Real World Efficacies of First Line Treatments in Non-Transplant-Eligible Newly Diagnosed (ND-NTE) Multiple Myeloma (MM) Patients: A Challenge to Maia ? an Analysis from the Austrian Myeloma Registry (AMR)
Authors: Willenbacher Ella , Sormann Siegfried , Pichler Petra , Maria-Theresa Krauth , Agis Hermine , Strassl Irene , Podar Klaus , Weger Roman , Willenbacher Wolfgang 
Published: December 2024

Introduction:
Since the approval of the MAIA protocol (Daratumumab-Lenalidomid and Dexamethason - DRd) in ND-NTE MM, this regime has become standard of care wherever D is available and long-term updates have been published setting a clinical benchmark reporting a median PFS of 61.9 mo., and a median OS not reached at 64.5 mo./ 73.6 mo. of follow up respectively[i].
Scope:
Aim of this retrospective analysis was to challenge this outstanding results in a real-world (RW) ND-NTE population derived from the AMR with a focus on outcomes, feasibility of the long-term application of MAIA, frequency of dose reductions, regime modifications and subsequent therapies.
Methods:
All pts. receiving DRd in 1st line of treatment (LoT) were extracted from the AMR a unique national MM-specific database of standardized clinical and management data of more than 1600 patients. Furthermore pts. receiving alternative triplets or doublets from 2019 onwards were analyzed comparatively as a group.
Cytogenetic high risk (HR) was defined as the occurrence of either t(4;14), t(14;16), t(14:20), amp1q, or del17p. Progression-free survival (PFS) was measured from start of treatment until progression. Overall survival (OS) describes the period from initial diagnosis to death or loss to follow-up. Follow-up time defines the period from the start of treatment to data collection (12/07/2024).
Results:
186 pts. were identified as receiving DRd, their median age was 77 years, 55% of these were male, cytogenetics were available in 69% of which 34% demonstrated high risk cytogenetic features. An ECOG≤1 was reported in 74.59%, and a R-ISS of I/II in 56.56% of pts.
Most pts were treated with DRd (55.74%), 37.7% with a Proteasom-inhibitor (Pi) & Dd, 18% with PiRd, Doublets: 19.7%. A switch from R to a Pi was attributed mainly to renal-insufficiency (median creatinine with PI: 1.5mg/dl, 0.91-2.87 mg/dl v.s. R: 0.95 mg/dl, 0.77-1.25mg/dl; p=0.044). In addition, a high proportion of pts with ECOG&gt;1 (31.8 %) were identifyed in the PIDd cohort. The use of VRd may be explained by the younger age in this group (69.5 years: 62-74 years; p&lt;0.001), intended to keep the option of transplantation open at treatment initiation.
The median follow in our entire cohort was 42 mo. 89.43 % of pts. survived, OS was 97.8 mo. in the DRd cohort and of those 80.3 % survived without progression (80.43 % in the DRd cohort). The median overall PFS was 11.42 m (5.13-25.59 mo.; DRd cohort 22.77 mo, 6.9-30.1 mo; p=0.47). Treatment could be continued without dose reductions in 73.91% of pts. in the MAIA cohort. Adverse events occurred most frequently in pts. on the MAIA protocol (28.26%). In the MAIA cohort, 58.7% of pts are still on treatment (compared to 41.67% of pts. receiving other regimes). The median duration of treatment (DOT) is 8.82 m in MAIA cohort compared to 5.32 m (3.09-11.27 m) in the others (p=0.054). First-line treatment with D achieved a VGPR or better in 80% with an overall response rate (ORR) of 95.6% compared to the mixed group with a VGPR or better of 61% and an ORR of 85.37% (p=0.038). The effect of MAIA on ORR persists when age, HR and gender are taken into account in multivariate analyses (p=0.039): Subsequent treatment is reported in 21.13% of pts. , with a median treatment-free interval of 2.74 m, 0.41-11.41 m).
Conclusions:
Under RW conditions DRd proofed to be superior to a mixed group of comparators with respect to ORR, best response, and PFS. Nevertheless, this real-world population underperformed significantly compared to the MAIA trial population with respect to PFS (22.7 mo. vs. 61.9 mo.) and most other outcome parameters. Documented higher age, a higher proportion of cytogenetic high risk pts., and worse ECOG performance status, as well as more frequently applied dose modifications, delays and regime changes may all contribute to this findings and will be presented in more detail.
Furthermore our findings illustrate, that despite DRd being the current gold standard in ND-NTE-MM: Even more efficient treatments are needed, especially in high risk pts. This might be an opportunity to investigate modified quadruplets as in the recently published IMROZ trial[ii], as well as the introduction of immune-oncological therapies (e.g. bispecific antibodies) in 1st LoT.The necessity to develop even better tolerated therapies enabling longterm treatment approaches.
[i] Kumar S. et al. Blood 2022; 140 (Suppl.1)#4559
[ii] Facon T. et al. ASCO 2024, #7500