Current and Emerging Therapies

for Relapsed/Refractory Multiple Myeloma

Kenneth Anderson, M.D.

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Director, Jerome Lipper Multiple Myeloma Center

Dana-Farber Cancer Institute

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Kraft Family Professor of Medicine

Harvard Medical School

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Disclosures

Consultant: Astrazeneca, Janssen, Pfizer

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Board/Founder: Dynamic Cell Therapies, C4 Therapeutics, �Next RNA, Oncopep, Starton, Window, Predicta

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PERSEUS: Daratumumab-Lenalidomide Bortezomib Dexamethasone (Dara-RVd), ASCT, and Dara-R Maintenance vs RVd, ASCT, and R Maintenance)

MRD negativity (10^–5)

MRD negativity (10^–6)

Sustained MRD negativity (10^–5) ≥12 months

D-VRd�(n = 355)

VRd�(n = 354)

75.2%

47.5%

P <0.0001^b�Odds ratio, 3.40 �(95% CI, 2.47-4.69)

D-VRd�(n = 355)

VRd�(n = 354)

65.1%

32.2%

P <0.0001^b�Odds ratio, 3.97�(95% CI, 2.90-5.43)

D-VRd�(n = 355)

VRd�(n = 354)

64.8%

29.7%

P <0.0001^c�Odds ratio, 4.42�(95% CI, 3.22-6.08)

• Deep and durable MRD negativity was achieved with D-VRd
• 64% (207/322) of patients receiving maintenance in the D-VRd group

MRD-negativity rate, %

Sonneveld et al; NEJM 2024; 390:301-13

Projected median PFS for Dara RVD in SR MM 16 years

DRIVE RANK SCORE 0

Presented by P Sonneveld at the 65th American Society of Hematology (ASH) Annual Meeting; December 9-12, 2023; San Diego, CA, USA

Add QR �code here on �slide master

0.75” x 0.75“

Phase 3 Study: Isatuximab,Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) Versus VRd for Transplant-Ineligible Patients With NDMM (IMROZ)

At median F/U 5 years (59.7 months), Isa-VRd followed by Isa Rd

reduced risk of progression or death by 40.4%

Facon et al NEJM 2024; 391: 1797-1609

Projected median PFS for Isa-VRDin SR MM 90 Months

DRIVE RANK SCORE 0

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Minimal Residual Disease Negativity in Newly Diagnosed

and Relapsed Refractory MM: Prolonged PFS and OS and OS

Munshi et al., Blood Adv 2020; 4: 5988-99.

PFS

OS

NDMM

Transplant-eligible

RRMM

NB: Unanimous vote 4-12-24 FDA ODAC to use MRD-CR as an endpoint for accelerated approval of new drugs in MM.

High Risk Multiple Myeloma Continues to Evolve�with Advances in Profiling Tumor/Host and Therapies

1. del(17p), with cutoff of >20% clonal fraction, and/or TP53 mutation;

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• an IgH translocation including t(4;14), t(14;16), or t(14;20) along with +1q and/or del(1p)

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• monoallelic del(1p32) along with +1q or biallelic del(1p32); or

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4. b2 microglobulin >5/5 mg/L with normal creatinine(<1.2 mg/dL).

Avet-Loiseau et al, J Clin Oncol, in press.

Based on 2024 IMS/IMWG Consensus:

Disease and Patient Factors Influence Treatment Choices in Relapsed Refractory MM

The most effective regimen, safe and maintaining QoL

Attrition Through Lines of Therapy

9

Lin e 1

Lin e 2

Lin e 3

Lin e 4

Lin e 5

Trans p lan t

Non -trans p lan t

79%

55%

22%

35%

42%

24%

14%

8%

Fon s eca etal. BMC Cancer 2020

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Therapy for Relapsed MM

Active In Len and Bort refractory MM

Carfilzomib Pom Dex (no neuropathy)

Dara Pom Dex, Dara Carfilzomib Dex (deep responses)

Elo Pom Dex (well tolerated)

Isatuximab Pom Dex, Isa Carfilzomib Dex

Active in Bort refractory MM

Elotuzumab Len/Dex (indolent relapse), Ixazomib Len Dex (all oral), Carfilzomib Len Dex (no neuropathy), Dara Len dex (MRD- responses)

Active in Len refractory MM

Pom Bort Dex, Selinexor Bort Dex, Dara Bort Dex (MRD- responses)

Ciltacel CAR T cells

Active in Len, Pom, Bort, Carfil, Dara refractory MM

Selinexor (GI side effects), Belantomab mafodotin (keratopathy), Idecel and Ciltacel CAR T cells; Teclistamab, Elranatamab, Talquetamab bispecific T cell engagers

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Relapsed/Refractory Multiple Myeloma Landscape

ASCT, autolog ous s tem cell tran s p lan t; R-len alidom ide; K-carfilz om ib; D-daratum um ab; Ix a-ix az om ib; P-p om alidom ide; V- bortez om ib; Is a-Is atux im ab; Cy-cyclop h os p h am ide; Seli-s elin ex or; Ven -v en etoclax (n otFDA); *Dara m on oth erap y forfrail p atien ts . ^†Ven etoclax on ly forp atien ts with t(11;14).

IMiD Refractory, PI Refractory, Anti-CD38 MoAB Refractory

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• Ide-cel
• Cilta-cel
• Teclis tam ab
• Talq uetam ab
• Elran atam ab
• Sd
• Ben dam us tin e-bas ed reg im en s
• VTd-PACE/VdCEP
• Cyclop h os p h am ide-bas ed reg im en
• Autolog ous Stem Cell

Tran s p lan t

ASCT Can didate?

• SCT n ot performed as p art of frontline therap y
• Durable remis s ion after1^{s t}ASCT (≥24 months)

4+ PriorLin es

Korde, Mailan kody, Usm an i. Bethesda Handbook of Clinical Hematology. 2023

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Management of Relapsed Myeloma: Not Lenalidomide-Refractory

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Dimop oulos et al. JCO 2023; Siegel etal. JCO 2018; Richardson et al. JCO 2021; Dimopoulos et al. BCJ 2020

Redin dicates res ults m eetin g p re-s p ecifieds tatis tical s ig n ifican ce

• With increasing use of m aintenance, m os t patients are lenalidomide refractory
• 3 drug combinations are cons is tently better than 2 drugs in this s etting

Management of Relapsed Myeloma: Lenalidomide-Refractory

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Sonn eveld et al. JCO 2023; Grosicki et al. Lancet 2020; Us m ani etal. Bl Adv 2023; Martin etal. BCJ 2023;

Richardson et al. JCO 2021; Dimopoulos et al. Blood 2022; Dimopoulos etal. JCO 2023

Final Results CARTITUDE-1 : Time-to-Event Outcomes (3-Year F/U)�(~3-Year Follow-Up)

Median DOR: 33.9 months (95% CI, 25.5–NE)

Estimated 62.9% of patients were alive at 3-year follow-up

Berdeja JG et al. Lancet 2021;398:314-24; Martin T et al. J Clin Oncol 2023;41:1265-74; Munshi N et al. EHA;2023.

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13

Survival probability, %

PFS

mPFS: 34.9 months (95% CI, 25.2–NE)

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Ciltacel CAR T Cells in RRMM

Safety and Efficacy of Ciltacel for Relapsed MM

16 US academic centers: 255 pts leukopheresed, 236 pts received Ciltacel,

And 54% did not meet CARTITUDE 1 criteria

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Cytokine release syndrome 75%, (grade > 3, 5%)

Immune effector cell associated neurotoxicity 14%, (grade > 3, 4%)

Delayed neurotoxicity 10%

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ORR 94%, CR 70% (conforming Ciltacel ORR 94%, CR 74%; conforming Ciltacel

with Cy/Flu lymphodepletion ORR 95%, CR 76%)

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Non relapse mortality 10%, most commonly infection

At median F/U 13 months: median PFS NR, 12 mo est PFS 68%

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High ferritin, HR disease, EMD independently associated with inferior PFS

Secondary malignancies 5.5%, myeloid malignancies 1.7%

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Sidana et al Blood 2025; 145: 85-97.

CARTITUDE-4: 1 to 3 Prior Therapies�Primary Endpoint – PFS (ITT Population)

Cilta-cel vs SOC

Len Refractory

SOC Dara Pom Dex or Dara Vel Dex

12-month PFS rate: 76% vs 49%

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Progression-free survival^a

Patients progression free and alive, %

Progression-free survival, months

No. at risk

Cilta-cel arm

SOC arm

208

211

177

176

172

133

166

116

146

88

94

46

45

20

22

4

9

1

1

0

0

0

0

0

20

40

60

80

100

3

Week 8

6

9

12

15

18

21

24

27

30

mPFS: not reached (95% CI, 22.8–NE)

mPFS: 11.8 months (95% CI, 9.7–13.8)

Hazard ratio, 0.26 (95% CI, 0.18–0.38); P<0.0001^b,c

San Miguel J, et al. ASCO;2023. Abstract LBA106. San Miguel J, et al. EHA;2023. San Miguel J, et al. NEJM 2023; 389: 335-47.

Cartitude 4 Followup

�Significantly increased overall MRD- rates compared with SOC at 10–5 (89% vs 38% pts)

MRD responses with cilta-cel were deeper (10–6) than with SOC (86% vs 19%)

MRD- onset was rapid with cilta-cel (within 2 months)

All prespecified subgroups showed an MRD- benefit with cilta-cel

Higher rates of MRD- in CARTITUDE-4 vs CARTITUDE-1

Popat et al, ASH 2024

More patients achieved sustained (≥12 mo) MRD-negative ≥CR with cilta-cel vs SOC

(52% vs10% pts;P<0.0001), with PFS (93.2%) and OS (97.3%) at 30 mos

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KarMMa Idecel CAR T Cells

Mun s h i NC etal. N Eng l J Med 2021;384:705-716

Response

Adverse Events

4 or more prior therapies

Real World Outcomes with Idecabtagene Vicleucel (Ide-cel) CAR-T Therapy� for Relapsed/Refractory Multiple Myeloma

• Largest real-world study CAR-T cell therapy in patients with RRMM (N=821).
• Heavily pre-treated population and co-morbidities that would have made a majority of patients ineligible for KarMMa clinical trial.
• Ide-cel demonstrated a favorable safety and efficacy profile, comparable to trial population and previously reported real-world data for ide-cel.
• Overall response rate of 73% and median PFS of 9 months with median 7 prior LOT.
• Key adverse prognostic factors for PFS: Extramedullary disease, high-risk cytogenetics, high disease burden, ISS stage III, prior BCMA therapy within 6 months and bendamustine lymphodepletion.

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Sidana et al ASH (abstr) 2023

Anitocabtagene Autoleucel BCMA CAR T for RRMM (iMMagine-1)

Small D-Domain construct facilitates high transduction efficiency and CAR positivity, with low total cell dose

D-Domain CARs stable and lack tonic signaling

D-Domain binder fast off-rate and high CAR surface expression, promoting

tumor cell killing without prolonged inflammation

At median follow-up 9.5 months:

ORR 97%, sCR/CR 62%

93.1% MRD evaluable patients (n=54/58) MRD- (10^-5 or lower)

Median PFS and OS not reached; 12-month PFS 78.5%, OS 96.5%

No delayed or non-ICANS neurotoxicities (Parkinsonism, cranial nerve palsies, GBS)

86% pts no or Grade 1 CRS; 91% pts no ICANS

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Freeman et al, ASH 2024

GPRC5D Targeted CAR T Cell Therapy

in Relapsed Refractory Multiple Myeloma

* MRD assessment by multicolor flow cytometry (sensitivity: 1 in 10⁵)

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Mailankody, Smith et al N Engl J Med 2022; 387: 1196-1206.

Arlocabtagene Autoleucel (BMS-986393) GPRC5D CAR T (Phase 1 Study)

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ORR (%)

Efficacy-evaluable population^a

Bal et al ASH 2024

Median DOR 18.0 mo

> CR: 85% (22/26) MRD-

Most skin, nail, oral on-target/off-tumor AEs resolve

• Teclistamab BCMA×CD3 bispecific antibody (Tec) FDA approved 165 pts 76% refractory to IMiD, PI, CD 38 Ab; median 5 lines prior therapy
• ORR 63%, CR 39%, 26% MRD-; Median PFS 11.3 mo, DOR 18.4 mo
• CRS 72.1% (0.6% grade 3); 64.2%, 37%, and 21.2% > grade 3 low WBC, Hct, and Plts
• Infections 76.4% ( 44.8% grade 3)

Lenalidomide stimulates CTL/NK cells, downregulates Tregs; Daratumumab expands CTLs

• Tec/Len/Dara: 93.5% ORR, 54.8% CR; 90.3% > VGPR including Dara and/or Len refractory MM; 25/31 (80.6%) progression-free on treatment
• CRS 81% (no grade 3); 90.6% > grade 3 AEs including low WBC, Hct, and Plts in 78.1%, 15.5%, and 12.5%
• Patients w > 1 infection 90.6% (37.5% grade > 3, 2 deaths)

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Nooka A, et al. ASCO;2022. Moreau P, et al. N Engl J Med. 2022; 387:495. Searle E, et al. ASH;2022.

Teclistamab Alone and with SC Daratumumab and Lenalidomide in RRMM

SC elranatamab once weekly after 2 step-up priming doses.

After 6 cycles, persistent responders switched to biweekly dosing.

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Cohort A without prior BCMA-directed therapy (n = 123):

ORR 61.0% (75/123); 35.0% ≥ CR

50 pts biweekly dosing, 40 (80.0%) improved or maintained response for ≥6 months.

At median follow-up 14.7 mo, median DOR, PFS, OS NR

AE (any grade; grade 3–4): infections (69.9%, 39.8%), CRS (57.7%, 0%), anemia (48.8%,

37.4%), neutropenia (48.8%, 48.8%).

Biweekly dosing: grade 3–4 AE decreased from 58.6% to 46.6%.

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Elranatamab induced deep and durable responses with manageable safety profile.

Switching to biweekly dosing improved long-term safety without compromising efficacy.

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Phase 2 MagnetisMM-3 Trial of Elranatamab in RRMM

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Lesokhim AM et al Nat Med 2023; 29: 2259-67.

Talquetamab GPRC5D BiTE in Patients with Prior T-Cell Redirection

• Median 6 (3–15) prior lines of therapy
• 70.6% (n=36) prior CAR-T cell therapy
• 35.3% (n=18) prior bispecific antibody therapy
• 3 patients both
• 7.8% (n=4) refractory to belantamab
• Most patients received QW (n=43) vs Q2W (n=8) talquetamab dosing

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• ORR 62.7%
• 72.2% ORR (26/36) prior CAR-T therapy
• 44.4% ORR (8/18) prior BiTE treatment
• Median DOR: 12.7 months at median F/U 11.8 months

Chari et al NEJM 2022; 387: 2232-44.

Combined bulk and SC WGS and CNV analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy:

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2 relapse by expansion of existent BCMA-clones with focal biallelic deletions

5 relapse by newly detected, nontruncating, missense mutations or in-frame deletions in

ECM domain of BCMA, despite detectable surface BCMA

4 relapse with biallelic mutations of GPRC5D, 2 convergent evolution where multiple

subclones lost GPRC5D through somatic events.

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Immunoselection of BCMA- or GPRC5D-negative or mutant clones drives relapse post-targeted therapies.

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Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies.

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Profiling tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.

Mechanisms of Antigen Escape from BCMA- or GPRC5D-Targeted Immunotherapies in Multiple Myeloma

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Lee H et al Nat Med 2023; 29: 2295-2306.

Monitoring immune profile before and during therapy can inform schedule of TCE to optimize response and limit T cell exhaustion, relapse, and increased risk of infection.

Friedrich MJ, et al. Cancer Cell. 2023;41(4):711-725.e6.

Midha S, Anderson KC. Nat Rev Clin Oncol. 2023;20(8):505-6.

Single-cell TCR tracing identifies

conserved T cell responses to TCEs

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Clonal expansion of effector CD8+ T cells

is a driver of TCE therapy response

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Naive T cells require additional MHC class I

signal and differentiate upon TCE activation

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The abundance of exhausted CD8+ clones

predicts response failure

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T Cell Landscape Determines Response to

Bispecific T Cell Engagers (TCE) in Multiple Myeloma

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Combinations: Lenalidomide and Pomalidomide Enhance �Cytotoxicity of Bispecific T Cell Engager in MM

IMiD pretreatment enhanced potency of AMG 701–induced T cytotoxicity against MM cells

AMG 701 combination treatment with lenalidomide effectively prevented myeloma regrowth in vivo

Cho SF et al. Blood Adv 2020; 17: 4195–4207.

Teclistamab-Daratumumab-Pomalidomide (MajesTEC-2 and TRIMM-2)

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Promising efficacy at >2 yrs F/U in RRMM, including Dara-exposed:

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High rate of deep responses, improved in earlier LOT

Overall: ORR 85.2%, ≥CR 59.3%

1–3 prior LOT: ORR 94.1%, ≥CR 64.7%

≥3 prior LOT: ORR 70.0%, ≥CR 50.0%

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Longer DOR and PFS in less heavily pretreated pts

1–3 prior LOT: median DOR NE, 24-month PFS 59.8%

≥3 prior LOT: median DOR 25.6 months, 24-month PFS 46.7%

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Intensified recommendations for Ig replacement and infection prophylaxis

improved infection profile

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D’Souza et al ASH 2024

Talquetamab and Pomalidomide Combination

MonumenTAL-2 – Tal + Pom

• Eligibility: ≥2 prior lines of therapy incl. IMiD + PI
• Design: Step-up TAL; Pom from C2 (2 mg 🡪 4 mg)
• Enrolled:
• n=35 (16+19); 3 prior LOT
• Refractoriness: Pom – 25% / 5.3%; TCR: 31.3% / 21.1%
• HRCA – 31% / 21%
• Safety: G3-4 neutropenia 54.3%; Infections: 22.9%; CRS 2.9%; � Taste related 86% (G1-2); skin 74% G1-2 / 5.7% G3-4; nail 69% (G1-2)
• Efficacy: ORR 93.8% / 84.2%; 62.5% / 36.8% ≥CR; med DOR not reached; � 9mo PFS 93.8% / 75.5%

Matous J et al. ASH 2023

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19th International Myeloma Society Annual Meeting

RedirecTT-1: Dual Targeting of BCMA and GPRC5D in RRMM

Phase 1b trial of teclistamab + talquetamab safety consistent with each monotherapy

64%Grade 3 or 4 infections

78% ORR at all dose levels

80% ORR (61% EMD) at RP2D

18 mo PFS: 86% at RP2D, 82% EMD, 77% all dose levels

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Cohen et al NEJM 2025; 392: 138-49.

FcRH5 novel therapeutic target in MM

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Cevostamab monotherapy manageable safety profile

Most Gr 3–4 AEs reversible cytopenias

Gr ≥3 infection rate 19.2%

Majority of CRS Gr 1 (Gr 2 16.7%; no Gr 3) with TS dosing

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ORR 44.3% Cevostamab in RRMM, 60.6% BCMA -naïve patients

Median DoR 10.4 mos; in > VGPR mDoR 21.2 mos

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Patients maintain response beyond the fixed 12-mo treatment

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Dose of Q3W 160mg TD with C1 0.3/1.2/3.6/160mg TS for future single agent and

combination studies

Cevostamab in RRMM

Richter et al, ASH 2024

Mezigdomide (MEZI) Combination Therapies in RRMM

E3 Ligase Modulator with greater binding affinity and stability to cereblon triggering cytotoxicity even in pomalidomide-resistant MM

MEZI with dexamethasone In RRMM:

ORR: 50% in BCMA treated

MEZI with daratumumab (DARA) or elotuzumab (ELO) in RRMM:

ORR: MEZI DARA d 82.6%; MEZI E d 45.0%

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EZH2, BET, and RAS-RAF-MEK-ERK pathways associated with disease progression and poor prognosis

ORR: MEZI TAZ (EZH2 inhibitor) 50.0% , MEZI BMS-986158 (BET inhibitor) 35.0%, MEZI TRAM (MEK inhibitor) 75.0%

Most grade 3/4 TEAEs hematologic: neutropenia most common grade 3/4 TEAE, managed with

G-CSF and dosing schedule adjustments

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Richardson et al; N Engl J Med; 389; 2023:1009-22; Richardson et al ASH 2023; Costa et al ASH 2024

BCMA

GSK2857916

Tai et al Blood 2014; 123: 3128-38.

Bone Marrow Stromal Cell

GSK2857916

MM

ADCC

Apoptotic

MM cells

FcRIII

Apoptosis

MM

ADPC

APRIL

BAFF

MM cell lysis

NFκB

Inhibition of NFκB signaling

Anti-MM Activity of BCMA Auristatin Immunotoxin (Belantamab Mafodotin)

FcRII

Mφ engulfing MM

MMAF released at

lysosome to

induce G₂/M arrest

followed by apoptosis

Macrophage

Belantamab Mafodotin Bortezomib Dex vs Daratumumab Bortezomib Dex� in RRMM (DREAMM-7)

Hungria et al NEJM 2024; 391: 393-407.

35

BVd median PFS was 23 months longer than DVd (36.6 vs 13.4 months)

(No. of Events)

243

(0)

230

(6)

220

(13)

211

(17)

205

(21)

200

(25)

192

(28)

183

(32)

175

(36)

171

(39)

163

(45)

158

(46)

155

(48)

150

(51)

147

(53)

140

(59)

137

(60)

131

(63)

128

(66)

127

(67)

125

(67)

122

(69)

120

(70)

118

(71)

115

(74)

110

(78)

105

(79)

94

(81)

79

(82)

72

(86)

56

(86)

41

(88)

31

(89)

25

(89)

15

(90)

11

(90)

8

(90)

6

(91)

3

(91)

2

(91)

1

(91)

0

(91)

BVd

251

230

214

205

194

183

176

155

148

141

132

124

115

107

103

99

94

91

87

80

78

73

68

67

65

61

59

52

39

33

22

19

12

11

5

2

1

1

1

1

0

0

(0)

(9)

(22)

(29)

(37)

(47)

(53)

(71)

(75)

(81)

(90)

(97)

(106)

(113)

(116)

(119)

(121)

(124)

(128)

(133)

(135)

(138)

(143)

(144)

(145)

(148)

(149)

(151)

(153)

(154)

(154)

(154)

(156)

(156)

(157)

(158)

(158)

(158)

(158)

(158)

(158)

(158)

DVd

No. at Risk

Time since randomization (months)

PFS (probability)

DVd

BVd

Median

13.4 months

Median

36.6 months

69%

43%

18-months

PRESENTED BY:

DREAMM-7: deeper IRC assessed responses with BVd vs DVd^a

Hungria et al NEJM 2024; 391: 393-407

36

BVd was associated with ≥CR rate

double that with DVd

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MRD negativity (sensitivity of 10^-5)^a with BVd more than double with DVd (P value <.00001)

PRESENTED BY:

High extent and frequency of MRD- can be achieved in RRMM

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Triplets combining lenalidomide, pomalidomide, bortezomib, kyprolis, daratumumab, isatuximab, elotuzumab, and selinexor are effective to

treat relapse after 1-3 lines prior therapy; prior drug exposure informs best choice, ie lenalidomide sensitive vs refractory.

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BCMA CART and BITES (BCMA, GPRC5D) were approved to treat relapse after 4 lines prior therapy, now also approved/under evaluation to treat earlier relapse.

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Future strategies include immune agents (GPRC5D CART, FcRH5 BiTE), targeted agents (mezigdomide), immunotoxin (belamaf) , and combinations (BiTEs with IMiDs)

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Profiling of both tumor and immune status is needed to inform optimal use of

targeted and immune therapies in the future.

Summary and Future Directions