Upfront ASCT + RVd improves PFS in NDMM

Upfront autologous stem cell transplantation (ASCT) plus lenalidomide, bortezomib, and dexamethasone (RVd) significantly improves progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM), results of the phase III DETERMINATION trial showed.

“The addition of ASCT to triplet induction therapy with lenalidomide maintenance until progression resulted in a highly significant increase in PFS [with] an improvement in median of over 21 months,” said Professor Paul Richardson from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, US, at ASCO 2022.

These results confirm the PFS benefit with early ASCT as well as lenalidomide maintenance until progression as standard of care, said Richardson.

Patients aged 18–65 years with NDMM were randomized to receive either three cycles of RVd*, stem cell mobilization, followed by five cycles of RVd (non-transplant arm; n=357; median age 57 years, 43 percent female) or intravenous melphalan (200 mg/m²), ASCT, and two cycles of RVd (ASCT arm; n=365; median age 55 years, 41 percent female). All patients subsequently received maintenance lenalidomide (10–15 mg/day) until disease progression or intolerance (n=291 and 289 in the non-transplant and ASCT arms, respectively, for a median 36.4 and 41.5 months, respectively).

Fourteen and thirteen percent of patients in the non-transplant and ASCT arms, respectively, had stage III MM, and 19.8 and 19.4 percent, respectively, had high-risk cytogenetics**. The patients were followed up for a median 76 months (328 events of disease progression or death).

The risk of progression was significantly increased among patients in the non-transplant vs the ASCT arm (median PFS 46.2 vs 67.5 months; hazard ratio [HR], 1.53, 95 percent confidence interval, 1.23–1.91; p<0.0001; 5-year PFS: 41.5 percent vs 55.6 percent). [ASCO 2022, abstract LBA4; N Engl J Med 2022;doi:10.1056/NEJMoa2204925]

The PFS outcomes were consistent in patients with stage I or II disease (median not reached vs 52.0 months [ASCT vs non-transplant arm] and median 62.5 vs 46.2 months, respectively [HRs, 1.83 and 1.38, respectively]), but were less clear in the stage III disease population (median 35.9 vs 40.3 months; HR, 1.14). The PFS benefit with ASCT was also noted in patients with high cytogenetic risk (median 55.5 vs 17.1 months [non-transplant arm]; HR, 1.99) and standard cytogenetic risk (median 82.3 vs 53.2 months; HR, 1.38).

Time to progression (TTP) was significantly improved among patients in the ASCT vs non-transplant arm (5-year TTP: 58.4 percent vs 41.6 percent; HR, 1.66; p<0.001). Preliminary data show a higher rate of minimal residual disease (MRD)-negative responses in the ASCT vs non-transplant group at maintenance therapy onset (54.4 percent vs 39.8 percent), though 5-year PFS rates did not differ between groups in MRD-negative patients (53.5 percent vs 59.2 percent).

Similar proportions of patients in the ASCT and non-transplant groups had a partial response or better (97.5 percent vs 95.0 percent [median duration of response 56.4 vs 38.9 months]) and complete response or better (46.8 percent vs 42.0 percent). Five-year overall survival (OS) was also comparable between groups (80.7 percent vs 79.2 percent; HR, 1.10; p>0.99).

Grade ≥3 treatment-related adverse events (TRAEs) occurred more frequently in the ASCT than non-transplant arm (94.2 percent vs 78.2 percent), as did grade ≥3 haematological TRAEs (89.9 percent vs 60.5 percent; p<0.001). Serious RVd-related AEs occurred in 47.1 and 40.3 percent of the ASCT and non-transplant regimen recipients, respectively, and treatment-related serious infections during maintenance therapy in 16.6 and 11.3 percent, respectively. At 5 years, second primary malignancies occurred in 10.8 and 9.7 percent of patients in the ASCT and non-transplant arm, respectively. Ten patients in the ASCT arm developed myelodysplastic syndrome or acute myeloid leukaemia vs none in the non-transplant arm.

According to the authors, the lack of OS benefit with ASCT could be due to “the multiple, highly efficacious options available after first-line therapy that have emerged” in the past decade.

“[This, together with] considerations regarding real-world factors such as treatment burden, acute and long-term toxic effects, patient preference, and quality of life, [may] be taken into account when making treatment decisions,” they said.

“[These results] support personalized approaches because we see no OS difference to date, and it allows us the option of considering keeping transplant in reserve for selected patients,” concluded Richardson.