Key Drivers for Treatment Choice in Lenalidomide-Exposed and Refractory Multiple Myeloma Patients in the Real World. Analysis Conducted in the EU5 Countries and the US
Authors: Nicolas Blin , Mai Christine , Ertl Siegfried , Schneider Elodie , Leberre Marine , Yilmaz Melissa , Raffy Alexandre 
Published: December 2024

Background:
Progress in multiple myeloma (MM) treatment includes improved risk stratification, recognition of clonal heterogeneity, personalized therapies (1, 2). MM remains complex with significant impact of therapies on long-term outcomes due to mutational burden, immune exhaustion, infections, myelosuppression, organ damage, extramedullary escape (3).
Definition of relapsed/refractory MM (RRMM) is clarified with progressive disease based on IMWG criteria (4) after at least a minimal response or disease progression less than 60 days of the last treatment (5, 6), and primary refractory disease defined by lack of at least minimal response on a given treatment (7).
Lenalidomide is a cornerstone in 1st (L1) and 2nd (L2) line treatments, but many patients become refractory to lenalidomide by L2+.
Guidelines recommend treatment selection at relapse based on timing of relapse, response to prior therapy, disease aggressiveness, patient's performance status (8).
Treatment selection principles include using triplets considering at least 2 new drugs, considering transplant, enrolling in clinical trials.
Despite these guidelines and availability of efficient new combinations at relapse, treatment for lenalidomide refractory MM varies significantly among institutions and countries.
Aims:
The study aimed to identify in the real world setting the main regimens used in lenalidomide refractory L2+ MM patients and analyze key drivers for drug selection across France, Germany, Italy, Spain, UK (EU5) and the US.
Methods:
Anonymous patient charts from hematologists in EU5 and the US were analyzed. The study included 2802 patient charts in L2, 2128 in L3, 1660 in L4, 1008 in L5+ from Q4 22 to Q4 23. Among these, 432 in L2, 682 in L3, 739 in L4, 511 in L5+ were lenalidomide exposed and refractory. The analysis focused on regimens used in different lines and key drivers for drug selection comparing EU5 and the US.
Among lenalidomide exposed/refractory L2 patients (n=432), common regimens were DVd (17%), DKd (12%), Kd (7%), Isa-Kd (7%), DPd (7%), PVd (5%), KPd (5%). Higher carfilzomib-based combinations in the US: DKd (17% vs 12% in EU5).
DVd was preferred for older patients (mean age 73 vs 67 for DKd, 70,9 for DPd, 71,7 for PVd) and those with at least 1 comorbidity (92%) vs DKd (74%) DPd (94%). High-risk cytogenetics were more common in DKd and PVd (36% and 20% vs 14% and 13% for DVd and DPd). No difference regarding ISS score. DKd was associated with better ECOG status (77%) ECOG 0-1 vs PVd (73%), DVd (64%).
L3 (n=682): common regimens were Isa-Pd (11%), Kd (10%), Pd (8%), EPd (7%), DPd (7%). Isa-Pd was more frequent in EU5 (12%) vs the US (1%).
Subgroup analysis didn't show differences except Del17p slightly more frequent in the Kd subgroup (10%) and at least 1 comorbidity in Isa-Pd (91%), Kd (89%), Pd (96%), EPd (96%).
L4 (n=739): Common regimens were Isa-Pd (14%), teclistamab (10%), Darzalex monotherapy (mono) (9%), belantamab mafodotin mono (8%), Pd (6%), Kd (5%), ide-cel (5%), Dd (5%). Mean age was similar; Isa-Pd and teclistamab (70,1), belantamab mafodotin mono (68,7), Pd (70,9). Subgroup analysis didn't show differences except higher proportion of high-risk cytogenetic profile and del17p mutation in the ide-cel group.
L5+ (n=511): Regimens included belantamab mafodotin mono (16%), teclistamab (15%), Pd (9%), ide-cel (6%), cilta-cel (5%). CAR T subgroups had younger patients; ide-cel (mean age: 66.1), cilta-cel (63.5) vs belantamab mafodotin (70,8), teclistamab (69,8). High-risk cytogenetics were more frequent in cilta-cel (15% del17p, 58% ISS III) vs ide-cel (6% del17p, 75% ISS III) teclistamab (10% del17p, 56% ISS III).
Cardiac disease or high blood pressure reduced the likelihood of carfilzomib based regimen use, peripheral neuropathy or cardiac dysfunction reduced bortezomib use across all countries and lines of therapy.
Conclusion:
This real-world study reveals heterogeneous treatment choices in L2+ lenalidomide refractory patients among EU5 and the US. Carfilzomib-based treatments are preferred for younger patients without cardiovascular comorbidities and with high-risk cytogenetics. Pomalidomide-based treatments are common in L3 and L4 regardless of age and comorbidities. Anti-BCMA bispecifics are standard from the L4 and anti-BCMA CAR T cells in L5, especially for younger, fit patients with high-risk disease.
Treatment differences between regions are mainly due to access and prescriber experience.