Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices
Authors: Skarbnik Alan P , Ma Esprit , Lafeuille Marie-Hélène , Fortier Jonathan , Feldman Tatyana , Duh Mei Sheng , Ng Yvette , van de Velde Helgi , Dow Edward , Niculescu Liviu , Bonthapally Vijayveer , Goy Andre 
Published: October 2019

Abstract
Background
The outcome of MCL has improved thanks to the use of dose-intensive strategies ± ASCT and novel therapies in the relapsed/refractory setting. IV BTZ was the first agent approved by the FDA in relapsed/refractory MCL, in 2006, based on the phase 2 PINNACLE study (Fisher et al, J Clin Oncol 2006); overall response rate (ORR) was 32%, with 8% CR/CRu, median TTP was 6.7 mos, PFS was 6.5 mos, time to next therapy (TTNT) was 7.4 mos, and OS was 23.5 mos. Common grade ≥3 adverse events (AEs) included 13% peripheral neuropathy (PN) and 12% fatigue. Recently, the phase 3 LYM-3002 study demonstrated the efficacy and safety of IV BTZ plus rituximab, cyclophosphamide, doxorubicin, and prednisone vs R-CHOP in frontline MCL (Cavalli et al, ASCO 2014; median PFS 24.7 vs 14.4 mos). SQ BTZ was FDA approved in January 2012 based on the phase 3 MMY-3021 trial, which showed non-inferior efficacy (ORR after 4 cycles) and an improved systemic safety profile (including a significant reduction in PN) with SQ vs IV BTZ in relapsed multiple myeloma (MM) (Moreau et al, Lancet Oncol 2011). While there are a number of ongoing SQ BTZ clinical studies in MCL, there are limited published data in relapsed MCL in the real-world clinical setting. This retrospective, observational study evaluated treatment patterns and outcomes with SQ BTZ in relapsed MCL pts in US community oncology practices.
Methods
Data on pts diagnosed with MCL aged ≥18 yrs who had received at least 1 prior line of therapy and who subsequently received ≥1 SQ BTZ dose between April 2006 and April 2014, either as a single agent or in combination, were extracted from the Altos OncoEMR™ oncology-specific electronic medical records database and medical charts. Treatment patterns, including treatment regimens and exposure, and outcomes, including ORR, TTP, PFS, TTNT, OS, and AEs, were descriptively analyzed.
Results
A total of 1,281 pts diagnosed with MCL were identified in the database; 134 had received ≥1 BTZ dose, including 53 relapsed MCL pts with ≥1 SQ BTZ dose. Among these 53 pts (see Table), median treatment duration was 2.4 mos (median 4 21-day-equivalent cycles); 28 received SQ BTZ as a single agent, and 25 received it in combination; combination regimens included 13 with rituximab (R), 3 with R+bendamustine, 3 with dexamethasone (dex), 2 with R+dex, and 1 with idelalisib, R+cyclophosphamide, and R+lenalidomide+dex (1 regimen unknown). Median time from MCL diagnosis was 2.1 yrs; pts had received a median of 2 lines of prior therapy (1 for pts receiving single-agent BTZ, 2 for those receiving SQ BTZ in combination), including 9% with prior transplant and 17% with prior IV BTZ treatment as induction; 40% of pts were refractory to their last prior therapy. ORR (CR+PR) was 22%, including 17% CR (1 CR in 7 evaluable pts with prior IV BTZ). Median observation period was 5.3 mos; at data cut-off, 45% of pts had progressed, 38% had started a new line of therapy, and 42% had died. Median PFS was 4.7 mos (IQR: 1.9–11.3); median OS was 11.3 mos (IQR: 5.1–not reached [NR]). The most common AEs included 42% fatigue, 36% anemia, 25% nausea, 25% neutropenia, 21% thrombocytopenia, and 21% neuropathy; 9%/8%/4% reported local redness/rash/tenderness. Grade ≥3 AEs included 1 pt (2%) each with CHF (pt with baseline arrhythmia), diarrhea, fatigue, neuropathy, rash, and vomiting.
Conclusions
These findings indicate that SQ BTZ, alone or in combination, was active and generally well tolerated in relapsed MCL. In the context of findings from PINNACLE, these data appear consistent with the non-inferior efficacy and improved safety profile of SQ BTZ in MM, notably the low rate of neuropathy (21%; 2% grade ≥3). As data mature, additional analyses will further evaluate treatment outcomes.
Table AllN=53 Single agentn=28 Combinationn=25 Median age, yrs 70.8 75.2 68.6 Age ≥75 yrs, n (%) 19 (36) 14 (50) 5 (20) Male, n (%) 37 (70) 20 (71) 17 (68) Baseline neuropathy, n (%) 7 (13) 3 (11) 4 (16) Median treatment duration, mos 2.4 1.4 2.4 ORR, n/N evaluable (%) 8/36 (22) 3/22 (14) 5/14 (36) CR, n/N evaluable (%) 6/36 (17) 2/22 (9) 4/14 (29) Stable disease, n/N evaluable (%) 5/36 (14) 4/22 (18) 1/14 (7) TTP, mos* 5.3 (2.6–NR) 4.1 (1.4–NR) 5.1 (3.2–NR) PFS, mos* 4.7 (1.9–11.3) 3.8 (1.0–11.3) 5.1 (3.2–15.2) TTNT, mos* 7.9 (5.1–NR) 10.3 (3.8–10.3) 6.3 (5.1–NR) OS, mos* 11.3 (5.1–NR) 9.1 (5.7–NR) 13.4 (4.9–NR) Any AE, n (%) 42 (79) 21 (75) 21 (84) Any grade ≥3 AE, n (%) 6 (11) 3 (11) 3 (12) Any / grade ≥3 neuropathy, n (%) 11 (21) / 1 (2) 6 (21) / 0 5 (20) / 1 (4)
*Median (IQR)

Disclosures
Ma: Millennium: The Takeda Oncology Company: Employment. Lafeuille:Millennium: The Takeda Oncology Company: Research Funding. Fortier:Millennium: The Takeda Oncology Company: Research Funding. Feldman:Spectrum: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Duh:Millennium: The Takeda Oncology Company: Research Funding. Ng:Janssen Global Services, LLC.: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Dow:Millennium: The Takeda Oncology Company: Employment; Takeda Pharmaceuticals International Co.: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment; Takeda Pharmaceuticals International Co.: Equity Ownership; Pfizer: Equity Ownership. Bonthapally:Millennium: The Takeda Oncology Company: Employment; Takeda Pharmaceuticals International Co.: Equity Ownership. Goy:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.