APOLLO: SC daratumumab an effective, convenient option in R/R MM

Subcutaneous (SC) daratumumab in combination with pomalidomide and dexamethasone (Pd) improves progression-free survival (PFS) and achieves deeper responses vs Pd alone in patients with relapsed/refractory multiple myeloma (R/R MM), results of the phase III APOLLO trial have shown.

“These results, together with an adverse event [AE] profile consistent with previous studies, suggest that SC daratumumab plus Pd [D-Pd] is an effective and convenient treatment option for patients with R/R MM who have received ≥1 prior line of therapy, including lenalidomide and a proteasome inhibitor [PI],” said senior study author Professor Meletios Dimopoulos of National and Kapodistrian University of Athens, Greece. [Dimopoulos M, et al, ASH 2020, abstract 412]

“With a median administration duration of 5 minutes, SC daratumumab increases convenience for patients and reduces treatment burden,” he added.

Improved PFS, deeper responses

SC daratumumab has demonstrated noninferior efficacy and pharmacokinetics vs intravenous (IV) daratumumab, with significantly lower infusion-related reaction (IRR) rates and a shorter administration duration vs the IV formulation. [Lancet Haematol 2020;7:e370-e380]

“APOLLO is the first phase III study of SC daratumumab combination therapy in MM. Results showed a significant 37 percent improvement in the primary endpoint of PFS in patients randomized to receive D-Pd [n=151] vs those who received Pd alone [n=153],” reported Dimopoulos.

After a median follow-up of 16.9 months, median PFS was 12.4 months in the D-Pd arm vs 6.9 months in the Pd arm (hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.47 to 0.85; p=0.0018). PFS rate at 12 months was 52 percent vs 35 percent.

“The PFS benefit of SC D-Pd was generally consistent across subgroups, regardless of age, International Staging System [ISS] disease stage, number of lines of prior therapy, cytogenetic risk profile, Eastern Cooperative Oncology Group performance status [ECOG PS], and refractoriness to lenalidomide,” said Dimopoulos.
PFS HRs were 0.69 (95 percent CI, 0.44 to 1.09) for patients <65 years of age and 0.55 (95 percent CI, 0.38 to 0.81) for those ≥65 years of age. For those with ISS stage 1, 2 or 3 disease, PFS HRs were 0.62 (95 percent CI, 0.39 to 0.98), 0.54 (95 percent CI, 0.33 to 0.87) and 0.75 (95 percent CI, 0.42 t0 1.32), respectively.

Patients who had received ≥4 lines of prior therapy appeared to obtain a greater PFS benefit from D-Pd, with a PFS HR of 0.40 (95 percent CI, 0.18 to 0.90), compared with 0.70 (95 percent CI, 0.30 to 1.67) and 0.66 (95 percent CI, 0.48 to 0.92) for those who had received one prior line and 2–3 prior lines of therapy, respectively.

PFS HRs were 0.85 (95 percent CI, 0.49 to 1.44) for patients with high cytogenetic risk, 0.51 (95 percent CI, 0.32 to 0.81) for those with standard cytogenetic risk, 0.66 (95 percent CI, 0.49 to 0.90) for patients refractory to lenalidomide, and 0.36 (95 percent CI, 0.15 to 0.83) for those not refractory to lenalidomide.

“Objective response rate [ORR], rates of very good partial response or better [≥VGPR] and complete response or better [≥CR], and minimal residual disease [MRD] negativity rate were all significantly higher in the D-Pd vs Pd arm,” Dimopoulos highlighted.

ORR was achieved by 69 percent of patients in the D-Pd arm vs 46 percent of those in the Pd arm (odds ratio, 2.68; 95 percent CI, 1.65 to 4.35; p<0.0001). In the D-Pd arm, 51 percent of patients achieved ≥VGPR, while 25 percent achieved ≥CR. In the Pd arm, ≥VGPR and ≥CR were achieved by 20 percent and 4 percent of patients, respectively.

MRD negativity was achieved by 9 percent of patients in the D-Pd arm vs 2 percent of those in the Pd arm (p=0.0102) – a 4.3-fold increase with SC D-Pd.

No unexpected safety signals

The open-label, multicentre APOLLO trial included 304 patients (median age, 67 years) with R/R MM previously treated with ≥1 prior line of therapy, including lenalidomide and a PI. The patients, recruited from 12 European countries, were randomized to receive D-Pd or Pd given in 28-day treatment cycles.

At baseline, 45 percent, 33 percent and 22 percent of patients in each arm had ISS stage I, II and III disease, respectively. Thirty-eight percent of patients in the D-Pd arm vs 32 percent of those in the Pd arm had high cytogenetic risk. Most patients (75 percent vs 74 percent) had received 2–3 prior lines of therapy and were refractory to lenalidomide (79 percent vs 80 percent), while about half were refractory to PI (47 percent vs 49 percent) or to both PI and lenalidomide (42 percent vs 42 percent).

“Almost all patients [95 percent] in the D-Pd arm started treatment with SC daratumumab. Ninety-eight percent of patients in the D-Pd arm received SC daratumumab,” said Dimopoulos. “The median duration of study treatment was 11.5 months in the D-Pd arm vs 6.6 months in the Pd arm.”

“Treatment-emergent AEs [TEAEs] in the D-Pd arm were consistent with the known AE profiles of SC daratumumab and Pd, with no new safety concerns observed,” he continued. “TEAEs that were more common in the D-Pd vs Pd arm included neutropenia [grade 3/4, 68 percent vs 51 percent], febrile neutropenia [grade 3/4, 9 percent vs 3 percent] and infections [grade 3/4, 28 percent vs 23 percent].”

IRRs were reported in 5 percent of patients in the D-Pd arm, with all events being grade 1 or 2. The incidence of local injection site reactions with SC daratumumab was 2 percent, with all events being grade 1.

“The most common serious TEAEs were pneumonia [15 percent vs 8 percent in the D-Pd vs Pd arm] and lower respiratory tract infection [12 percent vs 9 percent],” said Dimopoulos. “TEAEs led to treatment discontinuation in only 2 percent vs 3 percent of patients in the D-Pd vs Pd arm, and to death in 7 percent of patients in each arm. The incidence of second primary malignancy was 2 percent in each arm.”

An effective and convenient treatment

“SC D-Pd demonstrated a 37 percent reduction in risk of disease progression or death vs Pd, along with significantly deeper responses, including a >6 times higher ≥CR rate and a >4 times higher MRD negativity rate, with a manageable safety profile,” said Dimopoulos.

“These results, together with the low IRR rate and short administration duration, support SC D-Pd as an effective and convenient treatment option for patients with R/R MM who have received ≥1 prior line of therapy, including lenalidomide and a PI,” he concluded, adding that SC daratumumab was recently approved in North America, South America, Europe and Asia.