Identification and Targeting of Mutant Neoantigens in Multiple Myeloma Treatment

Multiple myeloma (MM) is a hematologic malignancy of clonal plasma cells accumulating in bone marrow, producing an M-protein and causing immunosuppression, cytopenias, lytic bone disease, and renal impairment. MM accounts for ~1% of all cancers and is the second most common hematologic cancer, typically diagnosed at 66–70 years, with higher incidence in men. MM often evolves from MGUS or smoldering MM (SMM) with defined risks of progression. Diagnostic work-up includes serum/urine electrophoresis, bone marrow assessment, imaging for lytic lesions, and labs (creatinine, calcium). Criteria distinguish MGUS, SMM, and symptomatic MM based on M-protein, clonal plasma cell percentage, and myeloma-defining events/biomarkers. Therapeutic advances over two decades—high-dose therapy with auto-HCT, IMiDs, proteasome inhibitors, and monoclonal antibodies—have improved OS and PFS, yet most patients relapse and develop resistance, underscoring need for novel mechanisms. Given prolonged immune exposure to tumor-associated neoantigens prior to MM onset, and advances in antibody formats (bispecific/trispecific, ADCs) and CAR-T cells, this review examines neoantigens in MM as prognostic markers and therapeutic targets and synthesizes recent data on these emerging immunotherapies, including CAR-T in RRMM.

The review surveys: (1) Neoantigens and vaccination strategies: Defines tumor-associated antigens (TAAs) versus tumor-specific antigens (TSAs/neoantigens), with public (shared driver mutation-derived) and private (patient-specific passenger mutation-derived) categories. Discusses NGS and bioinformatics pipelines, LC-MS, WES/RNA-seq-based discovery, HLA typing, and need for functional validation. Summarizes MM driver mutations (KRAS, NRAS, BRAF, NF-κB pathway genes; epigenetic regulators) and studies linking higher neoantigen burden with shorter PFS and worse OS; relapsed MM shows higher neoantigen load; shared neoantigens identified (e.g., KRAS, NRAS, IRF4). Introduces NAIRscore incorporating neoantigen load, cytolytic score, and HLA-I. (2) Antibody-drug conjugates (ADCs): Highlights belantamab mafodotin (anti-BCMA) with ORR ~60%, median PFS ~12 months; typical AEs include corneal events and thrombocytopenia. Notes other ADCs targeting BCMA (AMG224, MEDI2228, CC99712), CD38 (TAK-573/TAK-169), CD138 (indatuximab ravtansine), CD56 (lorvotuzumab mertansine), with phase 1/2 outcomes and safety. (3) Bispecific antibodies (BiAbs): Mechanisms (CD3xTumor), Fc/no-Fc formats; AMG420 (BCMAxCD3) produced ORR 31% overall, 70% at MTD; talquetamab (GPRC5DxCD3) with ORR ~64–70% and manageable CRS/skin/dysgeusia; teclistamab (BCMAxCD3) with ORR ~63–65%, median duration of response 18.4 months, PFS 11.3 months, AEs include CRS, cytopenias, infections, neurotoxicity. (4) Trispecific antibodies: Preclinical data for CD38xCD3xCD28 showing markedly enhanced killing and T-cell co-stimulation; NK-engaging trispecifics in development (e.g., CD16A/BCMA/CD200). (5) CAR-T cells: Focus on BCMA-targeted and dual-target (BCMA/CD19; BCMA/CD38) approaches. Summarizes early-phase trials with high ORR, notable CRS incidence, variable neurotoxicity/hematologic toxicity; dual-target CARs show high sCR/CR rates; correlations of CRS severity with outcomes and cytokines; issues of prolonged hematologic toxicity and persistence of CAR-T cells reported.

This is a narrative review. The authors synthesize recent literature on neoantigens in MM and emerging immunotherapies (ADCs, bispecific/trispecific antibodies, CAR-T cells). Evidence is summarized from clinical trials (phase 1/2) and key translational studies, with tabulated overviews of neoantigen prognostic studies (Table 1), antibody-based therapies (Table 2), and CAR-T trials (Table 3). No primary data collection or meta-analysis was performed; instead, the review collates reported efficacy, safety, mechanistic insights, and translational implications.

• Neoantigen burden and prognosis in MM:
  • Higher neoantigen load correlates with shorter PFS (Miller et al.) and worse OS (Dong et al.).
  • Relapsed MM has higher neoantigen burden and includes shared neoantigens in KRAS, NRAS, IRF4 (Perumal et al.).
  • NAIRscore (integrating neoantigen load, cytolytic score, HLA-I) associates with overall survival trends (Jian et al.).
• ADCs:
  • Belantamab mafodotin (anti-BCMA): ORR ~60%; median PFS ~12 months; median duration of response ~14.3 months; frequent AEs: corneal events, thrombocytopenia, anemia.
  • Indatuximab ravtansine (anti-CD138) combinations: ORR ~71–72%; clinical benefit ~85–88%; common AEs: neutropenia, anemia, thrombocytopenia.
  • Lorvotuzumab mertansine (anti-CD56): generally few grade 3–4 AEs; no infusion reactions; stable disease in >75%; median OS ~26.7 months.
• Bispecific antibodies:
  • AMG420 (BCMAxCD3): ORR 31% overall; 70% at MTD (400 µg/day); AEs include infections, polyneuropathy; no CNS toxicities/anti-drug antibodies.
  • Talquetamab (GPRC5DxCD3): ORR 70% (weekly) and 64% (q2w); AEs: CRS ~77–80%, skin events ~57–63%, dysgeusia ~57–63%.
  • Teclistamab (BCMAxCD3): ORR 63–65%; median duration of response 18.4 months; median PFS 11.3 months; AEs: CRS, neutropenia, anemia, thrombocytopenia; infections (~76% in one study); neurotoxicity including ICANS (~14.5%).
• Trispecific antibodies:
  • Preclinical CD38xCD3xCD28 trispecific shows 3–4 log higher killing vs daratumumab, suppresses MM growth in mice, expands effector/memory T cells and reduces Tregs in primates.
• CAR-T cells:
  • BCMA CAR-T: ORR up to ~77%; sCR/CR achieved in substantial subsets; median OS ~29 months and PFS ~10 months in one study; CRS common (including grade ≥3 in some), reversible neurotoxicity reported; one treatment-related death from severe CRS/encephalopathy in one trial.
  • Dual-target CARs (BCMA/CD19; BCMA/CD38): sCR/CR rates high (e.g., 12/22 achieving sCR/CR; ORR 90.9% in one BCMA/CD38 study); 1-year OS/PFS ~75%/68.8% in one BCMA/CD19 study; CRS incidence high (up to 100% with mostly grade 1–2, but severe in some); ICANS observed in a minority; prolonged hematologic toxicity associated with worse PFS/OS in affected patients.
• Combinatorial/adjunct strategies:
  • γ-secretase inhibitors may upregulate BCMA, improving efficacy of BCMA-targeted BiAbs/CAR-T and reducing soluble antigen interference.
  • Immune checkpoint targets (PD-1, LAG-3, TIM-3, TIGIT) and depletion of immunosuppressive cells (e.g., via daratumumab) may enhance BiAb efficacy.
  • Tumor-T cell metabolic competition and T-cell metabolic reprogramming are emerging determinants of immunotherapy response.

The review addresses whether MM neoantigens can serve as prognostic biomarkers and therapeutic targets. Evidence indicates higher neoantigen burden associates with inferior outcomes (shorter PFS/worse OS), while certain shared neoantigens suggest potential for non-personalized targeting. The NAIRscore attempts to quantify the quality of neoantigen-directed immunity. Translationally, multiple immune effector platforms (ADCs, BiAbs, CAR-T) demonstrate significant activity in RRMM, validating cell-surface antigens (notably BCMA, also GPRC5D, CD38, CD138, CD56) as actionable targets. Safety profiles are characterized by CRS, cytopenias, ocular events (for ADCs), infections, and neurotoxicity, typically manageable with current supportive measures. The findings support integrating neoantigen biology with therapeutic design—e.g., leveraging shared neoepitopes where present, or using platform therapies independent of individual neoepitope presentation (BiAbs/CAR-T against conserved surface antigens). The discussion emphasizes combination approaches to overcome resistance and immune suppression: γ-secretase inhibitors to augment BCMA expression; combinations with checkpoint inhibitors; and strategies to modulate Treg/MDSC compartments (e.g., daratumumab with BiAbs). Additionally, tumor-immune metabolic interactions are posited as a next frontier to enhance T-cell function and durability. Collectively, these data reinforce the promise of immunotherapies in MM while highlighting the need for rational sequencing/combination and biomarker-driven personalization.

Emerging immunotherapies—neoantigen-informed strategies, ADCs, bispecific/trispecific antibodies, and CAR-T cells—have improved outcomes in RRMM, achieving high response rates in heavily pretreated patients. Neoantigen burden appears prognostic, and limited sets of shared neoantigens may be targetable. ADCs and BiAbs show ORR generally >50% with manageable toxicities; trispecifics offer mechanistic advantages via co-stimulation in preclinical models; CAR-T therapies against BCMA (and dual-target constructs) achieve deep responses but face challenges of manufacturing, access, and toxicity. Future directions include: improving neoantigen discovery/validation and vaccine platforms; optimizing sequencing/combination of ADCs, BiAbs, and CAR-T (including γ-secretase inhibitor co-therapy); integrating immune checkpoint modulation and depletion of suppressive cells; and addressing T-cell metabolic fitness to enhance efficacy and persistence. Continued clinical trials and biomarker development are needed to reduce relapse/resistance and move toward durable disease control in MM.

Key limitations highlighted include: (1) Neoantigen strategies: few tumor antigens meet stringent neoantigen criteria; limited efficient screening/validation methods; long timelines for personalized vaccine development; challenges in vaccine formulation/delivery. (2) CAR-T: manufacturing time and availability; requirement for lymphodepleting chemotherapy; significant inflammatory, hematologic, and neurologic toxicities; incomplete understanding of resistance and optimal post-progression strategies; need to position CAR-T among other anti-BCMA therapies. (3) Combination therapies may introduce unforeseen toxicities and require careful evaluation. More broadly, as a narrative review, findings are constrained by heterogeneity of trial designs, small early-phase cohorts, and evolving standards of care.