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BCMA-Targeting Antibody-Drug Conjugates in Multiple Myeloma: History
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Contributor: Lijie Xing , Yuntong Liu , Jiye Liu

Multiple myeloma (MM) is an incurable cancer of the plasma cells. Over the years, treatment strategies have evolved toward targeting MM cells—from the shotgun chemotherapy approach to the slightly more targeted approach of disrupting important MM molecular pathways to the immunotherapy approach that specifically targets MM cells based on protein expression. Antibody-drug conjugates (ADCs) are introduced as immunotherapeutic drugs which utilize an antibody to deliver cytotoxic agents to cancer cells distinctively. Recent investigations of ADCs for MM treatment focus on targeting B cell maturation antigen (BCMA), which regulates B cell proliferation, survival, maturation, and differentiation into plasma cells (PCs). Given its selective expression in malignant PCs, BCMA is one of the most promising targets in MM immunotherapy. Compared to other BCMA-targeting immunotherapies, ADCs have several benefits, such as lower price, shorter production period, fewer infusions, less dependence on the patient’s immune system, and they are less likely to over-activate the immune system. 

  • B cell maturation antigen
  • multiple myeloma
  • antibody-drug conjugates
  • Anti-BCMA ADC
  • drug resistance

1. B Cell Maturation Antigen (BCMA)

B cell maturation antigen (BCMA) was first identified in 1992 on the short arm of chromosome 16 at 16p13.1 in malignant human T-cell lymphoma [1]. It is a type III transmembrane glycoprotein with 6 conserved cysteines in its extracellular domain. It belongs to the tumor necrosis factor receptor (TNFR) superfamily as TNRSF17 and is primarily present in a perinuclear structure that overlaps the Golgi apparatus, but functional BCMA is also found on the cell surface [1][2][3][4].
BCMA functions in conjunction with two related TNFR superfamily members, B-cell activation factor receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Their collaboration regulates various aspects of B cell activities, such as proliferation, survival, maturation, and differentiation into plasma cells (PCs) [2][3][5]. Upon binding its cognate ligands, BAFF and APRIL, BCMA can activate the NF-kB, Elk-1, p38, or JNK pathways to transduce signals for corresponding functions [4][6][7][8]. Conversely, a soluble form of BCMA (sBCMA), generated by γ-secretase (GS), neutralizes APRIL as a decoy and hinders the activation of subsequent BCMA pathways [9]. The sBCMA level has been suggested as a biomarker since it is significantly higher in MM patients compared to healthy individuals, and higher levels are associated with poor prognosis [10][11], MM progression, and poor response to BCMA-targeted therapy [11][12].
Since its discovery, various studies have demonstrated that BCMA is a promising immunotherapeutic target for multiple myeloma. BCMA expression is restrictively found on the surface of plasmablasts and differentiated PCs, with no expression on CD34+ hematopoietic stem cells, naive B cells, memory B cells, and other normal tissue cells [13]. Furthermore, it has a high expression on the surface of the MM cell and is necessary for the survival of long-lived bone marrow plasma cells [14][15]. Both BCMA mRNA and protein have higher expression in malignant PCs than normal PCs, as validated by multiple gene expression profiling [13][16][17] and immunohistochemistry studies [13]. Moreover, Carpenter et al. [13] found BCMA cDNA in several hematologic tissues, including blood leukocytes, bone marrow, spleen, lymph node, and tonsil, but no BCMA cDNA in other normal human tissues except for the testis, trachea, and some gastrointestinal organs, where low levels of BCMA cDNA were detected, likely from plasma cells present in lamina propria and Peyer’s patches. These findings indicate BCMA is a desirable therapeutic target.

2. Anti-BCMA ADC

An antibody-drug conjugate (ADC) solves many of the above problems. An ADC comprises three components: a monoclonal antibody against a target, a cytotoxic agent (payload), and a stable linker connecting the two [18][19][20]. Since only a small amount of injected antibodies localize to tumor cells, most payloads are highly potent, with cytotoxicity in the picomolar range, often targeting tubulin or causing DNA damage [20][21][22]. The linker covalently binds the payload to the antibody and is critical to ADC efficacy, pharmacokinetics, pharmacodynamics, and therapeutic index. A stable linker ensures the release of the cytotoxic drug to target tissue and minimizes toxic effects. On the other hand, an overly strong linker impedes the delivery of the drug. Both cleavable and non-cleavable linkers, which rely on the physiological environment and degradation in endosomes and lysosomes, respectively, have been developed [23][24].
In MM treatment, BCMA is considered one of the most promising targets of ADCs. Following binding to BCMA, the ADC is internalized by endocytosis. The drug is released by cleavage or degradation in endosomes or lysosomes and then causes DNA damage, inhibits transcription, or disrupts microtubules, which leads to apoptosis (Figure 1). The development of anti-BCMA ADCs is an active area of research, and several anti-BCMA ADCs are in various stages of clinical trials (Table 1).
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Figure 1. General mechanism action of an anti-BCMA ADC in myeloma cell. Created with BioRender.com.
Table 1. Summary of current clinical trials of anti-BCMA ADC.
Drug Clinical Trial Prior Lines of Therapy (Median) N Results Most Common AEs Ref.
Belamaf DREAMM-1 (NCT02064387), phase I ≥2 73 Dose expansion part (n = 25): ORR 60%, CR 3%, 43% VGPR, 9% PR, mPFS 12 months, mDoR 14.3 months Nausea, fatigue, thrombocytopenia, anemia, vision blur, chills, dry eye, aspartate aminotransferase increase, pyrexia [25][26]
Belamaf (2.5 vs. 3.4 mg/kg) DREAMM-2 (NCT03525678), phase II ≥3 197 ORR 31% vs. 35%, ≥VGPR 19% vs. 24%, mDoR NR vs. 6.2 months, mPFS NR vs. 8.4 months Keratopathy, thrombocytopenia, anemia, neutropenia [27][28][29]
Belamaf vs. Pd DREAMM-3 (NCT04162210), phase III ≥2 325 ORR 41% vs. 36%, ≥VGPR 25% vs. 8%, mPFS 11.2 months vs. 7 months, does not meet the primary endpoint of PFS, mOS 21.2 months vs. 21.1 months   [30][31]
Belamaf + Pd ALGONQUIN (NCT03715478), phase I/II 1–5 (3) 60 ORR 88.9%, ≥VGPR 74.1%, mPFS 24.2 months Keratopathy, blurred vision, fatigue, neutropenia, thrombocytopenia, fever, diarrhea, constipation, dry eye [32]
Belamaf + pembrolizumab DREAMM-4 (NCT03848845), phasen I/II 3–13 (5) 34 ORR 47%, CR 12%, VGPR 18%, PR 18%, mDoR 8.0 months, mPFS 3.4 months Keratopathy, blurred vision, thrombocytopenia [33][34]
Belamaf-containing combinations (e.g., Belamaf + nirogacestat) DREAMM-5 (NCT04126200), phase I/II 3–10 (4.5) 10 ORR 60%, VGPR 20%, PR 40% Ocular events [35][36]
Belamaf + Len + Dex vs. Belamaf + Bortezomib + Dex DREAMM-6 (NCT03544281), phase I/II 1–11 (3) 45 ORR 78%, ≥VGPR 50% Keratopathy, blurred vision, dry eye, thrombocytopenia [37]
Belamaf + Bortezomib + Dex vs. Daratumumab + Bortezomib + Dex DREAMM-7 (NCT04246047), phase III   575 (estimated)      
Belamaf + Pd vs. Bortezomib + Pd DREAMM-8 (NCT04484623), phase III   300 (estimated)      
Belamaf + VRd vs. VRd DREAMM-9
(NCT04091126), phase I		   144 (estimated)      
MEDI2228 NCT03489525, phase I 2–11 82 ORR 61%, VGPR 24.4%, PR 36.6%, DoR not reached Photophobia, thrombocytopenia, rash, increased gamma-glutamyltransferase, dry eye, pleural effusion [38]
AMG 224 NCT02561962, phase I 2–11(7) 42 ORR 23%, CR 5%, VGPR 5%, PR 13%, mDoR 14.7 months Thrombocytopenia, fatigue, nausea, aspartate aminotransderase increase, anemia [39]
HDP-101 NCT04879043, phase I/II 5–16 (11) 4     [40]
CC-99712 NCT04036461, phase I   160 (estimated)      
Pd: pomalidomide and dexamethasone; Len: lenalidomide; Dex: lexamethasone; VRd: bortezomib, lenalidomide, and dexamethasone; AE: Adverse event; ORR: overall response rate; CR: complete response; VGPR: very good partial response; PR: partial response; mDoR: median duration of response; NR: not reached; mPFS: median progression-free survival; mOS: median overall survival.

2.1. Belantamab Mafodotin

Belamaf (J6M0-mc–MMAF, belantamab mafodotin, GSK2857916) is the most well-studied ADC in myeloma. Its antibody component is an afucosylated IgG1 directed to BCMA (Kd of ~0.5 nM)  [16]. Once it binds BCMA on the MM cell membrane, the entire ADC is internalized and digested in the lysosome, which breaks the non-cleavable maleimidocaproyl (MC) linker and releases the drug monomethyl auristatin F (MMAF). MMAF blocks tubulin polymerization and induces G2-M growth arrest, thus causing caspase 3/7-dependent apoptosis  [16]. MMAF is a synthetic analog of dolastatin, a common drug component in ADCs. Its non-cell-permeable nature reduces the toxicity to healthy cells.

The benefits of Belamaf are not limited to its ability to induce apoptosis directly. The NF-kB signaling pathway essential for MM cell growth and survival is blocked by Belamaf as its specifically engineered anti-BCMA antibody competes with APRIL and BAFF for binding to BCMA  [16]. It is worth noting that blocking BAFF and APRIL can impair the function of immune cells, such as T cells and NK cells, and potentially lead to an increased susceptibility to infections and other diseases  [41]. It was also noted that the afucosylation of its Fc domain substantially enhances the binding affinity to the FcγR (FcγRIIIa) present in effector cells, such as NK cells, monocytes, and macrophages. Consequently, the killing of MM cells is further improved by elevated antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The safety and efficacy results from clinical results supported the approval of Belamaf as a Breakthrough Therapy by the FDA and as a priority medicine (PRIME) by the European Medicines Agency (EMA) in 2017. It was approved by the FDA in 2020 as a monotherapy treatment for R/R MM patients who have received 4 prior therapies including anti-CD38 mAb, PI, and IMiDs.

2.2. MEDI2228

MEDI2228 includes a fully humanized BCMA antibody conjugated to pyrrolobenzodiazepine (PBD) via a protease-cleavable linker. In pre-clinical models, this ADC targets bulk MM cells as well as patient MM progenitor cells that are CD19 + CD138- and kills cells by inducing multiple DNA damage response genes via phosphorylating ATM/ATR kinases, checkpoint kinases 1/2 (CHK1/2), and H2AX regardless of p53 status [42]. Unlike Belamaf, MEDI2228 preferentially binds to membrane-bound BCMA over sBCMA [43], which makes it more efficient than Belamaf and means its cytotoxicity is minimally affected by sBCMA levels. MEDI2228 demonstrated impressive single-agent clinical activity in heavily pre-treated MM patients that had received previous immunotherapy. In vitro and in vivo studies suggest that MEDI2228 has a synergistic effect with bortezomib and DNA damage response checkpoint inhibitors [44]. Furthermore, as MEDI2228 upregulates expression of CD38 and NKG2D ligands on the MM cell surface, it increases NK cell immune activity and restores daratumumab-induced ADCC, supporting the combination of CD38- and BCMA-targeted immunotherapies  [45].

2.3. AMG 224

AMG 224 is composed of an anti-BCMA antibody, the non-cleavable linker 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (MCC), and the cytotoxic agent DM1. DM1, a derivative of the ansamycin antibiotic maytansine, is a tubulin development inhibitor that prevents tumor growth [46]. Its safety and benefits were proved in the clinical trial in R/R MM patients.

2.4. HDP-101

HDP-101 is another anti-BCMA ADC, but its cytotoxic agent, amanitin, is a new class of payload that impedes the transcription process by inhibiting RNA polymerase II. This reduces cell proliferation and causes cell apoptosis at very low concentrations. In in vitro MM cell models, the picomolar range of HDP-101 was cytotoxic to BCMA+ cells but not BCMA− cells [47]. In mouse xenograft models, tumor reduction and complete remission were observed depending on the HDP-101 dose. The safety of HDP-101 was further evaluated in nonhuman primates, where only a transient, mild to moderate increase in liver enzymes and lactate dehydrogenase was observed, indicating good tolerability and therapeutic index. Another recent study showed that it suppressed tumor burden in cell lines with a 17p deletion which remains an adverse prognostic factor of MM [48].

2.5. CC-99712

CC-99712 is an anti-BCMA ADC granted orphan drug designation by the FDA in 2021. Its payload is a non-cleavable maytansinoid. To date, no pre-clinical study has been published concerning this ADC.

This entry is adapted from the peer-reviewed paper 10.3390/cancers15082240

References

  1. Laâbi, Y.; Gras, M.P.; Carbonnel, F.; Brouet, J.C.; Berger, R.; Larsen, C.J.; Tsapis, A. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J. 1992, 11, 3897–3904.
  2. Laabi, Y.; Gras, M.-P.; Brouet, J.-C.; Berger, R.; Larsen, C.-J.; Tsapis, A. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Res. 1994, 22, 1147–1154.
  3. Madry, C.; Laabi, Y.; Callebaut, I.; Roussel, J.; Hatzoglou, A.; Le Coniat, M.; Mornon, J.P.; Berger, R.; Tsapis, A. The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor receptor superfamily. Int. Immunol. 1998, 10, 1693–1702.
  4. Hatzoglou, A.; Roussel, J.; Bourgeade, M.-F.; Rogier, E.; Madry, C.; Inoue, J.; Devergne, O.; Tsapis, A. TNF Receptor Family Member BCMA (B Cell Maturation) Associates with TNF Receptor-Associated Factor (TRAF) 1, TRAF2, and TRAF3 and Activates NF-κB, Elk-1, c-Jun N-Terminal Kinase, and p38 Mitogen-Activated Protein Kinase. J. Immunol. 2000, 165, 1322–1330.
  5. Mackay, F.; Schneider, P.; Rennert, P.; Browning, J. BAFF and APRIL: A Tutorial on B Cell Survival. Annu. Rev. Immunol. 2003, 21, 231–264.
  6. Marsters, S.A.; Yan, M.; Pitti, R.M.; Haas, P.E.; Dixit, V.M.; Ashkenazi, A. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr. Biol. 2000, 10, 785–788.
  7. Gross, J.A.; Johnston, J.; Mudri, S.; Enselman, R.; Dillon, S.R.; Madden, K.; Xu, W.; Parrish-Novak, J.; Foster, D.; Lofton-Day, C.; et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 2000, 404, 995–999.
  8. Thompson, J.S.; Schneider, P.; Kalled, S.L.; Wang, L.; Lefevre, E.A.; Cachero, T.G.; Mackay, F.; Bixler, S.A.; Zafari, M.; Liu, Z.-Y.; et al. Baff Binds to the Tumor Necrosis Factor Receptor–Like Molecule B Cell Maturation Antigen and Is Important for Maintaining the Peripheral B Cell Population. J. Exp. Med. 2000, 192, 129–135.
  9. Laurent, S.A.; Hoffmann, F.S.; Kuhn, P.-H.; Cheng, Q.; Chu, Y.; Schmidt-Supprian, M.; Hauck, S.M.; Schuh, E.; Krumbholz, M.; Rübsamen, H.; et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nat. Commun. 2015, 6, 7333.
  10. Sanchez, E.; Li, M.; Kitto, A.; Li, J.; Wang, C.S.; Kirk, D.T.; Yellin, O.; Nichols, C.M.; Dreyer, M.P.; Ahles, C.P.; et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br. J. Haematol. 2012, 158, 727–738.
  11. Ghermezi, M.; Li, M.; Vardanyan, S.; Harutyunyan, N.M.; Gottlieb, J.; Berenson, A.; Spektor, T.M.; Andreu-Vieyra, C.; Petraki, S.; Sanchez, E.; et al. Serum B-cell maturation antigen: A novel biomarker to predict outcomes for multiple myeloma patients. Haematologica 2017, 102, 785–795.
  12. Ali, S.A.; Shi, V.; Maric, I.; Wang, M.; Stroncek, D.F.; Rose, J.J.; Brudno, J.N.; Stetler-Stevenson, M.; Feldman, S.A.; Hansen, B.G.; et al. T cells expressing an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016, 128, 1688–1700.
  13. Carpenter, R.O.; Evbuomwan, M.O.; Pittaluga, S.; Rose, J.J.; Raffeld, M.; Yang, S.; Gress, R.E.; Hakim, F.T.; Kochenderfer, J.N. B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma. Clin. Cancer Res. 2013, 19, 2048–2060.
  14. Novak, A.J.; Darce, J.R.; Arendt, B.K.; Harder, B.; Henderson, K.; Kindsvogel, W.; Gross, J.A.; Greipp, P.R.; Jelinek, D.F. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: A mechanism for growth and survival. Blood 2004, 103, 689–694.
  15. O’Connor, B.P.; Raman, V.S.; Erickson, L.D.; Cook, W.J.; Weaver, L.; Ahonen, C.; Lin, L.-L.; Mantchev, G.T.; Bram, R.J.; Noelle, R.J. BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells. J. Exp. Med. 2004, 199, 91–98.
  16. Tai, Y.-T.; Mayes, P.A.; Acharya, C.; Zhong, M.Y.; Cea, M.; Cagnetta, A.; Craigen, J.; Yates, J.; Gliddon, L.; Fieles, W.; et al. Novel anti–B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 2014, 123, 3128–3138.
  17. Claudio, J.O.; Masih-Khan, E.; Tang, H.; Gonçalves, J.; Voralia, M.; Li, Z.H.; Nadeem, V.; Cukerman, E.; Francisco-Pabalan, O.; Liew, C.C.; et al. A molecular compendium of genes expressed in multiple myeloma. Blood 2002, 100, 2175–2186.
  18. Vezina, H.E.; Cotreau, M.; Han, T.H.; Gupta, M. Antibody-Drug Conjugates as Cancer Therapeutics: Past, Present, and Future. J. Clin. Pharmacol. 2017, 57 (Suppl. 10), S11–S25.
  19. Chau, C.H.; Steeg, P.S.; Figg, W.D. Antibody–drug conjugates for cancer. Lancet 2019, 394, 793–804.
  20. Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 2017, 16, 315–337.
  21. Azvolinsky, A. Conjugating Antibodies to Cytotoxic Agents: Getting the Best of Both Worlds? J. Natl. Cancer Inst. 2013, 105, 1765–1766.
  22. Donaghy, H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs 2016, 8, 659–671.
  23. Lu, J.; Jiang, F.; Lu, A.; Zhang, G. Linkers Having a Crucial Role in Antibody–Drug Conjugates. Int. J. Mol. Sci. 2016, 17, 561.
  24. Sievers, E.L.; Senter, P.D. Antibody-Drug Conjugates in Cancer Therapy. Annu. Rev. Med. 2013, 64, 15–29.
  25. Trudel, S.; Lendvai, N.; Popat, R.; Voorhees, P.M.; Reeves, B.; Libby, E.N.; Richardson, P.G.; Anderson, L.D., Jr.; Sutherland, H.J.; Yong, K.; et al. Targeting B-cell maturation antigen with GSK2857916 antibody–drug conjugate in relapsed or refractory multiple myeloma (BMA117159): A dose escalation and expansion phase 1 trial. Lancet Oncol. 2018, 19, 1641–1653.
  26. Trudel, S.; Lendvai, N.; Popat, R.; Voorhees, P.M.; Reeves, B.; Libby, E.N.; Richardson, P.G.; Hoos, A.; Gupta, I.; Bragulat, V.; et al. Antibody–drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: An update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019, 9, 37.
  27. Lonial, S.; Lee, H.C.; Badros, A.; Trudel, S.; Nooka, A.K.; Chari, A.; Abdallah, A.-O.; Callander, N.; Lendvai, N.; Sborov, D.; et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020, 21, 207–221.
  28. Lonial, S.; Lee, H.C.; Badros, A.; Trudel, S.; Nooka, A.K.; Chari, A.; Abdallah, A.-O.A.; Callander, N.S.; Sborov, D.W.; Suvannasankha, A.; et al. Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J. Clin. Oncol. 2020, 38, 8536.
  29. Lonial, S.; Lee, H.C.; Badros, A.; Trudel, S.; Nooka, A.K.; Chari, A.; Abdallah, A.; Callander, N.; Sborov, D.; Suvannasankha, A.; et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. Cancer 2021, 127, 4198–4212.
  30. Weisel, K.; Hopkins, T.G.; Fecteau, D.; Bao, W.; Quigley, C.; Jewell, R.C.; Nichols, M.; Opalinska, J. Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2019, 134, 1900.
  31. GSK Provides Update on DREAMM-3 Phase III Trial for Blenrep in Relapsed/Refractory Multiple Myeloma. Available online: https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-dreamm-3-phase-iii-trial-for-blenrep/ (accessed on 27 December 2022).
  32. Trudel, S.; McCurdy, A.; Sutherland, H.J.; Louzada, M.L.; Venner, C.P.; Mian, H.S.; Kotb, R.; Othman, I.; Camacho, F.; Gul, E.; et al. Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2021, 138, 1653.
  33. Trudel, S.; Nooka, A.; Fecteau, D.; Talekar, M.; Jewell, R.; Williams, D.; Evans, J.; Opalinska, J. 1105TiP-DREAMM 4: A phase I/II single-arm open-label study to explore safety and clinical activity of belantamab mafodotin (GSK2857916) administered in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM). Ann. Oncol. 2019, 30, v447.
  34. Suvannasankha, A.; Bahlis, N.J.; Trudel, S.; Weisel, K.; Koenecke, C.; Rocafiguera, A.O.; Voorhees, P.M.; Alonso, A.A.; Callander, N.S.; Mateos, M.-V.; et al. Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 Study. J. Clin. Oncol. 2022, 40, 8018.
  35. Richardson, P.G.; Biswas, S.; Holkova, B.; Jackson, N.; Netherway, T.; Bao, W.; Ferron-Brady, G.; Yeakey, A.; Shelton, C.; De Oca, R.M.; et al. Dreamm-5: Platform Trial Evaluating Belantamab Mafodotin (a BCMA-directed Immuno-conjugate) in Combination with Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM). Blood 2019, 134, 1857.
  36. Lonial, S.; Grosicki, S.; Hus, M.; Song, K.W.; Facon, T.; Callander, N.S.; Ribrag, V.; Uttervall, K.; Quach, H.; Vorobyev, V.I.; et al. Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study. J. Clin. Oncol. 2022, 40, 8019.
  37. Popat, R.; Nooka, A.; Stockerl-Goldstein, K.; Abonour, R.; Ramaekers, R.; Khot, A.; Forbes, A.; Lee, C.; Augustson, B.; Spencer, A.; et al. DREAMM-6: Safety, Tolerability and Clinical Activity of Belantamab Mafodotin (Belamaf) in Combination with Bortezomib/Dexamethasone (BorDex) in Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2020, 136, 19–20.
  38. Kumar, S.K.; Migkou, M.; Bhutani, M.; Spencer, A.; Ailawadhi, S.; Kalff, A.; Walcott, F.; Pore, N.; Gibson, D.; Wang, F.; et al. Phase 1, First-in-Human Study of MEDI2228, a BCMA-Targeted ADC in Patients with Relapsed/Refractory Multiple Myeloma. Blood 2020, 136, 26–27.
  39. Lee, H.C.; Raje, N.S.; Landgren, O.; Upreti, V.V.; Wang, J.; Avilion, A.A.; Hu, X.; Rasmussen, E.; Ngarmchamnanrith, G.; Fujii, H.; et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia 2021, 35, 255–258.
  40. Kaufman, J.L.; Orlowski, R.Z.; Strassz, A.; Pahl, A.; Michaels, T.; Last, A.; Szaboki, H.; Jentsch, G.; Schoenborn-Kellenberger, O.; Raab, M.-S. Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study. Blood 2022, 140, 7235–7236.
  41. Vincent, F.B.; Saulep-Easton, D.; Figgett, W.A.; Fairfax, K.A.; Mackay, F. The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013, 24, 203–215.
  42. Xing, L.; Lin, L.; Yu, T.; Li, Y.; Cho, S.-F.; Liu, J.; Wen, K.; Hsieh, P.A.; Kinneer, K.; Munshi, N.; et al. A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma. Leukemia 2020, 34, 2150–2162.
  43. Kinneer, K.; Flynn, M.; Thomas, S.B.; Meekin, J.; Varkey, R.; Xiao, X.; Zhong, H.; Breen, S.; Hynes, P.G.; Fleming, R.; et al. Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells. Leukemia 2018, 33, 766–771.
  44. Tai, Y.-T.; Xing, L.; Lin, L.; Yu, T.; Cho, S.-F.; Wen, K.; Kinneer, K.; Munshi, N.; Anderson, K.C. MEDI2228, a novel BCMA pyrrolobenzodiazepine antibody drug conjugate, overcomes drug resistance and synergizes with bortezomib and DNA damage response inhibitors in multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2019, 19, e154–e155.
  45. Xing, L.; Wang, S.; Liu, J.; Yu, T.; Chen, H.; Wen, K.; Li, Y.; Lin, L.; Hsieh, P.A.; Cho, S.-F.; et al. BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression. Clin. Cancer Res. 2021, 27, 5376–5388.
  46. O’Donnell, E.K.; Raje, N.S. New monoclonal antibodies on the horizon in multiple myeloma. Ther. Adv. Hematol. 2016, 8, 41–53.
  47. Ko, J.; Breunig, C.; Figueroa, V.; Lehners, N.; Baumann, A.; Pálfi, A.; Müller, C.; Lutz, C.; Hechler, T.; Kulke, M.; et al. Preclinical Evaluation of Hdp-101, a Novel Anti-BCMA Antibody-Drug Conjugate, in Multiple Myeloma. Blood 2017, 130, 3070.
  48. Singh, R.K.; Jones, R.J.; Shirazi, F.; Hong, S.; Wang, H.; Wan, J.; Kuitase, I.; Pahl, A.; Orlowski, R.Z. HDP-101, a Novel BCMA-targeted Antibody Conjugated to α-Amanitin, is Active against Myeloma with Preferential Efficacy against Pre-clinical Models of Deletion 17p. Clin. Lymphoma Myeloma Leuk. 2019, 19, e152.
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