Daratumumab Plus Rd Prolongs PFS in Frail, Newly Diagnosed, Transplant-Ineligible Myeloma

The addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone (D-Rd; Rd) resulted in improved progression-free survival (PFS) vs Rd alone in patients with newly diagnosed multiple myeloma who were not eligible for transplant—even in frail patients, according to data from a subgroup analysis of the phase 3 MAIA trial (NCT02252172).¹

In a subgroup analysis from the study focused on frailty status, the risk of disease progression or death was reduced by 38% in frail patients compared by 52% in non-frail patients.

“After more than 3 years of follow-up, D-Rd demonstrated improved efficacy versus Rd in transplant-ineligible patients with newly diagnosed multiple myeloma, regardless of frailty status,” said Sonja Zweegman, MD, PhD, in a presentation during the 2nd European Myeloma Network Meeting.

The MAIA trial enrolled 737 patients, 729 of which received at least 1 dose of treatment, with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation (ASCT) to receive D-Rd or Rd alone continuously in 28-day cycles until disease progression or unacceptable toxicity. All patients had an ECOG performance status of 0 to 2 and a creatinine clearance ≥30 mL/min.

The primary end point for the overall population was PFS and secondary end points included objective response rate (ORR), complete response (CR) or higher rate, minimal residual disease (MRD) negativity rate, and overall survival (OS).

In the overall population, the median age was 73 years (range, 45-90) with 44% aged ≥75 years. A total of 17% had an ECOG performance status of 2, 14.3% of patients had a high-risk cytogenetic profile, and 30% had International Staging System (ISS) stage III disease.

Earlier results for the overall population showed a 30-month PFS rate of 70.6% with D-Rd and 55.6% with Rd alone (HR, 0.56; 95% CI, 0.43-0.73; P < .001).²

The triplet regimen also demonstrated improved PFS over the doublet in the ≥75 years group, though it was noted that these patients tend to vary widely in terms of fitness levels, so investigators further explored efficacy in subgroups of the MAIA trial based on frailty assessment in a retrospective analysis.

In the analysis, frailty subgroups were determined by based on the 3-subgroup (fit [n = 146], intermediate [n = 250], and frail [n = 341]) and simplified 2-subgroup (frail and non-frail) frailty classifications from the retrospective frailty subgroup analysis of the FIRST trial.³

The phase 3 FIRST trial (NCT00689936) explored treatment of Rd in comparison with melphalan, prednisone, and thalidomide (Thalomid) in patients with newly diagnosed multiple myeloma who were ineligible for ASCT, which helped to establish Rd as a standard of care backbone in multiple myeloma.⁴ A retrospective analysis from the study established a frailty scale to predict outcomes based on age, Charlson Comorbidity Index, and ECOG performance status at baseline.³

When comparing the baseline characteristics across the subgroups, the investigators observed, unsurprisingly, that frail patients in the MAIA trial tended to be older, have a higher ECOG performance status, a higher ISS stage of disease, and have more renal impairment than the non-frail patients.¹

A higher proportion of frail patients discontinued treatment in the study, including 45% of those treated with D-Rd and 67% of those treated with Rd, in comparison with the non-frail patients at 33% and 60%, respectively. Disease progression was the number 1 reason for discontinuation across all subgroups and arms, though in the frail groups a larger number of patients discontinued treatment due to death compared with the non-frail patients.

Zweegman, head of the Department of Hematology, VU University Medical Center, Amsterdam University Medical Center, Netherlands, noted that this supports the need for antibiotic prophylaxis, especially in frail patients, as there were more infections in this population.

The median relative dose intensity was lower in the D-Rd arm than in the Rd arm, but this was even more pronounced in the frail patients, which was considered to be due to a number of dose modifications for lenalidomide, mostly due to adverse events (AEs). The daratumumab relative dose intensity was similar and close to 100% across the subgroups.

After a median follow-up of 36.4 months, the median PFS was greater with D-Rd treatment compared with Rd treatment in both the frail (HR, 0.62; 95% CI, 0.45-0.85; P = .003) and the non-frail patients (HR, 0.48; 95% CI, 0.34-0.68; P < .0001). Zweegman pointed out that the median PFS in the frail population treated with D-Rd was comparable, if not a bit better, than that of the non-frail patients treated with Rd alone.

Response rates were also superior in the D-Rd arm compared to the Rd arm in both the frail (87% vs 78%, respectively; P = .0265) and the non-frail patients (98% vs 85%, respectively; P < .0001). The same was seen with the CR or higher rate with frail patients achieving rates of 44% with D-Rd and 31% with Rd (P = .0144) compared with 55% and 24%, respectively, in non-frail patients (P < .0001).

MRD negativity rates at 10^-5 were similarly higher in both subgroups with D-Rd treatment as compared with Rd treatment. Among frail patients, 24% achieved MRD negativity with D-Rd versus 10% with Rd treatment (P = .0008) and 33% of non-frail patients had MRD negativity with D-Rd versus 9% with those patients treated with Rd alone (P < .0001).

The overall incidence of grade 3/4 treatment-emergent AEs (TEAEs) was higher in frail patients across the 2 arms (95% with D-Rd, 89% with Rd) compared with the non-frail patients (89% with D-Rd, 83% with Rd). Rates of neutropenia were especially higher among frail patients receiving daratumumab versus non-frail patients (58% vs 45%) as well as versus frail patients receiving Rd (58% vs 33%). Infections were similarly increased in the frail population that was treated with daratumumab (42% vs 28% with Rd, 32% non-frail with D-Rd). The most common infection was pneumonia. Overall, this safety profile was generally consistent with that of the overall population in the MAIA trial.

Events of neutropenia and pneumonia, while observed at higher rates in the frail population, these events were mostly clinically manageable, Zweegman noted.

TEAEs led to death in 12% of frail patients treated with D-Rd as compared with 12% of frail patients treated with Rd alone; among non-frail patients, TEAEs led to death in 4% of each arm. Serious TEAEs were observed in 74% and 73% of frail patients treated with D-Rd and Rd, respectively, as compared with 63% of non-frail patients in each arm. Deaths were reported in 34% of frail patients in each arm versus 13% of non-frail patients in the D-Rd arm and 23% of non-frail patients in the Rd arm.

“Although this is a retrospective analysis and we used a simplified frailty index, which might not necessarily reflect biological or functional frailty, we clearly showed that with this frailty index, you can identify frail patients that would definitely benefit from [daratumumab and] Rd over Rd,” Zweegman concluded.

References

1. Zweegman S, Usmani SZ, Hulin C, et al. Daratumumab Plus Lenalidomide And Dexamethasone (D-Rd) Versus Lenalidomide And Dexamethasone (Rd) In Transplant-Ineligible Newly Diagnosed Multiple Myeloma (Ndmm): Frailty Subgroup Analysis Of MAIA. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; Virtual. Abstract B05.
2. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115. doi:10.1056/NEJMoa1817249
3. Facon T, Dimopoulos MA, Meuleman N, et al. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial. Leukemia. 2020;34(1):224-233. doi:10.1038/s41375-019-0539-0
4. Benboubker L, Dimopoulos MA, Dispenzieri A, et al; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-917. doi:10.1056/NEJMoa1402551