Multiple myeloma is the second most common blood cancer diagnosis, after non-Hodgkin lymphoma, in the United States. The UNITO-MM-01/FORTE trial is a randomized Phase II study evaluating front-line treatment strategies in transplant-eligible patients with newly diagnosed multiple myeloma. Earlier analyses demonstrated that combining carfilzomib-lenalidomide-dexamethasone (KRd) with autologous stem cell transplant (ASCT) improved progression-free survival (PFS) compared to KRd without transplant (KRd12) and carfilzomib-cyclophosphamide-dexamethasone with ASCT (KCd-ASCT). Additionally, KR maintenance (carfilzomib + lenalidomide for 2 years) previously showed superior 3-year PFS versus lenalidomide alone.

KRd-ASCT consists of KRd induction followed by ASCT, and KR maintenance includes 2 years of carfilzomib alongside lenalidomide until progression. Carfilzomib is a second-generation proteasome inhibitor, and lenalidomide is an immunomodulatory agent, both forming the cornerstone of modern myeloma therapy.

With a median follow-up of 93.6 months from initial randomization (R1), KRd-ASCT achieved a median PFS of 99 months, significantly longer than KRd12 (70 months) and KCd-ASCT (64 months). The PFS benefit was consistent across subgroups, including high-risk and very high-risk patients. The median time to next therapy (TTNT) was not reached at 8 years in the KRd-ASCT arm. 

From the second randomization, KR maintenance continued to demonstrate a PFS benefit over lenalidomide alone, especially during the first four years (4-year PFS: 75% vs. 66%).Secondary primary malignancies (SPMs) occurred in 6% of patients, more frequently in those who underwent ASCT, though incidence was consistent with similar populations.

KOL insights

“When you look at the sustained 1‑year rates of MRD negativity, you see patients from the KRd‑plus‑ASCT arm have a significantly higher rate than those given KCd plus ASCT and compared with KRd continuous treatment, progression‑free survival of high‑risk and double‑hit patients is very good, with a 4‑year PFS of around 85%.” – Expert Opinion

Conclusion

The main treatment options include stem cell transplant, chemotherapy, targeted therapy, corticosteroids, proteasome inhibitors, immunomodulators, monoclonal antibodies, surgery, and radiation therapy. Also, survival of patients with myeloma has also improved due to the development and approval of new treatments. Proteasome inhibitors approved over the past 20 years have significantly enhanced outcomes for patients with multiple myeloma. Reversible proteasome inhibitors approved by the FDA are VELCADE and NINLARO, irreversible inhibitors approved are KYPROLIS for multiple myeloma treatment.

The updated UNITO-MM-01/FORTE results confirm KRd-ASCT followed by KR maintenance as a highly effective frontline strategy in transplant-eligible patients. With a median PFS of 99 months and sustained benefit across risk groups, it significantly outperformed both KRd12 and KCd-ASCT. KR maintenance also provided superior PFS over lenalidomide alone, especially in the first 4 years. These findings support KRd-ASCT + KR maintenance as a new benchmark for long-term disease control.