Belantamab mafodotin, carfilzomib, lenalidomide и дексаметазон для рецидива или рефракта множественной миеломы.

Introduction

Multiple myeloma (MM) remains an incurable hematologic malignancy. Despite treatment modality advancements that have substantially enhanced outcomes, most patients ultimately experience relapsed and/or refractory (RR) disease. A need persists for innovative therapeutic strategies to surmount resistance, improve response rates, and reduce new emergent adverse events, particularly infections with B-cell maturation antigen (BCMA)-targeting bispecific antibodies and chimeric antigen receptor T cells. 1 Consequently, the development of novel combination regimens is essential to enhance the survival and quality of life of patients with MM.

Belantamab mafodotin (belamaf), an antibody-drug conjugate targeting BCMA, has exhibited encouraging activity in patients with heavily pretreated MM. The DREAMM-2 study assessed the efficacy of belamaf monotherapy in patients diagnosed with RRMM who had undergone previous treatment with proteasome inhibitors (PIs), immunomodulatory drugs, and anti-CD38 therapy. 2 The findings indicated an overall response rate of 31%, accompanied by a median progression-free survival (PFS) of 2.8 months within the 2.5 mg/kg belamaf dosing cohort. 2 Despite its therapeutic efficacy, belamaf has been linked to keratopathy in up to 72% of clinical trial participants, with grade ≥3 events occurring in ∼30%. 2 , 3 This condition can lead to vision-related adverse events, necessitating dose modifications.

Comparatively, daratumumab, an antibody targeting CD38, has been extensively integrated into MM treatment regimens due to its capacity to enhance both the depth and durability of therapeutic responses. Daratumumab-based triplet and quadruplet regimens, particularly those that include PIs and immunomodulatory drugs, significantly enhance outcomes for patients with RRMM. 4 , 5 The DREAMM-7 study examined the efficacy of belamaf in combination with bortezomib and dexamethasone, showcasing promising effectiveness and improved PFS relative to daratumumab-based regimens. 6 This study provides additional support for incorporating belamaf into multidrug therapeutic strategies for individuals with RRMM. Nevertheless, further investigations are necessary to identify optimal treatment combinations and attenuate associated toxicities.

Carfilzomib, a second-generation PI, has exhibited significant efficacy against MM, characterized by sustained therapeutic responses, particularly when administered in combination with lenalidomide and dexamethasone. The ASPIRE trial enrolled patients who had received 1 to 3 previous treatments and found that the carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy considerably prolonged PFS compared with lenalidomide and dexamethasone alone, with reported durations of 26.3 months vs 17.6 months. 7

In light of the successful application of quadruplet therapies and the distinct mechanisms of action, incorporating belamaf into the KRd regimen may further enhance myeloma cytotoxicity and mitigate potential resistance mechanisms. Herein, this phase 1/2 trial evaluates the safety, tolerability, and preliminary efficacy of belamaf in combination with KRd (KRd-b) for patients with RRMM. By reducing belamaf administration to every 8 weeks, this study aims to minimize the corneal toxicity profile of belamaf within the regimen, providing critical insights into its feasibility as part of a multiagent MM treatment approach. By leveraging belamaf’s BCMA-targeting mechanism alongside the well-established efficacy of KRd, this trial seeks to define a novel, more effective therapeutic strategy for patients with RRMM.

Methods

Trial design and patients

This ongoing, open-label, phase 1/2 study ( ClinicalTrials.gov identifier: NCT04822337 ) is being conducted at the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. Herein, the phase 1 dose-escalation and expansion results are reported. Eligible patients were aged ≥18 years with RRMM, received at least 1 previous line of therapy, had measurable disease (defined by at least 1 of the following: serum monoclonal protein level of ≥0.5 g/dL, 24-hour urinary M-protein of ≥200 mg, involved free light chain level of ≥10 mg/dL plus an abnormal free light chain ratio [defined as <0.26 or >1.65]), no previous progression on full-dose (25 mg on days 1-21 of a 28-day cycle) lenalidomide, had an Eastern Cooperative Oncology Group performance status of 0 to 1, and had adequate organ and cardiac function. All patients provided informed consent. A washout period of ≥14 days and adequate recovery from toxicity of previous chemotherapy were required before enrollment. The study was approved by the Wake Forest University School of Medicine institutional review board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonization.

Belamaf dose escalation followed a 3+3 design to determine the maximum tolerated dose (MTD). KRd dosing remained fixed. In the absence of disease progression or the emergence of unacceptable toxicity, patients could receive up to 18 cycles of the treatment regimen, followed by lenalidomide maintenance. Treatment consisted of IV belamaf (dose level 0, 1.4 mg/kg; dose level +1, 1.9 mg/kg; dose level −1, 1.0 mg/kg) on day 1 of odd cycles (ie, every 8 weeks), IV carfilzomib (20 mg/m 2 cycle 1, day 1; 56 mg/m 2 thereafter) on days 1, 8, and 15, oral lenalidomide (25 mg) on days 1 to 21, and oral dexamethasone (40 mg [20 mg for patients ≥75 years]), on days 1, 8, 15, and 22 of 28-day cycles. On days that required dosing with both carfilzomib and belamaf, carfilzomib was administered first.

Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dose-limiting toxicity (DLT) was defined as a treatment-related toxicity that occurred during the first cycle (4 weeks) of treatment, according to the following definitions: (1) any grade febrile neutropenia; (2) grade 4 thrombocytopenia; (3) grade 3 thrombocytopenia with clinically significant bleeding or requiring platelet transfusion; (4) grade 3 rash; (5) grade ≥3 nonhematologic toxicity (excluding grade 3 nausea, vomiting, diarrhea, and hyperglycemia controlled within 48 hours and asymptomatic grade ≥3 electrolyte disturbances controlled with repletion within 72 hours); (6) grade 4 corneal toxicity per the keratopathy visual acuity scale; (7) liver toxicity per stopping criteria (alanine aminotransferase [ALT] of ≥5 × upper limit of normal [ULN]; ALT of ≥3 × ULN persisting for 4 weeks; ALT of ≥3 × ULN and total bilirubin of 2 × ULN; ALT of ≥3 × ULN and international normalized ratio of >1.5; ALT of ≥3 × ULN cannot be monitored weekly for 4 weeks; and ALT of ≥3 × ULN associated with new or worsening symptoms believed to be related to liver injury or hypersensitivity); and (8) treatment-related death.

End points and assessments

The primary end point for dose-escalation and expansion was a binary variable for each participant indicating the occurrence of a DLT during cycle 1. Safety end points were treatment-emergent adverse events, serious adverse events, treatment administration, and the rate and severity of belamaf-mediated keratopathy. Key secondary end points included response, PFS, duration of response (DOR), and overall survival (OS). Response was evaluated using International Myeloma Working Group (IMWG) 2016 response criteria. 8 PFS was defined as duration from enrollment to first occurrence of disease progression (per IMWG criteria) or death or censored at last disease assessment before start of subsequent therapy. For patients achieving complete response (CR) or better, minimal residual disease (MRD) status was assessed by 2-tube, 10-color flow cytometry (sensitivity 10 −5 and 10 −6 ), which included specimen adequacy parameters. 9 , 10 For participants achieving partial response (PR) or better (per IMWG), DOR was defined as time from first response to disease progression or death or censored as described for PFS. OS was defined as time from enrollment to death, or censored at last follow-up.

Statistical analysis

Safety and efficacy analyses were performed in the intent-to-treat population, which included participants who initiated cycle 1, day 1 of KRd-b. The DLT evaluable population comprised participants who initiated cycle 1, day 1 treatment and experienced a DLT during cycle 1, or met the following criteria: (1) completed cycle 1; (2) received full dose of belamaf; (3) received 3 doses of carfilzomib; (4) received at least 17 doses of lenalidomide; (5) received at least 3 doses of dexamethasone; and (6) did not receive platelet transfusions, thrombopoietin mimetics, or neutrophil growth factors during cycle 1.

The primary analysis was dose escalation until the protocol-defined MTD was reached. For response variables, frequencies, and percentages were summarized, and 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Time-to-event analyses used Kaplan-Meier (KM) techniques. Cumulative dose delivered and dose intensity of belamaf were summarized quantitatively. Incident rates for adverse events were summarized. The rate and severity of belamaf-mediated keratopathy were summarized and compared with historical controls dosed every 3 weeks at 3.4 mg/kg using a single-sample exact test for proportions. Median durations of keratopathy events were also estimated with KM methods. Data cutoff for these results was 10 March 2025.

Results

Patient population

Phase 1 of the study enrolled 19 patients (12 in dose escalation, 7 in dose expansion; Figure 1 ) between 13 April 2021 and 19 February 2024. Six patients were treated at 1.4 mg/kg and 13 patients at 1.9 mg/kg belamaf. Median age was 63 years (range, 47-75; Table 1 ). Most (63%) patients were male, 42% were Black, and 53% had unfavorable risk features at enrollment in the study, including 1q gain and 1p deletion. Of 15 patients with available International Staging System staging data at diagnosis, 5 (33%) had stage III disease, 42% had disease refractory to maintenance-dose of lenalidomide, 11% had bortezomib-refractory disease, 26% had double-refractory disease, and 26% had daratumumab-refractory disease. The median line of previous therapy was 1 (range, 1-3). As of data cutoff, 5 participants remain on study treatment (2 on quadruplet therapy, 3 on study maintenance), and the median follow-up (reverse-KM method) was 23 months (range, 1.6-39.1). Figure 1. Participant flow diagram. CONSORT-style flow diagram illustrating patient screening, enrollment, dose escalation, and dose expansion in this phase 1 study of belamaf given every 8 weeks in combination with KRd. The figure reports the number of patients treated at each belamaf dose level, the number evaluable for DLT, and the reasons for exclusion from DLT evaluation or for treatment discontinuation. As of the data cutoff (10 March 2025), some participants had completed planned study therapy or transitioned to maintenance per protocol or per protocol amendment. Table 1. Patient characteristics at baseline Characteristic Belamaf (1.4 mg/kg) + KRd, n = 6 Belamaf (1.9 mg/kg) + KRd, n = 13 Total, N = 19 Age, median (range), y 66 (47-71) 62 (54-75) 63 (47-75) Age ≥75, n (%) 0 (0) 1 (8) 1 (5) Male, n (%) 2 (33) 10 (77) 12 (63) Race, n (%) African American/Black 2 (33) 6 (46) 8 (42) White 4 (67) 7 (54) 11 (58) Ethnicity, n (%) Hispanic or Latino 0 (0) 1 (8) 1 (5) Not Hispanic or Latino 6 (100) 12 (92) 18 (95) Cytogenetics at diagnosis, n (%) del (1p) 0 (0) 1 (8) 1 (5) del (17p) 1 (17) 1 (8) 2 (11) t(4;14) 0 (0) 0 (0) 0 (0) t(14;16) 0 (0) 0 (0) 0 (0) t(14;20) 0 (0) 0 (0) 0 (0) Gain (1q) 1 (17) 6 (46) 7 (37) Cytogenetics at study enrollment, n (%) ∗ del (1p) 0 (0) 0 (0) 0 (0) del (17p) 0 (0) 0 (0) 0 (0) t(4;14) 0 (0) 1 (8) 1 (6) t(14;16) 0 (0) 0 (0) 0 (0) t(14;20) 0 (0) 0 (0) 0 (0) Gain (1q) 3 (50) 4 (33) 7 (39) Functional high risk † at study enrollment, n (%) 2 (33) 3 (23) 5 (26) Unfavorable risk ‡ features at study enrollment, n (%) 4 (67) 6 (46) 10 (53) Median no. of lines of previous therapy (range) 1.5 (1-3) 1 (1-3) 1 (1-3) ISS class, n (%) § I 1 (20) 5 (50) 6 (40) II 2 (40) 2 (20) 4 (27) III 2 (40) 3 (30) 5 (33) R-ISS class, n (%) ǁ I 1 (20) 5 (56) 6 (43) II 3 (60) 3 (33) 6 (43) III 1 (20) 1 (11) 2 (14) Immune modulatory drug, n (%) Lenalidomide exposed 6 (100) 12 (92) 18 (95) Lenalidomide refractory 3 (50) 5 (38) 8 (42) Pomalidomide exposed 2 (33) 3 (23) 5 (26) Pomalidomide refractory 2 (33) 2 (15) 4 (21) PI drug, n (%) Bortezomib exposed 6 (100) 12 (92) 18 (95) Bortezomib refractory 0 (0) 2 (15) 2 (11) Carfilzomib exposed 2 (33) 5 (38) 7 (37) Carfilzomib refractory 1 (17) 3 (23) 4 (21) Anti-CD38 drug (daratumumab), n (%) Daratumumab exposed 2 (33) 5 (38) 7 (37) Daratumumab refractory 2 (33) 3 (23) 5 (26) ISS, International Staging System; R-ISS, revised ISS. ∗ One participant had insufficient cellularity to determine cytogenetics a baseline and therefore is considered unknown for the calculation of these rates. † Functional high risk is defined as early relapse within 18 months of autologous stem cell transplant or 12 months of induction. ‡ Participants could have >1 unfavorable risk feature at enrollment to the study. Unfavorable risk features included functional high risk or unfavorable cytogenetics including del17p, t(4;14), t(14;16), t(14;20), 1q gain, and/or 1p del. § ISS at initial diagnosis was unknown in 4 patients. ǁ R-ISS at initial diagnosis was unknown in 5 patients.

Safety

The DLT rates were 16.7% (1 of 6) and 0% (0 of 12) in the dose level 0 and dose level 1 cohorts, respectively. In the dose escalation part, a single DLT was experienced in the first cohort of 3 patients receiving belamaf at dose level 0 (1.4 mg/kg); therefore, per the 3+3 design, an additional cohort of 3 participants were enrolled at that dose. After no further DLTs were experienced in those participants, the next cohort of 3 participants were enrolled at dose level 1 (1.9 mg/kg). No DLTs were experienced in the first cohort of 3 participants enrolled at dose level 1, so an additional cohort of 3 participants were enrolled at that dose level. The MTD was established as dose level 1 because 0 of 6 DLT-evaluable participants treated at dose level 1 developed a DLT. An additional 6 DLT-evaluable participants were enrolled at the MTD as part of the phase 1 expansion. Based on the entirety of data, the recommended phase 2 dose (RP2D) was determined to be 1.9 mg/kg. Note, 1 participant enrolled in the dose expansion cohort was not DLT evaluable because they did not receive 3 doses of carfilzomib or at least 17 doses of lenalidomide in cycle 1.

All 19 participants enrolled in phase 1 were included in the safety analysis. All patients had at least 1 postbaseline safety assessment, and all participants experienced at least 1 adverse event of any grade. There were no grade 4 nonhematologic adverse events ( Table 2 ). Grade 3 infections occurred in 4 (21.1%) participants; no opportunistic or unusual infections were reported. Due to hypogammaglobulinemia, with immunoglobulin G of <400 mg/dL, 31.6% received IV immunoglobulin. Table 2. Select clinically relevant maximum severity grade adverse events (n = 19) categorized and graded according to common terminology criteria for adverse events version 5.0 Event Belamaf 1.4 mg/kg + KRd, n = 6 Belamaf 1.9 mg/kg + KRd, n = 13 Grade 1 Grade 2 Grade 3-4 All grades Grade 1 Grade 2 Grade 3-4 All grades n (%) n (%) Ocular Keratopathy 1 (16.7) 2 (33.3) 2 (33.3) 5 (83.3) 4 (30.8) 5 (38.5) 4 (30.8) 13 (100.0) Vision decreased 0 (0.0) 2 (33.3) 3 (50.0) 5 (83.3) 0 (0.0) 8 (61.5) 4 (30.8) 12 (92.3) Blurred vision 2 (33.3) 3 (50.0) 0 (0.0) 5 (83.3) 4 (30.8) 3 (23.1) 1 (7.7) 8 (61.5) Eye disorders, other ∗ 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 2 (15.4) 4 (30.8) 0 (0.0) 6 (46.2) Dry eye 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 5 (38.5) 1 (7.7) 0 (0.0) 6 (46.2) Cataract 0 (0.0) 4 (66.7) 0 (0.0) 4 (66.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Photophobia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 1 (7.7) 0 (0.0) 3 (23.1) Eye pain 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Conjunctivitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Glaucoma 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Infection Infections and infestations, other † 0 (0.0) 2 (33.3) 0 (0.0) 2 (33.3) 0 (0.0) 2 (15.4) 1 (7.7) 3 (23.1) Upper respiratory infection 0 (0.0) 2 (33.3) 0 (0.0) 2 (33.3) 0 (0.0) 3 (23.1) 0 (0.0) 3 (23.1) Lung infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 2 (15.4) 3 (23.1) Skin infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (23.1) 3 (23.1) Urinary tract infection 0 (0.0) 2 (33.3) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Abdominal infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Bronchial infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Eye infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Gum infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) Hematologic Neutrophil count decreased 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 5 (38.5) 6 (46.2) Platelet count decreased 0 (0.0) 0 (0.0) 1 (16.7) 1 (16.7) 0 (0.0) 0 (0.0) 5 (38.5) 5 (38.5) Anemia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 2 (15.4) 3 (23.1) Nonhematologic Diarrhea 2 (33.3) 2 (33.3) 0 (0.0) 4 (66.7) 5 (38.5) 1 (7.7) 1 (7.7) 7 (53.8) Fatigue 1 (16.7) 4 (66.7) 0 (0.0) 5 (83.3) 2 (15.4) 4 (30.8) 0 (0.0) 6 (46.2) Hypokalemia 1 (16.7) 1 (16.7) 1 (16.7) 3 (50.0) 2 (15.4) 4 (30.8) 1 (7.7) 7 (53.8) Cough 2 (33.3) 0 (0.0) 0 (0.0) 2 (33.3) 4 (30.8) 3 (23.1) 0 (0.0) 7 (53.8) Pain 3 (50.0) 1 (16.7) 0 (0.0) 4 (66.7) 4 (30.8) 1 (7.7) 0 (0.0) 5 (38.5) Hypophosphatemia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (53.8) 1 (7.7) 8 (61.5) Immune system disorders, other ‡ 0 (0.0) 3 (50.0) 0 (0.0) 3 (50.0) 0 (0.0) 4 (30.8) 1 (7.7) 5 (38.5) Hypomagnesemia 2 (33.3) 1 (16.7) 0 (0.0) 3 (50.0) 3 (23.1) 1 (7.7) 0 (0.0) 4 (30.8) Muscle cramp 3 (50.0) 0 (0.0) 0 (0.0) 3 (50.0) 1 (7.7) 3 (23.1) 0 (0.0) 4 (30.8) Constipation 3 (50.0) 1 (16.7) 0 (0.0) 4 (66.7) 2 (15.4) 0 (0.0) 0 (0.0) 2 (15.4) Dyspnea 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 3 (23.1) 2 (15.4) 0 (0.0) 5 (38.5) Nasal congestion 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 1 (7.7) 2 (15.4) 1 (7.7) 4 (30.8) Nausea 1 (16.7) 2 (33.3) 0 (0.0) 3 (50.0) 1 (7.7) 2 (15.4) 0 (0.0) 3 (23.1) Peripheral sensory neuropathy 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 1 (7.7) 3 (23.1) 0 (0.0) 4 (30.8) Productive cough 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 2 (15.4) 3 (23.1) 0 (0.0) 5 (38.5) Vomiting 2 (33.3) 1 (16.7) 0 (0.0) 3 (50.0) 1 (7.7) 2 (15.4) 0 (0.0) 3 (23.1) Abdominal pain 2 (33.3) 0 (0.0) 0 (0.0) 2 (33.3) 1 (7.7) 1 (7.7) 1 (7.7) 3 (23.1) Edema limbs 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 3 (23.1) 1 (7.7) 0 (0.0) 4 (30.8) Headache 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 3 (23.1) 1 (7.7) 0 (0.0) 4 (30.8) Rash acneiform 4 (66.7) 0 (0.0) 0 (0.0) 4 (66.7) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Skin and subcutaneous tissue disorders, other § 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 1 (7.7) 1 (7.7) 1 (7.7) 3 (23.1) Sore throat 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 4 (30.8) 0 (0.0) 0 (0.0) 4 (30.8) Weight loss 2 (33.3) 0 (0.0) 0 (0.0) 2 (33.3) 0 (0.0) 3 (23.1) 0 (0.0) 3 (23.1) Rash maculo-papular 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 3 (23.1) 0 (0.0) 0 (0.0) 3 (23.1) Tremor 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 2 (15.4) 0 (0.0) 0 (0.0) 2 (15.4) Alkaline phosphatase increased 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Anorexia 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 0 (0.0) 2 (15.4) 0 (0.0) 2 (15.4) Dizziness 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 2 (15.4) 0 (0.0) 0 (0.0) 2 (15.4) Gastrointestinal disorders, other ǁ 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 1 (7.7) 0 (0.0) 3 (23.1) Hyperglycemia 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 1 (7.7) 0 (0.0) 1 (7.7) 2 (15.4) Pain in extremity 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 1 (7.7) 0 (0.0) 3 (23.1) Pruritus 2 (33.3) 0 (0.0) 0 (0.0) 2 (33.3) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) ALT increased 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Back pain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 0 (0.0) 2 (15.4) Bloating 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Creatinine increased 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Dehydration 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Depression 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Dry skin 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 0 (0.0) 0 (0.0) 2 (15.4) Dysgeusia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Fever 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Influenza-like symptoms 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Flushing 2 (33.3) 0 (0.0) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Hoarseness 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (15.4) 0 (0.0) 0 (0.0) 2 (15.4) Hypertension 0 (0.0) 0 (0.0) 1 (16.7) 1 (16.7) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) Mucositis oral 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Neck pain 1 (16.7) 1 (16.7) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Neoplasms benign, malignant, and unspecified (including cysts and polyps), other ¶ 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) Otitis media 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Purpura 1 (16.7) 0 (0.0) 0 (0.0) 1 (16.7) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Surgical and medical procedures, other # 0 (0.0) 1 (16.7) 0 (0.0) 1 (16.7) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) Stroke 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 1 (7.7) This includes eye disorders, infections, hematologic events, stroke, and other nonhematologic events that occurred in at least 10% of patients. ∗ Double vision, cloudy vision, ocular pruritus, bilateral crusting, redness, stye, moderate corneal striae and edema, Fuchs dystrophy, and epitheliopathy. † COVID-19, metapneumovirus, and necrotizing fasciitis. ‡ Hypogammaglobulinemia, seasonal allergies, chest congestion, immune thrombocytopenia, and immunoglobulin deficiency. § Petechiae, painless bumps on inside of lips, skin peeling on hands, rosacea, and skin graft for cellulitis. ǁ Melena, light colored stools, and 24-hour gastrointestinal virus. ¶ Prostate hypertrophy and rectal carcinoma. # Elective implanted port placement and laryngeal biopsy.

For gastrointestinal disorders, diarrhea (57.9%), constipation (31.6%), nausea (31.6%), and vomiting (31.6%) were the most frequently reported events. Three (15.8%) participants experienced grade ≥3 gastrointestinal toxicity. Fatigue occurred in 11 (57.9%) participants and was low in grade (1-2). Only 1 (5.3%) infusion-related reaction was noted. Peripheral neuropathy developed in 6 (31.6%) participants, consistent with carfilzomib exposure, and was reversible with dose adjustments. Grade 3 elevation in hepatic transaminases occurred in only 1 (5.3%) participant.

All but 1 (94.7%) participant experienced at least 1 keratopathy adverse event: 5 (26.3%) grade 1, 7 (36.8%) grade 2, 6 (31.6%) grade 3, and no grade 4 keratopathy. Compared with historical controls dosed every 3 weeks (21% for 3.4 mg/kg dosing), the rate of grade ≥3 keratopathy is not significantly different (2-sided exact test, P = .26). Median time to onset of first keratopathy was 7.6 weeks (range, 4.0-49.1), and the median time to resolution of each keratopathy event was 3.9 months (range, 0.9-12.0 in n = 26 distinct keratopathy events). Median duration of grade ≥2 keratopathy was 1.9 months (range, 0.2-7.7 months; n = 18 distinct keratopathy events that were at least grade 2). Blurred vision occurred in 13 (68.4%) patients (6 [31.6%] grade 1, 6 [31.6%] grade 2, and 1 [5.3%] grade 3), and decreased vision occurred in 17 (89.5%) patients (10 [52.6%] grade 2 and 7 [36.8%] grade 3).

For hematologic toxicities ( Table 2 ), grade 3/4 neutropenia (5 [26.3%]), thrombocytopenia (6 [31.6%]), and anemia (2 [10.5%]) were observed but were manageable with growth factor support, transfusions, and dose interruptions of carfilzomib or lenalidomide.

The median number of quadruplet-treatment cycles administered was 12 (range, 2-18). Belamaf administration by dose cohort and cycle is shown in Figure 2 . Median total dose delivered to participants in the 1.4 mg/kg cohort was 6 mg/kg (range, 1.4-7.2) whereas the median dose intensity across evaluable cycles was 0.87 mg/kg (range, 0.71-1.4). Median total dose administered to participants in the 1.9 mg/kg cohort was 5.7 mg/kg (range, 1.9-14.1) whereas the median dose intensity was 1.06 mg/kg (range, 0.65-1.9). Among the participants in the 1.4 mg/kg dose level, 3 participants received belamaf at 1.0 mg/kg for a total of 13 cycles. Among the participants in the 1.9 mg/kg dose level, 1 participant received belamaf at 1.0 mg/kg for a total of 3 cycles and 5 participants received belamaf at 1.4 mg/kg for a total of 15 cycles. Figure 2. Belamaf dose modifications by cycle. (A) Overall, dose levels 0 and 1. (B) Dose level 0 (1.4 mg/kg) only. (C) Dose level 1 (1.9 mg/kg) only. Parentheses indicate the number of evaluable patients for each cycle.

Efficacy

All 19 enrolled participants were evaluable for efficacy. Objective response was achieved in 17 participants (89.5%; 95% CI, 66.9-98.7), with 15 (78.9%; 95% CI, 54.4-94.0) achieving very good PR or better ( Figure 3 ). Of 2 participants who did not achieve objective response, 1 had achieved PR on their first disease assessment after starting treatment but discontinued study participation entirely before that PR was confirmed. The other participant achieved PR for a single assessment time point, but the subsequent disease assessments did not confirm PR and instead noted minimal response (MR). Of 12 participants who achieved at least CR, all were minimal resedual disease (MRD) negative at 10 −5 sensitivity (9 were MRD negative at 10 −6 sensitivity). As shown in Figure 4 , most participants achieved PR or better by cycle 2. As of data cutoff, 4 participants have experienced PFS events (3 with documented disease progression, 1 death in the absence of disease progression). The 24-month PFS rate was 74.3% (95% CI, 44.1-89.8; Figure 5 A) and, among 17 participants with best confirmed response of PR or better, the 24-month DOR was 78.7% (95% CI, 46.4-92.8). Two participants have died (1 died 6 months after last dose of treatment due to bacterial infection, and 1 died due to MM), and the 24-month OS rate was 85.1% (95% CI, 52.3-96.1; Figure 5 B). Figure 3. ORR and MRD-negative rate. Best overall response per IMWG 2016 criteria for phase 1 participants (N = 19). MRD results provided for participants with at least CR. All participants with at least CR were MRD negative at 10 −5 sensitivity. Flow, flow cytometry; ORR, objective response rate; sCR, stringent CR; VGPR, very good PR. Figure 4. Swimmers plot for depth and DOR for each participant (N = 19). Because 5 participants are still on study treatment as of data cutoff (10 March 2025), responses could still deepen further. MR, minimal response; sCR, stringent CR; VGPR, very good PR. Figure 5. KM survival curves. PFS (A) and OS (B) for all phase 1 participants (N = 19). NE, not evaluable.

Discussion

This phase 1 dose-escalation study evaluated belamaf on an 8-week dosing schedule in combination with KRd for patients with RRMM after 1 to 3 previous lines of therapy. The RP2D of belamaf on an 8-week dosing regimen in combination with KRd was 1.9 mg/kg, with no DLTs at this level. KRd-b was generally well tolerated, with no new safety signals beyond the known ocular profile of single-agent belamaf. Hematologic and nonhematologic toxicities were predictable, manageable with standard supportive care, and did not preclude continued treatment in most cases. Ocular events, primarily keratopathy and blurred vision, were frequent but reversible and effectively managed with dose delays, reductions, and preservative-free ocular eye drops, and steroids-based eye drops.

A key advantage of the KRd-b regimen was the relatively low incidence of infections, a frequent and serious complication in patients with heavily pretreated myeloma. In contrast to chimeric antigen receptor T-cell therapies such as ciltacabtagene autoleucel in the CARTITUDE-1 and CARTITUDE-4 trials, in which grade ≥3 infection rates were 20% and 27%, respectively, 11 , 12 and bispecific antibodies such as teclistamab and elranatamab, with which grade ≥3 infections occurred in 45% to 55% and 40% to 42% of patients, respectively; 13 , 14 , 15 , 16 our cohort experienced a more favorable infection profile (21% grade 3). This may reflect the absence of T-cell redirection and prolonged cytopenias commonly seen with alternative immunotherapeutics.

Another strength of the KRd-b regimen is the manageable safety profile. Although ocular toxicity remains the most frequent adverse event, administering belamaf every 8 weeks, as opposed to every 3 weeks as used in earlier studies, resulted in a lower incidence of grade ≥3 keratopathy. In the DREAMM-2 study, grade ≥3 keratopathy occurred in 27% of patients receiving 2.5 mg/kg every 3 weeks, 2 whereas DREAMM-1 study reported grade 3 keratopathy in 14%. 17 Notably, in DREAMM-7 and DREAMM-8, which explored belamaf every 3 weeks in combination with other agents, the ocular adverse event rate remained a challenge despite reduced dosing frequency. 18 In our study, per protocol, ophthalmologic monitoring (slit-lamp examination and visual acuity testing before each dosing cycle) guided toxicity management. Grade 2 keratopathy mandated dose delay until resolution to grade ≤1; grade 3 keratopathy prompted both delay and reduction of belamaf to 1.4 mg/kg upon rechallenge. Dose delays for ocular events occurred in most of the affected patients; 2 individuals required a dose reduction at the RP2D. Our findings suggest that extended dosing intervals may offer a viable strategy to mitigate this toxicity and preserve efficacy.

Although the primary aim was to define the MTD and RP2D of belamaf, the regimen’s antimyeloma activity was striking. Efficacy signals were both rapid and durable, even within a high-risk, lenalidomide-refractory cohort. Of 19 patients evaluable for efficacy, most achieved at least a PR by the end of cycle 2, with many deepening to very good partial remissions or better with continued treatment. Only 1 patient experienced disease progression leading to death, underscoring the potent combination activity. Over a median follow-up of 16.8 months, the 24-month PFS rate was 80%. The DOR rate at 24 months was 81%, and the OS rate at 2 years was 95%. These survival outcomes compare favorably with historical KRd data, with which 24-month PFS typically ranges from 22 to 26 months and OS from 70% to 85%, 7 , 19 suggesting that belamaf may extend long-term disease control when added to this backbone.

Noticeably, the efficacy was maintained regardless of high-risk cytogenetic abnormalities (including del[17p] and t(4;14)), functional high risk by early progression, or lenalidomide refractoriness, indicating the combination’s potential to overcome mechanisms of resistance. Depth-of-response assessments hinted at substantial rates of complete remissions and stringent complete remission, and MRD negativity was achieved in a subset of patients, aligning with current paradigms associating deeper responses with improved survival. The median time to first response was rapid, most patients responded by cycle 2, and the median time to maximal response was ∼6 months, reflecting continued deepening of remissions with ongoing therapy. Mechanistically, the marked efficacy signals support the preclinical synergy observed between BCMA-targeted antibody-drug conjugates and proteasome-immunomodulatory backbones, and they build on the activity seen in the DREAMM-1 and DREAMM-2 monotherapy studies, with the quadruplet achieving higher and more durable responses than single-agent benchmarks. Furthermore, the consistent PFS and OS across subgroups, including those with lenalidomide-refractory disease, underscores the regimen’s ability to address unmet needs in difficult-to-treat populations. The durability of response is particularly notable: an 81% DOR rate at 2 years suggests a potential paradigm shift compared with previous KRd regimens.

Nonetheless, our study has limitations. Ocular toxicity, although reduced, remained the most common adverse event, and regular ophthalmologic monitoring is essential. Moreover, as a phase 1 trial, the sample size is limited, and longer follow-up is required to assess durability of response and long-term safety. A phase 2 study is warranted to confirm these findings and better define the benefit-risk profile of the KRd-b regimen.

Taken together, these preliminary efficacy data validate the RP2D of belamaf 1.9 mg/kg every 8 weeks in combination with KRd and strongly support advancement into phase 2, in which formal assessment of overall response rate, stringent CR, MRD negativity at 10 −6 sensitivity, time to next treatment, and patient-reported outcomes will be critical. In summary, KRd-b offers a compelling therapeutic option for patients with early RR myeloma, combining deep responses, manageable toxicity, and a low infection burden. Future studies will help clarify its positioning in the treatment paradigm, particularly for patients with lenalidomide-refractory disease.

Conflict-of-interest disclosure: S.A. reports consulting or advisory role with Pfizer and Sanofi; reports research funding from GlaxoSmithKline (GSK), Amgen, Karyopharm Therapeutics, Janssen Oncology (to institution), and Celgene/Bristol Myers Squibb (BMS; to institution); and reports honoraria from Janssen, GSK, and Sanofi. M.P. reports a consulting or advisory role with Caribou Biosciences; and reports research funding from Janssen (to institution), Amgen (to institution), BMS/Celgene (to institution), Takeda (to institution), AbbVie (to institution), Caribou Biosciences (to institution), and The Binding Site (to institution). B.P. reports advisory board participation with Johnson and Johnson, Sanofi, and AbbVie; and reports research funding from BMS. C.F. reports consulting role with Janssen; reports research funding from Janssen and Regeneron; and reports ownership of publicly traded stock in Affimed. P.V. reports consultancy or advisory role with AbbVie, AstraZeneca, BMS, Karyopharm, Lava Therapeutics, Sanofi, Regeneron, Janssen, and GSK; and reports research funding from AbbVie, GSK, Janssen, and Regeneron. The remaining authors declare no competing financial interests.

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Supplementary Material

Supplemental Tables and Figure

Acknowledgments

The authors thank Michelle L Wallander of Atrium Health Levine Cancer for editorial assistance.

This study was supported by research funding from Amgen and GSK LLC to S.A.

Authorship

Contribution: S.A. was responsible for study design, enrollment, and writing of the manuscript, and had a primary investigator role; J.T.S. was responsible for study design, analysis, and writing of the manuscript; M.M.R. was responsible for analysis and writing of the manuscript; S.N. and M.P. had roles in the clinical trial office, and were responsible for building protocol and writing of the manuscript; C. Flynn had a role in the clinical trial office, and was responsible for quality assessment and writing of the manuscript; K.B. and D.R. had roles in the clinical trial office and were responsible for building protocol and writing of the manuscript; X.B. had a role in the clinical trial office, and was responsible for data collection and writing of the manuscript; A.N., J.R., R.F., B.P., C.V., C. Ferreri, and M.P.-R. were responsible for enrollment of patients and writing of the manuscript; and M.B. and P.V. were responsible for enrollment of patients, concept and design, building of protocol, and writing of the manuscript.

Deidentified individual participant data that underlie the reported results are available, from the corresponding author, Shebli Atrash ( shebli.atrash@advocatehealth.org ), on request. The study protocol is included as a data supplement available with the full-text version of this article.

The full-text version of this article contains a data supplement.