Characteristics and Outcomes in Patients with Lenalidomide-Refractory Relapsed/Refractory Multiple Myeloma Treated with 1-3 Prior Lines of Therapy: Analysis of the Individual Patient-Level Data from Daratumumab Clinical Trials

Introduction: New treatment combinations using proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies have led to improved survival outcomes in patients with multiple myeloma (MM). However, for patients who have received multiple lines of therapy (LOT), especially those exposed to a PI and refractory to lenalidomide (len), selecting the next regimen remains a challenge. Limited data are available characterizing treatments and outcomes in this difficult-to-treat population.

Methods: Individual patient-level data were derived from a pooled analysis of daratumumab clinical trials that included the initial study and long-term follow-up, and all treatment arms and regimens with or without daratumumab (APOLLO, CASTOR, CANDOR, EQUULEUS, ALCYONE, MAIA, GRIFFIN, POLLUX, and CASSIOPEIA). Patients with MM who received 1-3 prior LOT including a PI and IMiD, were len-refractory, and had an ECOG <2 were identified. Time zero (T0) was the time when the subsequent LOT started after patient met inclusion criteria for each eligible index line; patients who received multiple therapies subsequent to meeting eligibility criteria contributed multiple observations. Treatment patterns and outcomes were analyzed by number of prior LOT. Descriptive statistics for patient characteristics were assessed at T0 for all index lines. Time to event analyses were estimated using the Kaplan-Meier method (starting at T0) for progression-free survival (PFS), time to next treatment (TTNT) and overall survival (OS).

Results: Out of a total of 4764 patients, 915 patients with 1,230 index lines (prior LOT, 1 [n=114]; 2 [n=516]; 3 [n=600]) met inclusion criteria. For all indexed lines, median age was 65.5 (range 30-90), 57.5% were male, 76.4% were white, and 3.2% were Black. Median time from diagnosis was 3.6 years (range 0-23), and at T0, 5.4% had baseline plasmacytoma, 16.1% had ISS stage III disease, and 14.3% had high-risk cytogenetics. 13.8% of all eligible index lines were triple-class refractory; 58.9% received stem cell transplant prior to T0. The most common treatment regimens subsequent to meeting eligibility criteria were DPd (13.3%), DKd (13.2%), Pd (11.4%), Kd (8.9%). The overall response rate for all patient indices was 50.1% (Figure 1A). The percent of patient indices with very good partial response or better was 29.0%, and the percent with complete response or better was 12.0%. Estimated median OS (95% CI) for all patient indices was 23.9 months (21.8, 25.8), PFS was 12.2 months (10.9, 13.5), and TTNT was 8.34 months (7.7, 9.3). Estimated median PFS, OS, and TTNT by number of prior LOT are presented in Figure 1A. Response rates and PFS (Figure 1B) decreased as number of prior LOT increased.

Conclusions: This analysis of patients enrolled in daratumumab randomized clinical trials demonstrates that for PI-exposed, len-refractory patients with 1-3 prior LOTs, response rates decrease with each additional prior LOT. These patients also have poor PFS and move quickly through available therapies, highlighting the need for a new effective and safe regimen for this patient population.

Figure 1: (A) Response rates and time-to-event analyses by number of prior LOT; (B) PFS by number of prior LOT

Dhakal:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; BMS: Honoraria, Research Funding; Natera: Consultancy; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Einsele:BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: travel grants. Schecter:Janssen: Current Employment, Current holder of stock options in a privately-held company. Roccia:Janssen: Current Employment, Current equity holder in publicly-traded company. Deraedt:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Lendvai:Janssen: Current Employment. Slaughter:Janssen: Current Employment, Current holder of stock options in a privately-held company. Lonardi:Janssen: Current Employment. Connors:Janssen R&D: Current Employment; Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Qi:Janssen: Current Employment. Londhe:Janssen: Current Employment. Carson:Janssen: Current Employment. Voelker:Janssen Scientific Affairs, LLC: Current Employment. Cost:Janssen: Current Employment, Current equity holder in private company. Valluri:Janssen: Current Employment, Current equity holder in publicly-traded company. Florendo:Legend Biotech: Current Employment. Pacaud:Legend Biotech USA: Current Employment.