Understanding and Managing Immune Effector Therapy in Multiple Myeloma: When You CART or BiTE
Saad Z. Usmani, MD MBA FACP FRCP FASCO
Chief of Myeloma Service, MSKCC
Professor, Weill Cornell Medical College, Cornell University
Disclosures
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
This is the age of immune therapy in MM therapeutics – our collective aim is cure.
Adapted from Cho S-F et al. Front Immunol. 2018;9:1821.
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Bispecific Antibodies (BsAbs) – Many Different Platforms
Adapted from Lejeune M et al. Front Immunol 2020 11:762.
Bispecific T-cell Engager or BiTE (Amgen)
Dual Affinity Re-Targeting or DART
(Janssen, Macrogenics)
Tandem diabodies or TandAb (Affimed)
BsAb armed activated T-cells or BAT (mostly academic)
T-cell dependent BsAb Xmab (Xencor, Glenmark, Amgen)
CrossMAb
(Celgene, Roche)
Duobody (Genmab)
Trifunctional Antibody or TriFAb
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Clinical Trail Data in Multiple Myeloma
Teclistamab – 1st EMA/FDA Approved BsAb for MM
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Summary of BCMA Bispecific Antibodies
| Teclistamab (n=165) | Linvoseltamab (n=167) | ABBV-383 (n=118) | Elranatamab (n=123) | Alnuctamab (n=68) |
Route | SC | IV | IV | SC | SC |
Dose and schedule | 1.5mg/kg/QW | Q1W x 16w W≥16: Q2W | Q3W | 76mg/Q1W C≥7: Q2W if PR | Q1W x 8 w Q2W C3-C7 C≥7 Q4W |
Median prior LoT | 5 (2-14) | 6 (2-17) | 5 (1-15) | 5 (2-12) | 4 (3-11) |
Triple refractory | 77.6% | 90% | 61% | 96% | 63% |
CRS, G≥3 | 72.1%, 0.6% | 47.9%, 0.6% | 54%, 3% | 57.7%, 0% | 53%, 0% |
Neurotoxicity, G≥3 | 3%, 0 | 4%, 0 | NR, 6 pts | 4, 3.4 | 2 pts, 3% |
Infections, G≥3 | 76.4%, 44.8% | NR | 32%, 17% | 66.7%, 35% | 34%, 9% |
ORR (%) | 63% | 75% 200-800 mg | 60%/81%* *at ≥40 mg | 61% | 53% |
≥CR (%) | 39.4% | 16% | 20%/30%* | 27.6% | 23% |
Median PFS (m) (95% CI) | 11.3 m (8.8-17.1) | Not reported | Not reported | NE (10.4-NE) | Not reported |
Median DoR (m) (95% CI) | 18.4 m (14.9-NE) | Not reached | Not reported | NE (12.0-NE) | Not reported |
MRD – (10-5) | 26.7% | 4/10 | Not reported | 90.9% (n=22) | 16/20 |
FDA APPROVED | X | | | X | |
Moreau P et al. NEJM 2022; Bahlis N et al. ASH 2022; Wong S et al. ASH 2022; Voorhees PM et al. ASH 2022 ;
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Summary of non-BCMA Bispecific Antibodies
Chari A et al. NEJM 2023; Carlo-Stella et al. ASH 2022; Trudel S et al. ASH 2021.
| Talquetamab (n=288) | Forimtamig (n=57 ) | Cevostamab (n=157) | |
Target | GPRC5d-CD3 | 2+1 GPRC5d-CD3 | FcRH5-CD3 | |
Route | SC (n=143) | SC (N=145) | SC | IV |
Dose and schedule | 0.4 mg/kg QW | 0.8mg/kg Q2W | 1200-7200 mcg/kg Q2W | Q3W |
Median prior LoT | 5 (2-13) | 5 (2-17) | 4 (2-14) | 6 (2-18) |
Triple refractory | 74.1% | 69% | 71.9% | 85% |
CRS, G≥3 | 79%, 2.1% | 72.4%, 0.7% | 78.9%, 1.8% | 81%, 1.2% |
Neurotoxicity, G≥3 | 13.9%, 1.6% | 10%, 1.8% | 12.3%, .6% | 14.3%, 0.6% |
Infections, G≥3 | 57.3%, 16.8%- | 50.3%, 11.7% | 45.6%, 26.4% | 45%, ND |
ORR (%) | 74.1% | 73.1% | 63.6% | 56.7% 132-198mg |
≥CR (%) | 33.6% | 32.4% | 25.5% | 8.4% |
Median PFS (m) (95% CI) | 7.5 (5.7-9.4) | 11.9 (8.4-NE) | NR | NR |
Median DoR (m) (95% CI) | 9.3 (6.6-12.7) | 13.0 (10.6-NE) | 12.5 (1.2-12.5) | 11.5 (6-18.4) |
MRD – (10-5) | NR | NR | 10/14 | 7/10 |
FDA APPROVED | X | X | | |
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Summary of Bispecific Antibodies - Infections
| Teclistamab n=165 | Elranatamab n=123 | Alnuctamab n=68 (sc) | ABBV-838 n=118 | Talquetamab n=288 [0.4-0.8mg/kg]* | Cevostamab n=161 | Forimtamig n=57 (SC) |
Median FUP (months, m) | 14.1 m | 10.4 m | 4.1 m | 4.3 – 8.0m | 14.9 – 8.6 m | 8.8 m | 8.0m |
Overall, n (%) | 126 (76.4) | 82 (66.7) | 23 (34) | 38 (32) | 57.3%-50.3% | 45% | 26 (45.6) |
Grade 3-4, n (%) | 74 (44.8) | 43 (35) | 6 (9) | 20 (17) | 16.8%-11.7% | ND | 15 (26.4) |
Bacterial | ND | ND | ND | ND |
| ND | ND |
Fungal | ND | ND | ND | ND |
| ND | ND |
Viral | ND | ND | ND | ND |
| ND | ND |
Opportunistic infections
|
6 patients NR (*1 patients with Adenoviral pneumonia) |
6 (4.9) 10 (8.1) |
ND ND |
ND ND
|
5(3.5%)–4(2.8%) ND 3 patients | ND | ND |
COVID infections, n (%) Overall Grade 3-4 |
29 (17.6) 20 (12.1) |
31 (25.2) 14 (11.4) |
ND ND |
ND ND |
13(9.1) – 16(11) 0.7% - 2.1% | ND |
12 (24.6) 2 (3.6) |
Infectious death, n (%) | 16/27 | NR | ND | 4 pts | NR | ND | ND |
Moreau P et al. NEJM 2022; Lesokhin A et al. ASH 2022. ; Wong S et al. ASH 2022; Voorhees PM et al. ASH 2022; Chari A et al. NEJM 2023; Carlo-Stella et al. ASH 2022; Trudel S et al. ASH 2021
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Teclistamab: Long-term Follow-up from MajesTEC-1
van de Donk NWCJ et al. ASCO 2023; Usmani SZ et al ASCO 2023.
165 pts, median f/u 2 years
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Mechanisms of resistance to BsAbs
Adapted from: van de Donk N, Themeli M, Usmani SZ. Blood Cancer Discov 2021;2:302–18
T-cell characteristics
MM microenvironment-related factors
BsAb characteristics
Tumor-related features
IMiD/CelMOD,
Check point
inhibitors
CD38 antibody: Elimination of Tregs
BCMA, B-cell maturation antigen; BM, bone marrow; BsAb, bispecific antibody; IMiD, immunomodulatory drug; MMC, multiple myeloma cell; Tregs, regulatory T-cells
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
TRIMM-2: Talquetamab and daratumumab
CR, complete response; CRS, cytokine release syndrome; dara, daratumumab; ICANS, immune effector cell-associated neurotoxicity syndrome; mAb, monoclonal antibody; ORR, overall response rate; PL, prior lines of treatment; PR, partial response; QW/Q2W, weekly/every 2 weeks; SC, subcutaneous; sCR, stringent CR; SD, stable disease; Tal, talquetamab; VGPR, very good partial response
van de Donk N et al. EHA 2022;abstract S183 (oral presentation)
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
aIncluding a PI and an IMiD. b1–3 step-up doses given within 1 week before a full dose.
cGlucocorticoid, antihistamine, and antipyretic.
Parameter | Evaluable | patientsa |
Tal 400 μg/kg QW + dara (n=14) | Tal 800 μg/kg Q2W + dara (n=37) | |
Follow-up, median (range) | 6.7 months (1.9–19.6) | 4.2 months (0.2–12.3) |
ORRb, n (%) | 10 (71.4) | 31 (83.8) |
CR/sCR | 4 (28.6) | 11 (29.7) |
VGPR | 4 (28.6) | 13 (35.1) |
PR | 2 (14.3) | 7 (18.9) |
SD | 4 (28.6) | 4 (10.8) |
PD | 0 | 2 (5.4) |
Time to first confirmed response, median (range) | 1.0 month (0.9–2.4) | 1.0 month (0.9–6.5) |
aResponse-evaluable patients had received ≥1 study treatment and had ≥1 postbaseline response evaluation by the investigator. bPR or better in response-evaluable patients; includes unconfirmed responses.
0; 18 (40.9%), grade 3/4 0
Phase 1b RedirecTT-1: Teclistamab + Talquetamab
Cohen YC et al. ASCO 2023. Abstract 8002.
Mateos M-V et al. EHA 2023. Abstract S190.
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
RedirecTT-1: Conclusions
Cohen YC et al. ASCO 2023. Abstract 8002.
Mateos M-V et al. EHA 2023. Abstract S190.
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Pros/Cons of Bispecifics
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Pros:
Cons:
Hot off the press…April 30, 2024.
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
BCMA-Targeted CAR T-Cell Therapies Indicated for MM
BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; MM, multiple myeloma; R/R, relapsed/refractory.
BCMA-Targeted Therapy | Indications |
Idecabtagene vicleucel |
|
Ciltacabtagene autoleucel |
|
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
KarMMa-3: Randomized Trial Ide-Cel vs SOC
Rodriguez-Otero P, et al. N Engl J Med. 2023;388(11):1002-1014.
14.8 months
9.7 months
Ide-cel
SOC
1.0
0.7
0.5
0.3
0.2
0.0
0.1
0.4
0.6
0.8
0.9
Probability of PFS
0
12
15
30
6
3
9
33
18
21
24
27
Months since randomization
254 | 206 | 178 | 149 | 110 | 62 | 40 | 22 | 14 | 4 | 2 | 0 |
132 | 75 | 42 | 32 | 25 | 13 | 10 | 7 | 6 | 2 | 1 | 0 |
Ode-cel
Standard regimen
No. at risk
0.73
0.40
0.55
0.30
Ide-cel
Standard of care
SOC regimens (n = 132):
43 Dara-Pd
30 Kd
30 Elo-Pd
22 Ixa-Rd
7 Dara-Vd
**93% were refractory to dara
| Ide-cel (n = 225) | SOC (n = 126) |
Median lines of therapy | 3 | 3 |
Extramedullary disease | 24% | 24% |
HR cytogenetics | 42% | 46% |
Triple-class refractory | 65% | 67% |
Penta-refractory | 6% | 4% |
Median dose of ide-cel:
445 x 106 CAR+ T cells
Duration of Response
Progression-Free Survival
(Intent-to-treat population)
| Ide-cel | Standard regimen |
Median PFS, months (95% CI) | 13.3 (11.8−16.1) | 4.4 (3.4−5.9) |
HR (95% CI) | 0.49 (0.38−0.65) | |
P value | <0.001 | |
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
CARTITUDE-4: Phase 3 Cilta-Cel vs SOC (DPd or VPd)
San-Miguel J, et al. N Engl J Med. 2023;389(4):335-347
Median follow-up 15.9 months | Cilta-cel (n = 208) | SOC (n = 211) |
Median lines of therapy | 2 (1–3) | 2 (1–3) |
Extramedullary disease | 21% | 17% |
HR cytogenetics | 59% | 63% |
Triple-class refractory | 25.5% | 26.1% |
Penta-exposed | 6.7% | 4.7% |
ORR | ITT: 84.6% As-tx: 99.4% | 67.3% |
MRD-neg (10-5) | ITT: 61% As-tx: 72% | 16% |
12-month DOR | 84.7 | 63.0% |
Cilta-cel was associated with superior PFS in the ITT population; patients in cilta-cel arm received DVd or VPd bridging, but had higher number of early progressions vs SOC
100
80
60
40
20
0
10
30
50
70
90
Percentage of patients surviving without disease progression
Months
Wk 8
0
3
6
9
12
15
18
21
24
27
30
Cilta-cel group
Standard-care group
No. at risk
Cilta-cel group
Standard-care group
208
211
166
116
45
20
1
0
9�1
22
4
94
46
146
88
172
133
177
176
0
0
HR* 0.40 (0.29–0.55); P < 0.0001
PFS: ITT Population
*unweighted
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Why Use CART Early?
Derman B, et al. Blood Adv. 2023;7(19):5703-5712. Song Y, et al. ASH. 2023;Abstract 1009. Mateos M-V, et al. J Clin Oncol. 2024;42(suppl 36):Abstract 439572.
Belantamab mafodotin + Vd in 2L+ had median PFS of 36.6 months
0
21
3
6
9
12
15
18
24
36
33
30
27
39
42
0.0
1.0
0.6
0.4
0.2
0.8
PFS (probability)
Time since randomization (months)
BVd
DVd
43%
69%
18 months
Median �13.4 months
Median �36.6 months
PFS | BVd �(n = 243) | DVd �(n = 251) | HR �(95% CI) | P-value |
Events, n (%) | 91 (37) | 158 (63) | | |
mPFS (95% CI), mo | 36.6�(28.4-NR) | 13.4�(11.1-17.5) | 0.41 �(0.31-0.53) | < 0.00001 |
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Why Use CART Early?
Derman B, et al. Blood Adv. 2023;7(19):5703-5712. Song Y, et al. ASH. 2023;Abstract 1009.
CARTITUDE-4 PFS
Appropriate for second-line CAR T | Later CAR T may be appropriate |
Triple-class refractory disease at first relapse | No anti-CD38 mAb resistance (anti-CD38 mAb) |
Value extended treatment-free period | Value weekly visits > hospitalization |
Place premium on efficacy > toxicity | Place premium on lower toxicity |
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Cytopenias After BCMA-Targeting CAR T
Logue J, et al, Blood Adv. 2022;6(24):6109-6119. Thibaud S, et al. Blood. 2022;140(Suppl1):614-616.
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Comparison of infectious complications with BCMA-directed therapies – the MSKCC Experience
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Nath K et al. Blood Cancer J 2024;14(1):88.
Estimated cumulative incidence of grade ≥3 infections over time
Secondary (Hematologic) Cancers Post-CAR T-Cell Therapy
Rodriguez-Otero P, et al. New Engl J Med. 2023; 388(11):1002-1014. Lin Y, et al. J Clin Oncol. 2023;41(16):Poster 8009. San-Miguel J, et al. New Engl J Med. 2023;389(4):335-347.
Trial | Secondary hematologic malignancy incidence |
Ide-cel (KarMMa-3) vs SOC | 2% vs 0% [all MDS/AML] |
Cilta-cel (CARTITUDE-1) | 10% [Mostly AML/MDS, 1 B-cell lymphoma] |
Cilta-cel (CARTITUDE-4) vs SOC | 3% vs 0% [2% AML/MDS, 1% TCL] |
Use of fludarabine/cyclophosphamide + risk of insertional mutagenesis raises specter of second hematologic cancers
Retrospective analyses | Details |
FDA | 33 cases of T-cell lymphoma among ~30K cases |
Ghilardi G,et al. Nat Med. 2024;30(4):984-989 | Case of TCL after CD19 CAR T; clone identified before CAR T infusion |
Harrison S, et al. Blood. 2023;142(Suppl1):6939 | TCL after cilta-cel; possibly driven by clone present before CAR T |
Elsallab M, et al. Blood. 2024;143(20):2099-2105 | FAERS database; Myeloid leukemias and T-cell lymphomas reported [estimated 0.1% incidence] |
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome, TCL, T-cell lymphoma
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Secondary (Hematologic) Cancers Post-CAR T-Cell Therapy
Black Box Warning:
Secondary hematological malignancies, including MDS, AML, T-cell malignancies
Longer follow-up from randomized trials of CAR T versus SOC should help to clarify the excess risk of secondary blood cancers
IS THERE A LINK?
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
Real World Ide-Cel
SOC, standard of care
Hansen DK, et al. J Clin Oncol. 2023;41(11):2087-2097.
10% underwent apharesis but never received their product
(KarMMA, 9%; KarMMA-3: 7.5%)
Leukapheresis for planned SOC ide-cel CAR T therapy
(N = 196)
Did not proceed to CAR T infusion (n = 17)
Pending ide-cel CAR T therapy infusion (n = 20)
Ide-cel infusion (n = 159)
Patients who are not infused were not included in initial outcomes analyses, which may inflate
PFS, OS, etc
Real World Ide-Cel
Compared to KarMMA:
Hansen DK, et al. J Clin Oncol. 2023;41(11):2087-2097.
Day 30 (n = 159)
Day 90 (n = 149)
Best ORR (n = 159)
0
25
50
75
100
Percent
CR or sCR: 30%
ORR: �78%
CR or sCR: 38%
CR or sCR: 42%
ORR:�84%
ORR: �72%
CR or sCR, MRD+
VGPR
PR
CR or sCR, MRD-
CR or sCR, MRD unknown
0
12
3
6
9
0.75
0.50
0.25
1.00
PFS (probability)
Months
No. at risk
All
159
21
0
115
68
All
Median PFS, 8.5 months
95% CI, 6.5 to NR
0
12
3
6
9
0.75
0.50
0.25
1.00
OS (probability)
Months
No. at risk
All
159
37
2
138
93
All
Median OS, 12.5 months
95% CI, 11.3 to NR
Best Overall Tumor Responses
PFS From Ide-Cel Infusion
OS From Ide-Cel Infusion
Real-World Cilta-Cel
Hansen DK, et al. J Clin Oncol. 2023;41(suppl16):8012.
Real-world pts, retrospective | N = 139 |
Median age, years | 64 (30–79) |
ECOG PS 0 or 1 | 89% |
High-risk Disease Features Extramedullary disease High-risk cytogenetics Plasma cell leukemia Prior BCMA therapy ISS-3/R-ISS 3 | 31% 41% 7% 12% 22% |
Penta-refractory disease | 34% |
Bridging Therapy | 80% |
Out of specification | 22% |
Grade >3 CRS and ICANS | 5% / 6% |
Delayed neurotoxicity Parkinsonism Bell’s/CN palsy | 12% 1% 6% |
*57% ineligible for CARTITUDE-1*
High-risk cytogenetics associated with inferior ORR, PFS, OS
Best ORR
ITT Best ORR
CR or sCR: 56%
ORR: �89%
CR or sCR: 53%
ORR: �84%
CR or sCR, MRD+
VGPR
PR
CR or sCR, MRD-
CR or sCR, MRD unknown
Real-World PFS
Real-World OS
0
12
3
6
9
0.75
0.50
0.25
1.00
0.00
PFS (probability)
Months
All
12-month PFS estimate: 67%
95% CI: 55-80%
No. at risk
All
159
56
8
141
119
0
12
3
6
9
0.75
0.50
0.25
1.00
0.00
OS (probability)
Months
All
12-month OS estimate: 79%
95% CI: 72-87%
No. at risk
All
153
60
9
145
123
Factors Associated With Outcomes in BCMA-Directed �CAR T-Cell Therapy
Criterion | Ide-Cel | Cilta-Cel | Source(s) | |||
Association with response | Association with PFS/OS | Association with response | Association with PFS/OS | |||
Higher ISS stage | Negative | Negative | Negative | Negative | Rodriguez-Otero, et al. Hemasphere. 2022; Rodriguez-Otero, et al. NEJM. 2023; Munshi, et al. NEJM. 2021; Martin, et al. JCO. 2022. | |
High-risk cytogenetics | Negative | Negative | Negative | Negative | Gagelmann, et al. Haematologica. 2023; Gagelmann, et al. JCO. 2024; Munshi, et al. NEJM. 2021; Martin, et al. JCO. 2022, Hashmi, et al. Haematologica. 2023; Hansen, et al. ASCO. 2023 | |
Extramedullary disease | Negative | Negative | Negative | Negative | Ibid | |
Plasma cell leukemia | Negative | Negative | Negative | Negative | Ibid | |
High/rapidly increasing disease burden | Negative? | Negative? | Negative? | Negative? | Rodriguez-Otero, et al. Hemasphere. 2022; Rodriguez-Otero, et al. NEJM. 2023; Martin, et al. JCO. 2022 | |
Prior BCMA-directed therapy - Antibody-drug conjugate - Bispecific antibody - CAR T-cell therapy (same product) - CAR T-cell therapy (diff product) |
Negative Negative Negative None | Negative Negative Negative None |
Negative Negative Negative Unknown | Negative Negative Negative Unknown | Cohen, et al. Blood. 2022; Ferreri, et al. BCJ. 2023; Hashmi, et al. Haematologica. 2023; Munshi, et al. NEJM. 2021; Martin, et al. JCO. 2022 | |
Patient-Related Factors | ||||||
ECOG Performance Status ≥ 2 | Negative | Negative | Negative | Negative | Hansen, et al. JCO. 2023 | |
Ferritin > upper limit of normal | Negative | Negative | Negative | Negative | Hashmi, et al. Haematological. 2023; Gagelmann, et al. JCO. 2024; | |
Conclusions
Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani
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