Isatuximab Short-Duration Fixed-Volume Infusion Plus Bortezomib (V) Lenalidomide (R) and Dexamethasone(d) Combined Therapy for Newly Diagnosed Multiple Myeloma (NDMM): Results from a Phase 1b Feasibility/Safety Study
Authors: Ocio Enrique M. , Perrot Aurore , Bories Pierre , San-Miguel Jesus F. , Blau Igor W , Karlin Lionel , Martinez-Lopez Joaquin , Pönisch Wolfram , Bringhen Sara , Ciceri Fabio , Mateos María-Victoria , Rodriguez-Otero Paula , Le Roux Nadia , Dong Yvonne , Fitzmaurice Thomas , Oprea Corina , Moreau Philippe 
Published: November 2020

Background: Isatuximab (Isa), a CD38 monoclonal antibody, is approved in combination with pomalidomide (P) and dexamethasone (d) for treatment of adults with relapsed/refractory multiple myeloma (MM). Bortezomib (V), lenalidomide (R), and d (VRd), is currently standard of care in patients (pts) with newly diagnosed MM not eligible for autologous stem cell transplant (ASCT) (Durie Lancet 2017). This study aims to evaluate the efficacy and safety of the approved short-duration fixed-volume infusion of Isa, combined with VRd in pts with NDMM ineligible or with no immediate intent for ASCT. A weight-based volume infusion of Isa-VRd in the same study (Part A) was well tolerated and efficacious (Ocio Blood 2018).
Methods: In Part B of this Phase 1b study (NCT02513186), Isa (10 mg/kg) is administered as a fixed-volume infusion of 250 mL (mL/h infusion rate vs mg/h) with standard doses of VRd. The primary endpoint is complete response rate of Isa-VRd. The purpose of this first analysis is to assess the feasibility and safety of the fixed-volume infusion, particularly in relationship to infusion reactions (IRs). Recommended premedications are: diphenhydramine 25-50 mg IV (or equivalent), dexamethasone 20 mg IV/PO, ranitidine 50 mg IV (or equivalent), acetaminophen 650-1000 mg PO, montelukast 10 mg PO (or equivalent). The use of montelukast is strongly recommended in Cycle 1, optional from Cycle 2 onward.
Results: Of 46 pts enrolled and treated in Part B, 39 (84.8%) were receiving study treatment at data cut-off (June 15, 2020). Median pt age was 70.0 years (range 49-87), with 8 (17.4%) pts ³75 years old. 24 (52.2%) pts were male. 23 (50.0%) pts were International Staging System Stage 1, with 19 (41.3%) and 3 (6.5%) pts at Stages 2 and 3, respectively. Similarly, 23 (50%) pts had an ECOG performance status of 0, with 22 (47.8%) and 1 (2.2%) pt(s) having an ECOG status of 1 and 2, respectively. Eight (17.4%) pts had bone marrow plasma cells ≥50%. Three (6.5%) pts had a creatinine clearance &lt;60 mL/min/1.73m2.
At data cut-off, 777 infusions had been initiated, median treatment duration was 7.8 months (range 0.5-14), and median number of cycles was 6 (range 1-12). The median duration of Isa infusion decreased from 3.6 hr (range 1.5-8.9) at 1st infusion, to 1.9 hr (range 1.3-4.8) at 2nd infusion, to 1.3 hr (range 1.1-3.4 hr) at 3rd infusion, with subsequent infusion durations averaging 1.3 hr (range 0.3-4.7hr). In Part A, the median duration of infusion was 3.7 hr at 1st infusion, 2.8 hr at 2nd infusion, 2.75 hr at 3rd and 2.5 hr at subsequent infusions.
IRs occurred less frequently with the fixed-volume short infusion method. A total of 15 IRs were reported in 12 (26.1%) pts vs 21 IRs in 17/27 (63.0%) pts in Part A. No Grade ≥3 IRs were reported in Part B vs 1 (5.9%) in Part A. In Part B, IRs occurred in 11 (91.7%) pts during the 1st infusion, 0 (0%) during the 2nd, 1 (8.3%) during the 3rd, 2 (16.7%) during the 4th, and 1 (8.3%) in subsequent infusions. This distribution is similar to Part A, in which 16 (94.1%) pts had IRs during the 1st infusion, 0 (0%) during the 2nd, 1 (5.9%) during the 3rd, 0 (0%) during the 4th, and 3 (17.6%) in subsequent infusions. In Part B, of the 12 pts with an IR, 8 (66.7%) had Isa dose interruption vs 14 (82.4%) pts in Part A. In Part B, 31 (67.4%) pts received montelukast as premedication, among them 7 (58.3%) had an IR.
All 46 pts had ≥1 treatment-emergent adverse event (TEAE). Of these, 28 (60.9%) had a Grade ≥3 event and 3 (6.5%) pts had a TEAE leading to permanent discontinuation of Isa. The most common non-hematologic TEAEs (all grades) included asthenia 25 (54.3%), peripheral edema 17 (37.0%) and fatigue 6 (13.0%). Grade ≥3 infections were reported in 5 (10.9%) and infection SAEs were reported in 17 (37.0%) pts. The most common hematologic abnormalities (Grade ≥3) included anemia (6.5%), neutropenia (34.8%), and thrombocytopenia 13 (28.3%). One pt died (on study) due to progressive disease.
At a median follow-up of 7.28 months (range 1.5-12.4), efficacy data are not sufficiently mature for analysis.
Conclusions: The results of this analysis confirm the safety and feasibility of fixed-volume Isa plus VRd in pts with NDMM. Median Isa infusion duration was approximately 1.3 hr from the 3rd infusion onwards vs 2.5 hr in Part A. IR incidence (26.1% all grade, 0% Grade ≥3) compared favorably with weight-based administration (63% all grade, 5.9% Grade 3) in Part A. These results support Isa 10 mg/kg administered with a 250 mL fixed-volume, plus VRd, in pts with NDMM.

Disclosures
Ocio: MDS: Honoraria; Oncopeptides: Consultancy; Secura-Bio: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Honoraria; GSK: Consultancy; Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Asofarma: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. San-Miguel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karlin:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Janssen: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Bringhen:Bristol-Myers Squibb: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:GlaxoSmithKline: Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding; BMS, Janssen, Amgen: Honoraria; Janssen, BMS: Other: Travel, accommodations, expenses; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria. Le Roux:Sanofi: Current Employment. Dong:Sanofi: Current Employment. Fitzmaurice:Sanofi: Current Employment. Oprea:Sanofi: Current Employment. Moreau:Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria.