Bhutani, Manisha

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Background: B-cell maturation antigen (BCMA) is widely expressed on normal plasma cells and malignant plasma cells in multiple myeloma (MM). MEDI2228 is an antibody-drug conjugate (ADC) that targets the extracellular domain of human BCMA with preferential binding to membrane-bound versus circulating soluble BCMA. The ADC is comprised of a fully human antibody to BCMA, site- specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker. After cell surface binding to BCMA, MEDI2228 is internalized and cleaved in the lysosomal compartment, releasing the active PBD, which cross-links DNA and leads to apoptotic cell death. We report the results from a phase 1, first-in-human, open-label, dose-escalation and expansion trial (NCT03489525) that evaluated the safety, pharmacokinetics (PK), and clinical activity of MEDI2228 in patients (pts) with relapsed/refractory MM (R/R MM). Methods: Eligible pts were ≥18 years old with confirmed R/R MM as defined by International Myeloma Working Group consensus criteria, had measurable disease, and had an Eastern Cooperative Oncology Group performance status ≤1. Pts had to have progressed after treatment with three classes of standard-of-care anti-myeloma drugs, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). Dose escalation was based on an accelerated titration design, with an mTPI-2 algorithm. During dose escalation, MEDI2228 was administered in sequentially ascending dose levels (0.0125, 0.025, 0.05, 0.1, and 0.2 mg/kg) intravenously every 3 weeks (Q3W). Due to dose-limiting toxicities (DLTs), the dose was de-escalated from 0.2 mg/kg to an intermediate dose level of 0.14 mg/kg. The primary endpoint was safety and tolerability. Secondary endpoints included assessment of preliminary efficacy, PK, and immunogenicity. Results: As of May 15, 2020, 82 pts received MEDI2228 during dose escalation and expansion. 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%). Pts received between 2-11 lines of prior regimens. At 0.2 mg/kg, 2 pts experienced DLTs (grade 3/4 thrombocytopenia) without bleeding; no DLTs were reported for other dose levels. The maximum tolerated dose was 0.14 mg/kg Q3W. Treatment-related adverse events (TEAEs) occurring in ≥20% of pts in the 0.14 mg/kg cohort were photophobia (53.7%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (19.5%), and pleural effusion (19.5%). No reports of keratopathy or visual acuity loss were observed in the 0.14 mg/kg cohort. The TEAE profiles at lower-dose levels were similar but with lower incidences compared with the 0.14 mg/kg level. Efficacy was demonstrated at all dose levels (dose, objective response rate [ORR], [n]): 0.0125 mg/kg, 33.3% [1/3]; 0.025 mg/kg, 16.7% [1/6]; 0.05 mg/kg, 33.3% [3/9]; 0.10 mg/kg, 27.8% [5/18]; 0.14 mg/kg, 61.0% [25/41]; 0.2 mg/kg, 40.0%, [2/5]. In the 0.14 mg/kg cohort, ORR was 61.0% (95% confidence interval [CI]: 44.5%, 75.8%); there were 10 (24.4%) very good partial responses (VGPRs), 15 (36.6%) partial responses, and 3 (7.3%) minimal responses. Four of the VGPR pts were immunofixation negative. Most (90.2%) pts in the 0.14 mg/kg cohort had received prior daratumumab. Median duration of response (DOR) in the 0.14 mg/kg cohort was not reached. MEDI2228 exhibited linear PK at doses of ≥0.05 mg/kg Q3W that was minimally impacted by circulating levels of soluble BCMA at baseline. There was no difference in BCMA expression by IHC in the bone marrow of responders compared with nonresponders. Thirty-six pts in the 0.14 mg/kg cohort discontinued treatment due to adverse events (n=24), progressive disease (n=8), patient decision (n=2), investigator decision (n=1), or death (n=1). Conclusion: 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. Disclosures Kumar: Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy. Bhutani:Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute. Spencer:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; Servier: Consultancy, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Other, Speakers Bureau; Secura Bio: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Antegene: Consultancy, Honoraria; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Pharmamar: Other. Ailawadhi:Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding. Kalff:Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; CSL: Honoraria. Pore:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Gibson:AstraZeneca: Current Employment, Other: Paid as a clinical scientist contractor. Wang:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Williams:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Kinneer:AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Other: Personal fees; BCMA Monoclonal Antibody-Drug Conjugate: Patents & Royalties: Pending. Zonder:Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Caelum: Consultancy; Celgene: Research Funding. Larsen:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Oncopeptide: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau.