Motixafortide + G-CSF hematopoietic stem cell mobilization in patients with multiple myeloma following quadruplet induction therapy

Abstract

Abstract Quadruplet (quad) induction (anti-CD38 mAb, IMiD, PI and steroid) has become the standard-of-care (SoC) in transplant-eligible newly diagnosed multiple myeloma (MM). However, quad induction is associated with impaired hematopoietic stem cell (HSC) mobilization. In the GENESIS Trial (NCT03246529), motixafortide (M) + G enabled 92.5% to collect ≥6×106 CD34+ cells/kg in ≤2 leukocytapheresis procedures (LPs). However, 3-drug induction (IMiD, PI and steroid) was SoC during GENESIS Trial enrollment, M was administered from 6-8pm and injection reactions occurred in >80% of patients with standard premeds. Therefore, we prospectively assessed the efficacy of M+G mobilization post-quad induction, while evaluating an earlier M administration time to optimize mobilization logistics and an enhanced premedication (premed) regimen to mitigate adverse effects (AEs). Lastly, we explored the mechanism of impaired HSC mobilization post-quad induction by immunophenotyping of HSC subsets. This was a prospective, open-label, 2-arm trial in patients with newly diagnosed MM (age 18-78 years, ECOG 0-1) receiving HSC mobilization with M (1.25 mg/kg, subcutaneous) + G (10 μg/kg, subcutaneous) following 3-6 cycles of quad induction (NCT06547112). All patients received G on Days 1-5. Arm 1 received M on Day 4 between 6-8pm with LP on Day 5 (~12 hrs post-M), as “standard” dosing. Arm 2 received M on Day 4 between 2-4pm with LP on Day 5 (~16 hrs post-M), as “early” dosing. All patients received “enhanced” premeds with: loratadine (10 mg, PO), famotidine (20 mg, PO) and montelukast (10 mg, PO) daily on Day 1-5; plus acetaminophen (975mg, PO), hydrocortisone (200 mg, IV), diphenhydramine (25 mg, IV) and famotidine (20 mg, IV) on Day 4 (30-45 mins pre-M). Peripheral blood (PB) mobilization kinetics (CD34+ cells/μl) and apheresis yields (CD34+ cells/kg) were tracked for each arm. Mobilization-related AE rates with enhanced premeds were assessed via CTCAE v5.0. The absolute number and relative proportions of CD34+ HSC subsets in the apheresis product were assessed by extended immunophenotyping via FACS. Twenty patients were enrolled (n=10 Arm 1, n=10 Arm 2). Patient and treatment characteristics were well-balanced between arms, with median age 61.5 years (range 46-76), 50% male, 85% white, 30% with prior radiation therapy and a median of 4 quad induction cycles (range 3-5). Overall, the median peak PB HSC mobilization was 62.5 CD34+ cells/μl with 80% collecting ≥6×106 CD34+ cells/kg in ≤2 LPs (historical control with M+G and 3-drug induction: 116 CD34+ cells/μl, 92.5% collecting ≥6×106 CD34+ cells/kg in ≤2 LPs). All patients collected ≥2×106 CD34+ cells/kg in ≤2 LPs. Of note, in Arm 1 the median peak PB HSC mobilization was 29.5 CD34+ cells/μl vs 98 CD34+ cells/μl in Arm 2, with the median peak PB HSC mobilization in both arms being the last recorded timepoint prior to LP (Arm 1: ~12hrs post-M vs Arm 2: ~16-hrs post-M) and HSC mobilization increasing from 12 to 16 hrs post-M in 80% of patients in Arm 2. In Arm 1, 60% collected ≥6×106 CD34+ cells/kg in ≤2 LPs; while in Arm 2, 100% collected ≥6×106 CD34+ cells/kg in ≤2 LPs. Following enhanced premeds, injection site reactions (e.g. pain, erythema, edema) of any grade occurred in 40% of patients (35% Grade 1, 5% Grade 3) relative to historical rates of 95.5% with single-agent premed and 80% with combination premeds; while systemic reactions (e.g. pruritis, flushing, rash) occurred in 40% of patients (30% Grade 1, 10% Grade 2) relative to historical rates of 90.9% with single-agent premed and 20% with combination premeds. Extended CD34+ immunophenotyping by mFACS is ongoing. In this prospective trial with M+G mobilization in MM, quad induction was associated with decreased HSC mobilization and collection yields relative to historical rates following 3-drug induction. However, 80% still collected ≥6×106 CD34+ cell/kg and 100% collected ≥2×106 CD34+ cell/kg in ≤2 LPs with M+G. Mobilization kinetics and HSC yields were not significantly different between early vs standard M dosing, suggesting flexible M dosing from 2-8pm is feasible without adversely impacting collection yields. Meanwhile, enhanced premeds were associated with a low rate of AEs relative to standard premeds. Ongoing extended immunophenotyping may shed insight into the mechanism of impaired HSC mobilization post-quad induction, possibly via targeted depletion of a large population of CD38+ HSCs within the CD34+ graft.