation of BCMA surface antigen
BCMA genetic mutations that no longer bind epitope
on CAR T or bsAbs
“Trogocytosis”: they give the BCMA to the T cell
itself, leading to fratricide!
Potential solutions:
Gamma secretase inhibitors, eg nirogacestat:
Gamma secretase needed to shed BCMA
Dual-targeting CAR T cells, eg BCMA and CD19:
Hypothesis: CD19 on myeloma progenitor cells, and
targeting both together makes resistance harder
Myelom
cell
CAR-T
cell
TME

42. Why Does BCMA Therapy Fail? Part 2
CAR-T cells lose their grip:
T-cell exhaustion, eg from PD-L1 expression on
myeloma cells or microenvironment
T-cell clearance or neutralization, eg by host
response including antidrug antibodies
Potential solutions:
Post–CAR T nivolumab in certain cases?
Better CAR engineering as discussed earlier
Post–CAR T maintenance therapy?
Replacing TCR (TRAC locus) with CAR to more
naturally mimic T-cell activation?
In these cases, retreatment with a new BCMA
therapy might work!
Myeloma
cell
CAR-T
cell
TME
PD-L1 = programmed death ligand 1.
Banerjee et al, 2022; Atilla & Atilla, 2022; van de Donk et al, 2021.

43. Why Does BCMA Therapy Fail? Part 3
van de Donk et al, 2021; Banerjee et al, 2022.
Suppressive microenvironment:
Difficulty trafficking into extramedullary disease
Suppressive signals from T-regulatory cells, M2
macrophages, and myeloid-derived suppressor
cells
Potential solutions:
“Armored” CAR-T cells that don’t respond to PD-
L1 expression by other cells
“Armored” CAR-T cells that can self-produce IL-2
and other pro–T-cell cytokines
Myeloma
cell
CAR-T
cell
TME

44. Case Study 1 (cont.)
Now 67-year-old female with RRMM
Line 1: Dara-VRd to ASCT to doublet maintenance
Line 2: Isa-Kd
Receives a BCMA bsAb on a clinical trial as third line of therapy
Week 1: grade 1 CRS with second dose, requires tocilizumab in hospital
Week 2: tolerates first full dose in clinic
Week 3: continues with treatment in clinic
Week 4: continues with treatment, now every 2 weeks
Week 5: IgG 300 mg/dL, gets first dose of IVIG
Week 6: labs return with M-spike 0 and normal serum free light chains
Returning to Our Patient

45. Case Study 1 (cont.)
Which of the following is true regarding the logistics and value of
assessing for MRD negativity at this timepoint?
a. NGS MRD assessments won’t be possible unless she has had a
baseline sample with trackable clonal mutations identified
b. NGF MRD assessments won’t be possible unless she has had a
baseline sample with her myeloma-specific immunophenotype identified
c. If she is MRD-positive, we should consider re-escalating her to bsAb
therapy every 1 week instead of every 2 weeks
d. If she is MRD-negative, we should consider stopping bsAb therapy
Question 2

46. Case Study 1 (cont.)
Which of the following is true regarding the logistics and value of
assessing for MRD negativity at this timepoint?
a. NGS MRD assessments won’t be possible unless she has had a
baseline sample with trackable clonal mutations identified
b. NGF MRD assessments won’t be possible unless she has had a
baseline sample with her myeloma-specific immunophenotype identified
c. If she is MRD-positive, we should consider re-escalating her to bsAb
therapy every 1 week instead of every 2 weeks
d. If she is MRD-negative, we should consider stopping bsAb therapy
Question 2

47. Case Study 1 (cont.)
IFE = immunofixation electrophoresis; MS = mass spectrometry; SPEP = serum protein electrophoresis.
Zajec et al, 2020.
MRD Versus Conventional Testing
Unlike SPEP or IFE, MS
can differentiate a
therapeutic IgG kappa
mAb (eg, daratumumab)
from a pathologic IgG
kappa M-spike

48. What Exactly Is MRD in Multiple Myeloma?
ctDNA = circulating tumor DNA; ID = identification.
Bertamini et al, 2021; Arroz et al, 2016.
ctDNA in Solid Oncology MRD in Myeloma
Sampling Almost always off blood
Generally from bone marrow aspirate
Detection Always looking for DNA
NGF (next-generation flow) or NGS
(next-generation sequencing)
“Off the shelf”? Yes Yes for NGF, not for NGS
Replace the need
for PET imaging?
No. Imaging and blood-based
assessments are complementary
No. Imaging and marrow-based
assessments are complementary
Established usage
Detection of new targetable mutation
mutation
No clearly established usage yet
Method Advantages Disadvantages
NGS
• FDA-cleared assay
• Perhaps slightly better sensitivity
(only 1 cell required, not ~20)
• Requires a “fingerprinting” sample to ID
clones from an earlier bone marrow biopsy
biopsy
• This ID process not always successful
NGF
• Does not require ID sample; no risk
risk of failing to ID distinct clones
• Perhaps slightly lower sensitivity (~20 positive
positive events required to identify an
abnormal clone)

49. Why Is Achieving MRD Negativity Good?
sCR = stringent complete response.
Munshi et al, 2020; Jiménez-Ubieto et al, 2021.
MRD+
Subgroup analysis of PETHEMA VRd
 ASCT  VRd  Rd study

50. Can MRD Be a “Middle-Point” to Guide Treatment?
Dara-KRd = daratumumab carfilzomib lenalidomide dexamethasone; HRCA= high-risk cytogenetic abnormalities.
Costa et al, 2022.
Most mature data to date: MASTER trial
71% of cohort was able to stop therapy (“MRD sure”) altogether!
(Median follow-up: 14.2 months)

51. Future Directions for MRD in Multiple Myeloma
Can we check MRD from the blood?
ctDNA and mass spectrometry tools, or even personalized mass spectrometry based on
myeloma cells’ DNA, are all under investigation
Should we intensify treatment to “force” MRD negativity?
The most burning question! Does achieving MRD negativity reflect underlying indolent
disease biology and does ”forcing” it in less indolent biology change that?
For now, we do not recommend doing this
What does “MRD resurgence” without clinical PD mean?
In other words, for patients who were once MRD-negative but now have MRD positivity
without any clinical evidence of progression
Should we treat these patients differently?
Can we stop BCMA bsAb therapy once MRD-negative?
Ask me again in 5 years!

52. Key Takeaways
Not all RRMM is created equally
Baseline cytogenetic/genomic risk factors, kinetics of relapse, nature of relapse,
and other factors all affect how aggressively to treat these patients
BCMA-targeted therapies offer immense promise in RRMM
FDA-approved options include several CAR T and bsAb therapies
Ongoing trials seek to establish BCMA-targeted therapies in earlier lines
There is no optimal way to sequence therapies in RRMM
The best therapy is the one that the patient can get!
BCMA-targeted therapies are the most prominent players in RRMM currently,
but other novel agents are under investigation as well
The story of MRD in multiple myeloma is still being written
Currently, MRD is not yet routinely being used to change decision making

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