Improved Survival with Daratumumab-Cybord Compared to Cybord As Frontline Therapy in Immunoglobulin Light Chain (AL) Amyloidosis

Background: AL amyloidosis is a potentially fatal plasma cell dyscrasia. In a randomized phase 3 study (Kastritis E et al, NEJM 2021;385:46-58), the addition of daratumumab to cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) significantly improved hematological and organ responses, and prolonged event-free survival (EFS). There was no overall survival (OS) difference at a median follow-up of 11.4 months.

Methods: A retrospective study of AL amyloidosis patients seen at our institution between January 2018 and December 2022 who received upfront Dara-CyBorD or CyBorD. We excluded patients who received other forms of upfront therapy (including modifications of the above regimens, such as bortezomib-dexamethasone or daratumumab-dexamethasone). We compared the hematologic and organ responses, EFS and OS between the two treatment groups. Hematologic response was assessed at 2 and 6 months from therapy initiation, while cardiac and renal responses at 6- and 12-month landmarks. In all response evaluations, we included responses up to autologous stem cell transplantation (ASCT) if used or second-line therapy for any reason. For EFS analysis, an event was defined as death of any cause, hematological progression, end-stage cardiac or renal failure, or need for subsequent anti-plasma cell therapy in the absence of hematological progression. OS was calculated from the time of treatment initiation to death or last follow-up.

Results: Among 641 newly diagnosed patients seen at our center between 2018 and 2022, 361 patients (56%) were included on intention-to-treat analysis [Dara-CyBorD =147 (41% of the cohort); CyBorD=214 (59%)]. There was no difference in the baseline characteristics between the treatment groups, including age, sex, difference between involved and uninvolved light chains, bone marrow plasma cells percentage, NT-proBNP and 24-hour proteinuria.

The 2-month hematologic complete response (hemCR; 15.3% vs 4.4%, P<0.001) and very good partial response or better (≥hemVGPR; 62.2% vs 32.5%, respectively; P<0.001) were higher with Dara-CyBorD compared to CyBorD. At 6 months, the hemCR and ≥hemVGPR were again in favor of the Dara-CyBorD group compared to CyBorD (32.0% vs 13.7%, and 72.8% vs 46.7%, respectively; P≤0.002).

The 6- and 12-month cardiac response rate in the Dara-CyBorD and CyBorD groups were 40.2% vs 22.6% (P=0.01) and 44.1% vs 23.2%, respectively (P=0.006). Cardiac ≥VGPR at the 6- and 12-month landmarks were statistically higher with Dara-CyBorD compared to CyBorD and increased in both arms between 6 and 12 months [20.5 % vs 9.3% (P=0.03) and 34.3 % vs 20.0% (P=0.04), respectively].

The 6-month and 12-month renal response to first-line therapy were numerically higher with Dara-CyBorD compared to CyBorD but were not statistically significant (48% vs 31.3%, P=0.10; 54.1% vs 30.1%, P=0.05). The 6 month and 12 months, renal ≥VGPR were numerically higher with Dara-CyBorD compared to CyBorD, again without statistical significance (26% vs 19.6%, P=0.63; 35.7% vs 17.2%, P=0.11, respectively).

Treatment with Dara-CyBorD was significantly associated with lower 6-month mortality rate compared to CyBorD (8.8% vs 16.3%, P=0.04). With a median follow-up of 43.3 months (30 vs 59.4 months for Dara-CyBorD vs CyBorD, respectively; P<0.001), the two-year EFS was superior in the Dara-CyBorD group compared to CyBorD (69.1% vs 30.3%, hazard ratio (HR) 0.36, 95% confidence interval (CI), 0.26 to 0.48, P<0.001). The 2-year OS was also statistically higher in the Dara-CyBorD group compared to CyBorD (82.0% vs 69.6%, HR 0.53, 95% CI, 0.36 to 0.79, P=0.003). 148 patients (40.9%) proceeded to second-line therapy with a median of 5.1 months from first line therapy. To adjust for difference in follow-up time between the two treatment groups, we analyzed the second line therapy utilization at the 12-month mark which was statistically higher with CyBorD compared to Dara-CyBorD (42.9% vs 14.9%, P<0.001). Also, at 12 months, a higher proportion of patients treated with CyBorD received ASCT compared to Dara-CyBorD (24.3% vs 13.6%, P= 0.01).

Conclusions: In this cohort of newly diagnosed AL amyloidosis patients in a large referral center, we confirmed higher hematological and organ response rates with Dara-CyBorD compared to CyBorD. We have also demonstrated that these higher response rates translate into a survival advantage of Dara-CyBorD over CyBorD.

Gertz:Johnson & Johnson: Other: personal fees; Sanofi: Other: personal fees; Dava Oncology: Honoraria; Astra Zeneca: Honoraria; Prothena: Other: personal fees; Alnylym: Honoraria; Medscape: Honoraria; Alexion: Honoraria; Janssen: Other: personal fees; Abbvie: Other: personal fees for Data Safety Monitoring board ; Ionis/Akcea: Honoraria. Dispenzieri:Takeda: Consultancy, Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Alnylam: Research Funding; BMS: Consultancy, Research Funding; HaemaloiX: Research Funding; Alexion: Consultancy, Research Funding. Dingli:Janssen: Consultancy, Honoraria; Sorrento: Consultancy, Honoraria; K36 Therapeutics: Research Funding; Genentech: Consultancy; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Leung:Checkpoint Therapeutics: Current holder of stock options in a privately-held company; AbbVie: Current holder of stock options in a privately-held company. Kapoor:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Pharmaceuticals: Research Funding; Ichnos: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Research Funding; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Kourelis:Novartis: Research Funding; Pfizer: Research Funding. Cook:Geron Corp: Other: Held $600 Geron Stock for one week and sold without profit . Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Legend: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy. Hwa:Pfizer: Other: Consulting fee located to Mayo Research fund; Shield Therapeutics: Honoraria; MultiMedia Medical, LLC: Consultancy; Janssen: Honoraria; GSK: Honoraria. Kumar:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Janssen: 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, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Novartis: Research Funding; Merck: Research Funding; Oncopeptides: Other: Independent review committee participation. Muchtar:Protego: Consultancy.