ASH 2023 Highlight 4

Two investigations provide novel insights into optimizing the therapeutic approach for patients with newly diagnosed multiple myeloma (NDMM) presenting high-risk features. High-risk categorization is contingent upon specific FISH abnormalities, such as del(17p), t(4;14), and t(14;16). Ultra-high-risk or double-hit myeloma patients exhibit two or more of these unfavourable cytogenetic features, warranting distinct management due to the lack of benefit from standard treatments.

The IFM 2018-04 trial, a pivotal phase 2 study, selectively enrolled high-risk patients, with over half classified as ultra-high risk. The regimen comprised induction therapy with 6 cycles of Dara-KRd before ASCT, followed by a consolidation phase involving 4 cycles of Dara-KRd, a second ASCT, and Dara-lenalidomide as a 2-year maintenance therapy. Notably, challenges were encountered in collecting sufficient stem cells for transplantation after 6 cycles, prompting a protocol modification to initiate stem cell collection after 3 cycles. Clinically, the outcomes were unprecedented, with approximately 80% of patients alive and without progression at a median follow-up of 30 months. A profound depth of response was evident, exemplified by 81% of patients achieving complete remission after the second consolidation, and over 90% exhibiting MRD negativity—an unprecedented result. This proof-of-concept study advocates for a tailored, intensive treatment approach for this subgroup of high-risk patients.

The Iskia study, a phase 3 prospective investigation, randomized transplant-eligible patients into two arms, receiving 4 cycles of KRd with or without isatuximab. Post-stem cell transplantation, patients underwent 4 consolidation cycles of KRd with or without isatuximab. Rather than the typical maintenance treatment, patients received a light consolidation with IsaKRd every 2 weeks after the first consolidation. The primary endpoint centred on MRD negativity, assessed at various intervals. Throughout the study, MRD depth improved after each treatment phase, with a conspicuous advantage observed in the quadruplet treatment arm, particularly in achieving more MRD negativity compared to those on KRd alone. Notably, high-risk patients, constituting 20% of the cohort, demonstrated substantial benefits from the quadruplet treatment, particularly in achieving MRD negativity at the 10^-6 cut off.

In summary, both studies offer a novel perspective on managing high-risk NDMM patients who are candidates for ASCT, suggesting the merit of more intensive and tailored therapeutic approaches for this subset.

References:

Touzeau C, ASH 2023. #207

Gay F, ASH 2023. #4

With the educational support of: