MEDI2228 / AstraZeneca - LARVOL DELTA

Dose Delays and Treatment Interruptions Secondary to Ocular Toxicity From BCMA-Directed Antibody Drug Conjugate Therapy in Relapsed Multiple Myeloma. (PubMed, Clin Lymphoma Myeloma Leuk) - "Treatment interruptions, dose reductions and drug discontinuation are common with BCMA-directed ADC therapy. Research to optimize the administration schedule of these agents is warranted. BelMaf and MEDI2228 produce distinct patterns of ocular side-effects, namely keratopathy and reduced visual-acuity with the former, and photophobia and dry eyes with the latter."

Journal • Dry Eye Disease • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Ophthalmology

Dose delays and treatment interruptions secondary to ocular toxicity from BCMA-directed antibody drug conjugate therapy in relapsed multiple myeloma (Clin Lymphoma Myeloma Leuk) - "Treatments included BelMaf monotherapy (n=56), BelMaf combination therapy (n=12) and MEDI2228 monotherapy (n=43). The overall response rate was 30% for BelMaf and 44% for MEDI2228. Photophobia was more common with MEDI2228 (any-grade: 12% vs. 49%, p<0.001), whereas keratopathy was more common with BelMaf (any-grade: 59% vs. 9%, p=0.002)."

Retrospective data • Multiple Myeloma

Ocular toxicity and tolerability of BCMA directed antibody drug conjugate (ADC) therapy in relapsed multiple myeloma (MM). (ASCO 2025) - "Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter."

Dry Eye Disease • Hematological Malignancies • Multiple Myeloma • Oncology • Ophthalmology

Phase 1 first-in-human study of MEDI2228, a BCMA-targeted ADC, in patients with relapsed refractory multiple myeloma. (PubMed, Leuk Lymphoma) - P1 | "In cohort B (n=25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug."

Journal • P1 data • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Thrombocytopenia

Effectiveness of anti-B-cell maturation antigen (BCMA)-targeting therapy after selinexor treatment (IMW 2023) - P1b/2, P2b, P3 | "The influence of selinexor-based treatment on T cell function, which may alter the efficacy of αBCMA agents following selinexor treatment, is unknown. We analyzed the effectiveness of non-cellular αBCMA (NCA) therapies in pts with MM treated in 4 clinical studies (STORM [NCT02336815]; STOMP [NCT02343042]; BOSTON [NCT03110562], XPORT-MM-028 [NCT04414475]) with selinexor + dexamethasone (Xd), with or without PIs, IMiDs, or αCD38 mAbs, followed by therapy with NCA...Thirty-seven pts (median age: 68, range: 40-87) received NCA therapy at any time following a selinexor regimen (Xd, n=12; Xd + bortezomib, n=9; Xd + pomalidomide, n=6; Xd + daratumumab, n=3; Xd + carfilzomib, n=5; Xd + ixazomib, n=2). NCAs included the ADC belantamab mafodotin (n=28), the BiS teclistamab (n=2), SEA-BCMA (n=2), AMG 701 (n=1), elranatamab (n=1), MEDI2228 (n=1), and investigational (n=3; 2 had αBCMA bispecific antibodies and 1 had αBCMA BITE) (1 pt received 2 NCAs, belantamab and..."

Hematological Malignancies • Multiple Myeloma • Oncology

Effectiveness of anti-B-cell maturation antigen (BCMA)-targeting therapy after selinexor treatment. (ASCO 2023) - P1b/2, P2b, P3 | " We analyzed the effectiveness of non-cellular αBCMA (NCA) therapies in pts with MM treated in 4 clinical studies (STORM [NCT02336815]; STOMP [NCT02343042]; BOSTON [NCT03110562], XPORT-MM-028 [NCT04414475]) with selinexor + dexamethasone (Xd), with or without PIs, IMiDs, or αCD38 mAbs, followed by therapy with NCA...Thirty-seven pts (median age: 68, range: 40-87) received NCA therapy at any time following a selinexor regimen (Xd, n = 12; Xd + bortezomib, n = 9; Xd + pomalidomide, n = 6; Xd + daratumumab, n = 3; Xd + carfilzomib, n = 5; Xd + ixazomib, n = 2). NCAs included the ADC belantamab mafodotin (n = 28), the BiS teclistamab (n = 2), SEA-BCMA (n = 2), AMG 701 (n = 1), elranatamab (n = 1), MEDI2228 (n = 1), and investigational (n = 3; 2 had αBCMA bispecific antibodies and 1 had αBCMA BITE) (1 pt received 2 NCAs, belantamab and teclistamab)... In this cohort of heavily-pretreated pts with MM who received a selinexor regimen prior to NCA, overall..."

Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology

Selinexor-Based Regimens in Patients with Multiple Myeloma after Prior Anti-B-Cell Maturation Antigen Treatment (ASH 2021) - P1b/2 | "X is approved with bortezomib (V) and dexamethasone (XVd) in patients (pts) with at least 1 prior therapy and is not associated with known long-term clinically significant toxicities such as visual loss, cardiac dysfunction, renal failure, neuropathy, irreversible bone marrow suppression, second malignancies, venous thromboembolism, or rash...Here we report on all pts in STOMP with prior anti-BCMA treatment who were treated on STOMP with X+pomalidomide +dexamethasone (XPd); XVd; X+carfilzomib+d (XKd); XPVd; and XPd+elotuzumab (E) (XPEd). Results In total, 11 pts with prior anti-BCMA therapy (6 pts with belantamab mafodotin; 1 each with MEDI2228, SEA-BCMA, BCMA BITE; 2 with idecabtagene vicleucel) were treated with 5 X-containing regimens (Table 1): 9 pts were treated with triplets XPd (4), XVd (3), or XKd (2) and 2 pts with quadruplets XPVd (1) or XPEd (1)...Conclusions In this follow-up cohort of heavily pretreated pts, a majority of whom with MM refractory to..."

Clinical • Cardiovascular • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • Pain • Renal Disease • Thrombocytopenia • Venous Thromboembolism

ANTIBODY DRUG CONJUGATES (ADCS) (EMN 2023) - P3 | "Belantamab Mafodotin (belamaf) is the first approved anti-BCMA ADC for the treatment of relapsed/refractory multiple myeloma (RRMM)...Three-phase III studies evaluate the safety and efficacy of belamaf in combination with pomalidomide (NCT04162210; DREAMM-3), daratumumab plus bortezomib (NCT04246047; DREAMM-7), or pomalidomide plus bortezomib (NCT04484623: DREAMM-8)...MEDI2228 has shown potent antitumor activity in preclinical models, including cell lines resistant to lenalidomide. Phase 1 data in heavily pretreated patients were encouraging."

IO biomarker • Anemia • Multiple Myeloma • Ophthalmology • Thrombocytopenia • EGFR • TNFA

Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to BCMA-targeting antibody-drug conjugate treatment (IMW 2022) - P2 | "All 13 who received cilta-cel had prior belantamab mafodotin (as last line of therapy [LOT] in 4 patients); 1 had also received MEDI2228 and 1 had also received BCMA-targeting bispecific antibody (REGN5459). MM patients who had previous exposure to an anti-BCMA ADC therapy had favorable responses, DOR, and PFS following cilta-cel. These results may inform treatment plans, including sequencing and washout period between BCMA-targeting agents."

Clinical • CNS Disorders • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Movement Disorders • Multiple Myeloma • Novel Coronavirus Disease • Oncology • Parkinson's Disease • Pneumonia • Respiratory Diseases

[VIRTUAL] Phase 1, First-in-Human Study of MEDI2228, a BCMA-Targeted ADC in Patients with Relapsed/Refractory Multiple Myeloma (ASH 2020) - P1 | "All pts had received prior therapy with an IMiD, PI, and mAb: lenalidomide, 76 (94%); pomalidomide, 68 (84%); bortezomib, 77 (95%); carfilzomib, 64 (79%); and daratumumab, 71 (87%). MEDI2228 is a BCMA-targeted ADC that demonstrated clinical efficacy at all dose levels explored. MEDI2228 0.14 mg/kg Q3W had a manageable safety profile and an ORR of 61% in a heavily pretreated population with myeloma that is R/R post PI, IMiD, and mAb therapies."

Clinical • IO biomarker • P1 data • Dry Eye Disease • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • Ophthalmology • Respiratory Diseases • Thrombocytopenia

MEDI2228 in Subjects With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=107 | Completed | Sponsor: MedImmune LLC | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

MEDI2228 in Subjects With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=107 | Active, not recruiting | Sponsor: MedImmune LLC | Trial completion date: Jun 2022 ➔ Mar 2022 | Trial primary completion date: Jun 2022 ➔ Mar 2022

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

MEDI2228, a Novel Bcma Antibody-PBD Conjugate, Sensitizes Human Multiple Myeloma Cells to NK Cell-Mediated Cytotoxicity and Upregulates CD38 Expression in MM Cells (ASH 2019) - P1; "MEDI2228 induces DNA damage responses (DDR) prior to apoptosis, as demonstrated by phosphorylation of ATM/ATR, CHK1/2, and gH2AX in MM cells regardless of p53 status and responsiveness to current MM therapies including bortezomib and IMiDs. Simultaneously, MEDI2228 induces IFN-stimulated genes, including CD38, resulting in enhanced MM cell lysis by daratumumab. These results indicate additional mechanisms of anti-MM activity for MEDI2228 and suggest that a combination of MEDI2228 and anti-CD38 mAbs may further improve outcome for MM patients."

IO biomarker • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • ATR • CD38 • CHEK1

Anti-Bcma PBD MEDI2228 Combats Drug Resistance and Synergizes with Bortezomib and Inhibitors to DNA Damage Response in Multiple Myeloma (ASH 2019) - P1; "Significantly, MM cells with lower BCMA expression and resistance to bortezomib or immunomodulatory drugs (IMiDs, i.e., lenalidomide, pomalidomide) are more susceptible to MEDI2228 vs its MMAF ADC homolog. Moreover, DDR checkpoint inhibitors, i.e., AZD0156 (ATMi), AZD6738 (ATRi), AZD1775 (WEE1i), synergize with MEDI2228 to enhance MM cell cytotoxicity (combination index < 1). This study therefore further supports clinical development of MEDI2228 (NCT03489525) as an important next-generation immunotherapy to improve outcome of MM patients."

IO biomarker • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Multiple Myeloma • Oncology • ATR • CHEK1 • IL6

BCMA-specific ADC MEDI2228 and Daratumumab induce synergistic myeloma cytotoxicity via enhanced IFN-driven innate immune responses and expression of CD38 and NKG2D ligands (IMW 2021) - "It overcame CD38 downregulation triggered by IL6 and bone marrow stromal cell culture supernatant (BMSC- sup), via activation of STAT1-IRF1 without phosphorylation of STAT3 in immunomodulatory drugs (IMiDs)- and bortezomib-resistant MM cell lines. Taken together, our data showed that MEDI2228 restored MM sensitivity to CD38 targeting by Dara without depleting NK cells and potentiated immunogenic cell death of MM cells. These results therefore provide the mechanistic rationale for clinical evaluation of combination CD38- and BCMA-directed immunotherapies to further improve patient outcome in MM."

IO biomarker • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Multiple Myeloma • Oncology • CCL2 • CCL22 • CCR7 • CD38 • CGAS • CSF2 • CXCL9 • GZMB • IFIT1 • IKBKE • IL6 • NKG2D • RUNX3 • SOCS1 • STAT1 • STAT3 • STING

MEDI2228 in Subjects With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=107; Active, not recruiting; Sponsor: MedImmune LLC; Trial completion date: Jul 2021 ➔ Jun 2022; Trial primary completion date: Jul 2021 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

BCMA-specific ADC MEDI2228 and Daratumumab induce synergistic myeloma cytotoxicity via IFN-driven immune responses and enhanced CD38 expression. (PubMed, Clin Cancer Res) - "These results provide the basis for clinical evaluation of combination MEDI2228 with Dara to further improve patient outcome in MM."

IO biomarker • Journal • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD38 • IL6 • NKG2D • STAT1 • STING

"Didn't they drop MEDI2228 from the pipeline?" (@tame_lioness)

Combinations and T-Cell Engagers Push Myeloma Paradigm Forward (OncLive) - "'There has been such a breadth of new data coming out in the non-CAR T-cell therapy setting for relapsed disease,' said Ailawadhi. 'The bottom line is we are not going to be using drugs as single agents; that is not where the benefit [of these agents] lies in multiple myeloma. [Also,] although the initial CAR T-cell therapy data have given us extremely good signals, T-cell engagers may provide an alternative [option]. Immunotherapy for myeloma has finally arrived.'"

Interview • Media quote

MEDI2228 in Subjects With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=107; Active, not recruiting; Sponsor: MedImmune LLC; Trial completion date: May 2022 ➔ Jul 2021; Trial primary completion date: May 2022 ➔ Jul 2021

Clinical • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Product discontinued (AstraZeneca Press Release) - Multiple Myeloma

Multiple Myeloma

"MEDI2228 has just been discontinued $AZN (no surprise: 45% ORR in 82 patients per #ASH20 abstract)" (@JacobPlieth)

Clinical

MEDI2228 in Subjects With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=142; Active, not recruiting; Sponsor: MedImmune LLC; Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

First-in-human trial of an anti-BCMA ADC for R/R myeloma (YouTube) - P1, N=NA; NCT03489525; Sponsor: MedImmune LLC; "Meletios Dimopoulos, MD...discusses the results of a Phase I, first-in-human dose-escalation trial (NCT03489525) of MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma....This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020."

Interview • P1 data • Video

Expert Selections From ASH 2020: Multiple Myeloma (Clinical Care Options) - "In this commentary, Shaji K. Kumar, MD, and Sagar Lonial, MD, share insights on selected abstracts from ASH 2020 about multiple myeloma (MM) and how these data are poised to affect clinical practice."