Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma
Simple Summary
Abstract
1. Introduction
2. Refractoriness to Lenalidomide in MM: A Growing Problem to Face the Disease
3. Mechanisms of Resistance to Lenalidomide
4. Treatment Strategies Against Recurrence: Current Weapons in Len-Refractory MM
4.1. PI-Based Doublets and Triplets Incorporating an Anti-CD38 MoAb
4.2. IMiD-Based Triplets Incorporating an Anti-CD38 or -SLAMF7 MoAb or a PI
5. T-Cell Redirecting Therapies and Immunoconjugate (Belantamab Mafodotin)-Based Triplets Reshaping the Future
6. Discussion
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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PI-Based Regimens | ||||||||||||||
Overall | Len Refractory | |||||||||||||
Studio [Ref] | Regimens | Prior LOTs (m) | mFU (mos) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) | Len-ref (%) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) |
CASTOR [30,31,32] | D-Vd vs. Vd | 2 (1–9) | 72.6 | 16.7 vs. 7.1 (27.0 vs. 7.9 as 2nd LOT) | 49.6 vs. 38.5 | 84 vs. 63 | 29 vs. 10 | 14 vs. 2 | 24 | 7.8 vs. 4.9 | / | / | / | / |
ENDEAVOR [33,34,35] | Kd56 vs. Vd | 2 (1–3) | 44.3 | 18.7 vs. 9.4 | 47.8 vs. 38.8 (51.3 vs. 43.7 as 2nd LOT) | 77 vs. 63 | 13 vs. 6 | / | 25 | 8.6 vs. 6.6 | 29.2 vs. 21.4 | / | 15.5 (Kd56) | / |
CANDOR [36,37,38] | D-Kd vs. Kd | 2 (1–5) | 50.6 | 28.4 vs. 15.2 | 50.8 vs. 43.6 | 84 vs. 73 | 22 vs. 8 | 28 vs. 9 | 32 vs. 36 | 28.1 vs. 11.1 | NR vs. 38.2 | 79.8 (D-Kd) | / | / |
IKEMA [39,40,41,42,43,44] | isa-Kd vs. Kd | 2 (1–4) | 56.6 | 35.7 vs. 19.2 | NR vs. 50.6 | 87 vs. 84 | 44 vs. 29 | 34 vs. 15 | 32 vs. 34 | HR 0.6 in favor of isa-Kd | / | / | 39 vs. 12 | 25 vs. 10 |
BOSTON [45] | SVd vs. Vd | 2 (1–3) | 28 | 13.2 vs. 9.5 (21.0 vs. 10.7 as 2nd LOT) | 36.7 vs. 32.8 (NR vs. 32.8 as 2nd LOT) | 76 vs. 62 | 17 vs. 11 | / | 37 vs. 39 | 10.2 vs. 7.1 | 26.7 vs. 18.6 | 67.9 vs. 47.2 | / | / |
IMiD-based regimens | ||||||||||||||
Overall | Len Refractory | |||||||||||||
Studio | Regimens | Prior LOTs (m) | mFU (mos) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) | Len-ref (%) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) |
OPTIMISMM [46,47,48] | PVd vs. Vd | 2 (1–3) | 64.5 | 11.7 vs. 6.9 (20.73 vs. 11.63 as 2nd LOT) | 35.6 vs. 31.6 | 82 vs. 50 | 13 vs. 3 | / | 71 vs. 69 | 17.8 vs. 9.5 (2nd LOT) | 29.8 vs. 24.2 | 85.9 vs. 50.8 | / | / |
APOLLO [49,50,51] | D-Pd vs. Pd | 2 (1–5) | 39.6 | 12.4 vs. 6.9 | 34.4 vs. 23.7 | 69 vs. 46 | 25 vs. 4 | 9 vs. 2 | 63 vs. 73 | 9.9 vs. 6.5 | / | / | / | / |
MM-014 [63.64] | D-Pd | 2 (1–2) | 41.9 | 23.7 | 56.7 | 78.6 | 26.8 | / | 76 | 23.0 | 53.6 | 77.6 | 22.4 | / |
ICARIA [52,53,54] | isa-Pd vs. Pd | 3 (2–4) | 52.4 | 11.5 vs. 6.5 | 24.6 vs. 17.7 | 60 vs. 35 | 9 vs. 2 | / | 94 vs. 92 | / | 22.7 vs. 17.5 | / | / | / |
ELOQUENT-3 [55,56] | elo-Pd vs. Pd | 3 (2–8) | 45 | 10.3 vs. 4.7 | 29.8 vs. 17.4 | 53 vs. 26 | 20 vs. 9 | / | 90 vs. 84 | / | / | / | / | / |
CAR-T-based regimens | ||||||||||||||
cilta-cel vs. SOC [57,58] | CARTITUDE-4 | 2 (1–3) | 33.6 | NR vs. 11.8 (30-mos PFS: 59.4% vs. 25.7%) | NR (30-mos OS: 76.4% vs. 63.8%) | 85 vs. 67 | 77 vs. 24 | 62 vs. 19 (ITT) 89 vs. 38 (MRD evaluable pts) | All | / | / | / | / | / |
Overall | Len Refractory | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Regimen | Studi | Prior LOTs (m) | mFU (mos) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) | Len-ref (%) | mPFS (mos) | mOS (mos) | ORR (%) | ≥CR (%) | MRD- (%) |
ide-cel vs. SOC [74,75] | KarMMa-3 | 6 (3–16) | 30.9 | 13.8 vs. 4.4 | 41.4 vs. 37.9 | 71 vs. 42 | 44 vs. 6 | 35 vs. 2 | 73 vs. 79 | / | / | / | / | / |
bela-Vd vs. D-Vd [76,77,78] | DREAMM-7 | ≥1 | 39.4 | 36.6 vs. 13.4 | NR in either group (36-mos OS: 74% vs. 60%) | 83 vs. 71 | 34.6 vs. 17.1 | 39 vs. 17 | 33 vs. 35 (28 vs. 31 ref 1 prior LOT) | 25.0 vs. 8.6 | / | 84 vs. 61 | 35 vs. 11 | 42 vs. 13 |
bela-Pd vs. PVd [79,80] | DREAMM-8 | ≥1 | 21.8 | NR vs. 12.7 (NR vs. 18.5 as 2nd LOT) | NR in either group (12-mos OS: 83% vs. 76%) | 77 vs. 72 | 40 vs. 16 | 24 vs. 5 (CR) 32 vs. 5 (VGPR) | 81 vs. 76 | 24.0 vs. 9.2 (NR vs. 13.1 as 2nd LOT) | NR in either group (12-mos OS: 82% vs. 72%) | 75 vs. 68 | 38 vs. 14 | 23 vs. 5 (CR) 31 vs. 5 (VGPR) |
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Mancuso, K.; Barbato, S.; Di Raimondo, F.; Gay, F.; Musto, P.; Offidani, M.; Petrucci, M.T.; Zamagni, E.; Zambello, R.; Cavo, M. Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma. Cancers 2025, 17, 1168. https://doi.org/10.3390/cancers17071168
Mancuso K, Barbato S, Di Raimondo F, Gay F, Musto P, Offidani M, Petrucci MT, Zamagni E, Zambello R, Cavo M. Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma. Cancers. 2025; 17(7):1168. https://doi.org/10.3390/cancers17071168
Chicago/Turabian StyleMancuso, Katia, Simona Barbato, Francesco Di Raimondo, Francesca Gay, Pellegrino Musto, Massimo Offidani, Maria Teresa Petrucci, Elena Zamagni, Renato Zambello, and Michele Cavo. 2025. "Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma" Cancers 17, no. 7: 1168. https://doi.org/10.3390/cancers17071168
APA StyleMancuso, K., Barbato, S., Di Raimondo, F., Gay, F., Musto, P., Offidani, M., Petrucci, M. T., Zamagni, E., Zambello, R., & Cavo, M. (2025). Forcing Ahead: Second-Line Treatment Options for Lenalidomide-Refractory Multiple Myeloma. Cancers, 17(7), 1168. https://doi.org/10.3390/cancers17071168