Belantamab mafodotin (belamaf) demonstrated deep and durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in DREAMM-2 (NCT03525678). Corneal events, ...specifically keratopathy (including superficial punctate keratopathy and/or microcyst-like epithelial changes (MECs), eye examination findings with/without symptoms), were common, consistent with reports from other antibody-drug conjugates. Given the novel nature of corneal events in RRMM management, guidelines are required for their prompt identification and appropriate management. Eye examination findings from DREAMM-2 and insights from hematology/oncology investigators and ophthalmologists, including corneal specialists, were collated and used to develop corneal event management guidelines. The following recommendations were formulated: close collaboration among hematologist/oncologists and eye care professionals is needed, in part, to provide optimal care in relation to the belamaf benefit-risk profile. Patients receiving belamaf should undergo eye examinations before and during every treatment cycle and promptly upon worsening of symptoms. Severity of corneal events should be determined based on corneal examination findings and changes in best-corrected visual acuity. Treatment decisions, including dose modifications, should be based on the most severe finding present. These guidelines are recommended for the assessment and management of belamaf-associated ocular events to help mitigate ocular risk and enable patients to continue to experience a clinical benefit with belamaf.
Introduction
Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody–drug conjugate ...(ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAF-containing ADCs.
Methods
Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy IVCM) of representative events were selected. A literature review on corneal events reported with other ADCs was performed.
Results
In most patients receiving single-agent belamaf (72%; 68/95), MECs were observed by slit lamp microscopy early in treatment (69% had their first event by dose 4). However, IVCM revealed hyperreflective material. Blurred vision (25%) and dry eye (15%) were commonly reported symptoms. Management of MECs included dose delays (47%)/reductions (25%), with few patients discontinuing due to MECs (1%). The first event resolved in most patients (grade ≥2 MECs and visual acuity each 77%, blurred vision 67%, and dry eye 86%), with no reports of permanent vision loss to date. A literature review confirmed that similar MECs were reported with other ADCs; however, event management strategies varied. The pathophysiology of MECs is unclear, though the ADC cytotoxic payload may contribute to on- or off-target effects on corneal epithelial cells.
Conclusion
Single-agent belamaf represents a new treatment option for patients with RRMM. As with other ADCs, MECs were observed and additional research is warranted to determine their pathophysiology. A multidisciplinary approach, involving close collaboration between eye care professionals and hematologist/oncologists, is needed to determine appropriate diagnosis and management of these patients.
Trial Registration
ClinicalTrials.gov Identifier, NCT03525678.
DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a ...frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3-72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8-not reached NR); median progression-free survival was 5.7 months (2.2-9.7); median overall survival was not reached (8.7 months-NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination 75%), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
The authors of the above mentioned article would like to highlight the following corrections, based upon recent changes to the FDA label and guidance on the use of belamaf
Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or ...refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.
DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing.
Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 27% of 95 patients in the 2·5 mg/kg cohort and 21 21% of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 20% and 33 33%), and anaemia (19 20% and 25 25%); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort).
Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
GlaxoSmithKline.
Background
On the basis of the DREAMM‐2 study (ClinicalTrials.gov identifier NCT03525678), single‐agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple ...myeloma (RRMM) who received ≥4 prior therapies, including anti‐CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM‐2 after 13 months of follow‐up among patients who received belamaf 2.5 mg/kg.
Methods
DREAMM‐2 is an ongoing, phase 2, open‐label, 2‐arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti‐CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee.
Results
As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty‐one of 97 patients (32%; 97.5% confidence interval CI, 21.7%‐43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression‐free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6‐3.6 months), respectively. Response and survival outcomes in patients who had high‐risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow‐up.
Conclusions
Extended follow‐up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.
Extended follow‐up of patients enrolled in the ongoing phase 2 DREAMM‐2 study confirms sustained clinical activity without new safety signals in patients with relapsed or refractory multiple myeloma who receive belantamab mafodotin 2.5 mg/kg every 3 weeks. These data show that belantamab mafodotin has the potential to shift the treatment paradigm in this heavily pretreated, anti‐CD38 monoclonal antibody–exposed patient population, which has a poor prognosis and few alternative treatment options.
Introduction: Patients refractory to an immunomodulatory agent and a proteasome inhibitor, and relapsed/refractory to an anti-CD38 antibody, are a population with a high unmet need given the poor ...prognosis in this setting. Single-agent belamaf (GSK2857916), a B-cell maturation antigen-binding antibody-drug conjugate, has demonstrated deep and durable responses with a manageable safety profile in heavily pretreated patients with RRMM. We used qualitative interviews to understand the patient perspective on clinical benefits and tolerability of belamaf.
Methods: Patients enrolled in the DREAMM-2 study (NCT03525678) received single-agent belamaf 2.5 or 3.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. All were invited to participate in interviews at Cycle 4 (C4) and end of treatment (EOT). If the patient discontinued treatment before C4, only one interview was conducted. Interview questions covered the patient symptom experience, treatment-related burden, and adverse events. Disease and treatment-related symptom severity and overall treatment satisfaction were rated 0-10 (0=not severe to 10=most severe/0=not at all satisfied to 10=extremely satisfied). Qualitative and quantitative analyses were conducted with interview results and select variables from the clinical trial dataset.
Results: A total of 104 patients (across both doses) participated in interviews before or at C4, with 56% (n=58) identified as responders to treatment (≥partial response by International Myeloma Working Group criteria). Among the 104, the most commonly reported disease symptoms were fatigue (reported by 68% of patients), neuropathy (43%), and bone pain (37%). Responders reported a decrease in severity of these symptoms from the start of the study to the time of interview, with ratings changing from 6.9 to 3.6 (bone pain), 4.6 to 3.4 (fatigue), and 4.5 to 3.7 (neuropathy). The severity ratings for nonresponders increased slightly for fatigue (4.4 to 4.5) and decreased for bone pain (4.9 to 4.4) and neuropathy (3.9 to 2.8). Fifty-nine (57%) patients interviewed at or before C4 reported visual impairments, including poor vision, blurred vision, and sensitivity to light, while 42 (40%) reported symptoms of eye irritation, including irritated eyes, dry eyes, itchy eyes, and the feeling of something in the eye. Twelve (12%) patients reported eye pain, including sore eyes and burning at or before C4. Responders interviewed before or at C4 reported a mean treatment satisfaction of 8.5, while nonresponders reported their satisfaction at 5.1.
A total of 26 patients were interviewed at EOT after C4, 22 (85%) of whom were responders to treatment. Patients interviewed at EOT reported decreased severity in their ocular symptoms between the time when the symptoms were at their worst and the 2-week period prior to their interview. Between worst symptoms and interview, participant severity ratings showed a decrease from 8.0 to 0.0 (for eye pain; n=4), 7.2 to 1.8 (for eye irritation; n=11), and 8.1 to 2.9 (for visual impairment; n=17).
All 26 patients interviewed at EOT indicated they expected the ocular side effects they experienced. Six patients considered stopping treatment due to their ocular symptoms, two of whom reported their doctor discontinued treatment for this reason. At EOT, these 26 patients reported high treatment satisfaction, with responders rating their satisfaction higher than nonresponders (8.1 and 6.7, respectively).
Conclusions: Trial-embedded interviews provide valuable insights into the patient experience with their disease, the course of treatment-related side effects, and their overall impact on patient satisfaction with treatment. Overall, responders to treatment with single-agent belamaf reported more improvement than nonresponders in key disease symptoms, including bone pain and fatigue. Many patients reported some type of ocular symptom, but these were shown to improve or resolve by EOT. Despite ocular symptoms, overall, patients reported high satisfaction while on treatment and a desire to remain on treatment, particularly in responders. These qualitative interviews, in addition to the efficacy data, support the use of belamaf in patients with RRMM.
Funding: GSK 205678; drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa.
Eliason:GSK: Current Employment, Current equity holder in publicly-traded company. Correll:Evidera: Current Employment. Martin:Evidera: Current Employment. Cardellino:GSK: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gorsh:GSK: Current Employment, Current equity holder in publicly-traded company. Sapra:GSK: Current Employment, Current equity holder in publicly-traded company. Popat:AbbVie: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).
In the randomized phase II DREAMM-2 study, single-agent belantamab mafodotin demonstrated deep and durable responses and a manageable safety profile in triple-class refractory relapsed/refractory ...multiple myeloma (RRMM). We present patient-reported outcomes (PROs) from this study for patients treated with the approved dose of belantamab mafodotin (2.5 mg/kg q3w). Disease and treatment-related symptoms, health-related quality of life (HRQOL), functioning, and patient-reported ocular changes were assessed using questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life questionnaires EORTC-QLQ-C30 and EORTC-QLQ-MY20, Ocular Surface Disease Index OSDI, and the National Eye Institute Visual Functioning Questionnaire 25 NEI VFQ-25) at baseline, during treatment (every 3 or 6 weeks), and at the end of treatment (EOT). Eye examinations were conducted at baseline, prior to each treatment cycle, and at EOT. Patients reported ocular symptoms in the OSDI and NEI VFQ-25 questionnaires, with the median time to worst severity of 45 to 64 days depending on symptoms considered. Some limitations in driving and reading were reported. Ocular symptoms were improved and median time to recovery was 23.5 to 44.0 days. EORTC-QLQ-C30 data suggest core MM symptoms (including fatigue and pain), overall HRQOL, and patient functioning were maintained while patients continued belantamab mafodotin treatment, even if meaningful worsening of vision-related symptoms occurred. These PRO results, together with the clinical efficacy of belantamab mafodotin, support its use in patients with RRMM and further evaluation of its use at earlier lines of therapy.
Introduction: Patients with heavily pretreated RRMM have a poor prognosis (median overall survival OS: 6-9 months) and a need for novel, well-tolerated treatments that induce lasting responses ...(Gandhi Leukemia 2019; Chari NEJM 2019). Belamaf (GSK2857916) is a first-in-class, B-cell maturation antigen-targeting, antibody-drug conjugate (ADC) containing monomethyl auristatin F (MMAF). In DREAMM-2 (NCT03525678), patients with heavily pretreated RRMM who responded to single-agent belamaf maintained deep and durable responses at 13-month follow-up (median OS: >13 months) with a manageable safety profile (Lonial ASCO 2020, Poster 436). Consistent with other MMAF-containing ADCs, ocular events were common (Farooq et al. Ophthal Ther 2020). These events included keratopathy (microcyst-like epithelial changes MECs: an eye exam finding with/without symptoms), best-corrected visual acuity (BCVA) changes, and symptoms (blurred vision and dry eye). Longer-term recovery data will help inform management strategies.
Methods: In DREAMM-2, eye exams were conducted at baseline and prior to each dose in patients received single-agent belamaf (2.5 or 3.4 mg/kg Q3W) and included a corneal exam and assessment of BCVA change from baseline (Snellen visual acuity VA). Dose modifications (delays/reductions) were permitted to manage these events. The corneal events were graded per the Keratopathy and Visual Acuity (KVA) scale, which combined corneal exam findings and BCVA changes from baseline. Dose modifications were determined based on the most severe KVA scale grade. These events were followed until recovery, defined as any Grade 1 exam findings/no exam findings, and ≤1-line decline in Snellen VA compared with baseline. A change to a BCVA 20/50 or worse (ie, limiting driving ability) in the better-seeing eye (in patients with BCVA better than 20/50 at baseline) was considered one definition of clinically meaningful VA decrease. Recovery of these events was defined as BCVA improvement to better than 20/50 (better-seeing eye). We report ocular event outcomes for patients receiving belamaf 2.5 mg/kg (recommended dose for future clinical development) from a 13-month follow-up post-hoc analysis.
Results: In patients receiving single-agent belamaf 2.5 mg/kg, 72% (68/95) experienced a treatment-related eye exam finding of keratopathy (MECs) (Farooq Ophthal Ther 2020).Fewer patients (56%; 53/95) had symptoms (eg, blurred vision or dry eye) and/or a ≥2-line BCVA decline (better-seeing eye). Treatment discontinuations due to ocular events were rare (3% 3/95 total; 1% 1/95 each due to keratopathy MECs, blurred vision, and reduced BCVA (Farooq Ophthal Ther 2020).
In patients with keratopathy (MEC) events Grade ≥2 per KVA, 48% (29/60) had >1 event. The first event recovered in 77% (46/60; Table; Farooq Ophthal Ther 2020). At last follow-up, 48% (29/60) had documented recovery of their most recent event (Farooq Ophthal Ther 2020). In patients with unrecovered events at last follow-up, 45% (14/31) are receiving treatment or in follow-up. The remaining 55% (17/31) are no longer in follow-up (9 died; 4 withdrew from study; 4 lost to follow-up). 84% (37/44) of patients with Grade 3/4 events were improving or had recovered events at last follow-up.
Seventeen (18%) patients had a clinically meaningful BCVA decline, with no reports of complete permanent vision loss (Farooq Ophthal Ther 2020). Of these patients, 76% (13/17) had 1 event and 24% (4/17) had 2 events (no patients had >2 events). 82% (14/17) had recovery of their first event and 82% (14/17) had recovery at last follow-up (Farooq Ophthal Ther 2020). Of the remaining 3 patients with unrecovered events, 1 patient is receiving treatment and 2 patients are no longer in follow-up (1 died due to disease progression; 1 withdrew from study).
Conclusions: Though keratopathy (MECs) were frequently observed on eye exam, the majority of patients did not experience a clinically meaningful BCVA decline, and events rarely led to treatment discontinuation. The first keratopathy (MEC) event or clinically meaningful BCVA decline recovered in the majority of patients with events. In this ongoing study, patients are being followed for recovery. Based on experience, it is anticipated these events will likely recover over time.
Funding: GSK (205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa.
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Lonial:Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Genentech: Consultancy. Nooka:Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Thulasi:Emory University: Current Employment. Badros:University of Maryland: Current Employment; Amgen: Consultancy. Jeng:Kedrion, Merck, GSK: Consultancy; University of Maryland: Current Employment; EyeGate: Current equity holder in publicly-traded company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Zaugg:University of Utah: Current Employment. Popat:Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria. Degli Esposti:GlaxoSmithKline: Consultancy, Honoraria; Moorfields Eye Hospital: Current Employment. Byrne:Adaptimmune, Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dana:Kala: Consultancy; Alcon: Consultancy; GSK: Consultancy; Aramis Biosciences, Claris Biotherapeutics, GelMEDIX: Current equity holder in private company; Novartis: Consultancy; Dompe: Consultancy; Massachusetts Eye and Ear; Harvard Medical School Department of Ophthalmology: Current Employment; NIH, DOD, Allegan: Current equity holder in publicly-traded company. Farooq:GlaxoSmithKline: Consultancy; University of Chicago: Current Employment. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Introduction: IRRs are commonly reported by patients receiving intravenous (IV) treatments for RRMM (Nooka et al. J Oncol Pract 2018); these can be troublesome for patients and can lead to ...discontinuation of treatment, negatively impacting durability of response. In the Phase II DREAMM-2 study (NCT03525678), single-agent belamaf (GSK2857916), a first-in-class B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, demonstrated deep and durable responses with a manageable safety profile in patients with heavily pre-treated RRMM (Lonial et al. ASCO 2020; poster 436). As expected with IV biologic agents, IRRs were commonly reported in this study, but were considered self-limited. Here, we report details on IRRs for patients receiving belamaf 2.5 mg/kg (the recommended dose for future clinical development) after 13-months of follow-up.
Methods: In the DREAMM-2 study, patients with RRMM progressing after ≥3 prior therapies, refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody, and who provided informed consent, received single-agent belamaf (2.5 or 3.4 mg/kg IV every 3 weeks) on Day 1 of each cycle until disease progression or unacceptable toxicity. Pre-medication for IRR prophylaxis was not protocol mandated (administered per investigator discretion, if deemed medically appropriate). These events were graded by Common Terminology Criteria for Adverse Events criteria version 4.03 and included the terms: IRR, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, hypotension, lethargy, and tachycardia. Grade 2 IRRs were managed by stopping the infusion, providing medical treatment and continuing the infusion at half the original infusion rate until resolution to Grade ≤1. Grade 3 IRRs were managed by discontinuing the infusion until recovery to Grade ≤1, after which the treatment could only continue (with pre-medication and a longer infusion time) following discussion with the study sponsor; all future infusions were pre-medicated. Patients experiencing Grade 4 IRRs were permanently withdrawn from the study. IRRs were followed until resolution/stabilization.
Results: After 13-months of follow-up, IRRs occurred in 20/95 (21%) patients; most were mild to moderate in severity, with no Grade 4 or 5 events (Grade 1, n=6 30%; Grade 2, n=11 55%; Grade 3, n=3 15%). Pyrexia was reported in 5/20 (25%) patients; chills, diarrhea, and nausea in 2/20 (10%) each; asthenia, hypertension, lethargy, and tachycardia in 1/20 (5%) patients each; and the adverse event term ’IRR’ was recorded for 16/20 (80%) patients. In most patients (18/20 90%), IRRs occurred during Cycle 1, and the incidence of these events declined thereafter (Figure). Of 73/95 (77%) patients without pre-medication at Cycle 1, 12 (16%) experienced an IRR. A total of 22/95 (23%) patients received a pre-medication at Cycle 1; of these, 8 (36%) had an IRR. Among the 20 patients experiencing an IRR, 11 (55%) received ≥1 pre-medication over the course of the study (most commonly: antihistamine, n=6 30%; analgesic (paracetamol); n=7 35%; steroid, n=6 30%). The median time of onset of the first IRR occurrence was at Day 1 (range: 1-22). The median duration of IRRs was 1 day (range: 1-3). Most patients experiencing IRRs (12/20 60%) had only one event; 3 (15%) experienced two IRRs and 5 (25%) patients had ≥3 events. Treatment was permanently discontinued due to IRRs in 1 (5%) patient (Grade 3 IRR at first and second infusion); no dose reductions or interruptions/delays occurred due to an IRR. At 13-month follow-up, IRRs were considered recovered/resolved in most (18/20 90%) patients (recovered/resolved with sequelae; recovering/resolving, n=1 5% each).
Conclusions: As expected with biologic treatments administered via IV infusion, IRRs were reported with belamaf in the DREAMM-2 study. However, IRRs were typically mild-to-moderate in severity and most were considered resolved at 13-month follow-up. Importantly, IRRs resulted in few dose modifications or discontinuations, allowing patients to continue active belamaf treatment, which has been associated with durable responses in patients with RRMM.
Funding: GSK (Study 205678; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.
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Nooka:Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Lee:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Voorhees:TeneBio: Honoraria, Other: Other relationship; Janssen: Honoraria, Other: Other relationship; Adaptive Biotechnologies: Honoraria, Other: Other relationship; Oncopeptides: Honoraria, Other: Other relationship; Novartis: Honoraria, Other: Other relationship; GSK: Honoraria, Other: Other relationship; BMS/Celgene: Honoraria, Other: Other relationship. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Karlin:Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Arnulf:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Zhi:GSK: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Lewis:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Cohen:Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Lonial:Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Genentech: Consultancy; Onyx: Honoraria.
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