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Daratumumab is a human immunoglobulin Gκ monoclonal antibody targeting CD38 with direct antitumor and immunomodulatory effects
.
Daratumumab intravenous administration (DARA IV) has been approved in many countries for monotherapy for relapsed/refractory multiple myeloma (RRMM) or in combination
with RRMM or standard therapy for newly diagnosed MM.
The subcutaneous formulation of daratumumab (DARA SC) was developed to shorten the administration time of treatment (DARA SC: 3-5 minutes, DARA IV: 37 hours) without compromising efficacy and safety
.
Based on the primary analysis of a previously published phase III COLUMBA study, DARA SC is approved as a combination therapy for RRMM monotherapy and RRMM or newly diagnosed MM in the U.
S
.
, EU, and other countries around the world.
The primary analysis of the Phase III COLUMBA study demonstrated that DARA SC was non-inferior to DARA IV
in terms of the common primary endpoint of efficacy (overall response rate [ORR]) and pharmacokinetics (maximum trough concentration [Ctrough], measured before dosing on day 1 of cycle 3).
At a median follow-up of 7.
5 months, the ORRs for DARA SC and DARA IV were 41% and 37%,
respectively.
The maximumCtrough was 593 (standard deviation [SD], 306) μg/mL in the DARA SC group and 522 (SD, 226) μg/mL in the DARA IV group; The geometric mean ratio is 107.
93%.
DARA SC was well tolerated and had a safety profile comparable to DARA IV, which had a lower incidence of infusion-related reactions (IRR) than DARA IV (13% vs.
34%; P<0.
0001).
Based on this, this study reported the final analysis of the phase III COLUMBA study with a longer follow-up of 29.
3 months (an increase of 21.
8 months after the main analysis).
This was a multicenter, open-label, non-inferiority, randomized phase III study
.
The inclusion criteria were: (1) relapsed and refractory patients diagnosed with MM according to the criteria of the International Myeloma Working Group; (2) Patients who have previously received ≥ 3rd line therapy, including proteasome inhibitors and immunomodulatory drugs, or patients who are refractory to both drugs
.
Eligible patients were randomized to receive DARA SC or DARA IV in a 1:1 ratio, stratified
by baseline weight (≤ 65 kg, 66-85 kg, >85 kg), previous treatment lines (≤ 4 or >4), and myeloma type (immunoglobulin G or non-immunoglobulin G).
Patients in the DARA SC group received a fixed dose of daratumumab 1800 mg with rHuPH20 2,000 U/mL co-preparation, and patients in the DARA IV group received daratumumab 16 mg/kg
.
Patients receive daratumumab once a week for cycles 1-2, every 2 weeks for cycles 3-6 (all cycles, 28 days), and every 4 weeks thereafter until disease progression or toxicity
.
Common primary endpoints are ORR and maximumCtrough
.
The primary secondary endpoints were: incidence of IRR, progression-free survival (PFS), very ≥ very good partial response (≥ VGPR) rate, and overall survival (OS).
A total of 522 patients (DARA SC: n=263; DARA IV: n=259)
were included.
Among patients receiving ≥ 1 therapeutic doses, the percentage of patients discontinued was similar across groups (DARA SC group: 90.
0% [n=234]; DARA IV group: 91.
1% [n=235]).
Disease progression (DARA SC group: 75.
4% [n=196]; DARA IV: 75.
6% [n=195]) was the most common cause of treatment discontinuation in both groups, consistent with
the main analysis.
At the end of the final analysis, 26 (10%) patients in the DARA SC group and 23 (8.
9%) patients in the DARA IV group were still receiving treatment
.
The median number of treatment cycles received in the DARA SC and DARA IV groups was comparable (7.
0 and 7.
5, respectively), with a median relative dose intensity of 100.
0% and 99.
9% for daratulumab in both groups, and a median duration of treatment of 5.
6 and 6.
1 months
, respectively.
Efficacy
The efficacy results at the time of the final analysis were generally consistent
with the results at the time of the main analysis.
ORR continued to improve in both treatment groups, from 41.
1% to 43.
7% in the DARA SC group and from 37.
1% to 39.
8%
in the DARA IV group.
Compared to the main analysis, the depth of mitigation continued to deepen over time, with ≥ VGPR rates increasing from 19% to 23.
6% in the DARA SC group and from 17% to 21.
6% in the DARA IV group (Figure 1).
Figure 1
At a median follow-up of 29.
3 months, the median PFS in both treatment groups was consistent with the main analysis, with 5.
6 months in the DARA SC and DARA IV groups at 5.
6 months and 6.
1 months, respectively (Figure 2).
Figure 2
The median OS was similar in both groups: 28.
2 months in the DARA SC group and 25.
6 months
in the DARA IV group.
The estimated 24-month OS rate was 55.
8% in the DARA SC group and 51.
6% in the DARA IV group (Figure 3).
The median OS was broadly similar
between the DARA SC and DARA IV subgroups in the different weight subgroups at baseline.
Figure 3
Pharmacokinetics and immunogenicity
The pharmacokinetic and immunogenicity results of the final analysis were consistent
with the main analysis.
In patients with pharmacokinetic analysis sets (DARA SC group: n=259; DARA IV group: n=257), the serum trough concentration of daratumumab was consistently higher than or comparable to that of DARA IV after treatment with DARA SC (Figure 4).
After weekly dosing, the serum trough concentration of daratulumab increased to a maximum, and both treatment groups developed
immediately before dosing on day 1 of cycle 3.
The mean maximumCtrough in the DARA SC and DARA IV groups was 581 (SD, 315) μg/mL and 496 (SD, 231) μg/mL
, respectively.
Figure 4
Pharmacokinetic analysis of different weight subgroups was consistent
with the results of the main analysis.
Overall, adequate and consistent exposure was achieved in all body weight subgroups, suggesting that DARA SC did not require dose
adjustment.
The overall safety profile of the DARA SC and DARA IV groups was similar and consistent with the main analysis after long-term follow-up, with 91.
5% (n=238) and 93.
0% (n=240) of patients in both groups experiencing adverse events (TEAEs) of any grade during treatment, with anemia, thrombocytopenia, and fever occurring in 91.
5% of patients in both groups, with anemia, thrombocytopenia, and fever occurring in the most common (>15%) patients; Grade 3/4 TEAEs (similar to those reported in previous primary analyses) occurred in 50.
8% (n=132) and 52.
7% (n=136) of patients in both groups, most commonly (≥10%), with thrombocytopenia, anemia, and neutropenia
.
The incidence of adverse events and common adverse events in the two groups are shown
in Table 1.
Table 1
There were no clinically significant differences
in overall tolerability and safety between DARA SC and DARA IV groups in the subgroup ≤ 65 kg body weight.
The frequency with which any grade and grade 3/4 TEAE occurred in patients in each body weight subgroup was similar
to that of the general population.
With longer follow-up, no new IRRs occurred, and the incidence of IRRs was still significantly lower in the DARA SC group compared with the DARA IV group (12.
7% [n=33] vs.
34.
5% [n=89]; P<0.
0001).
In the DARA SC group, one patient experienced an injection site reaction
at a longer follow-up.
Among patients converted from DARA IV to DARA SC (n=13), no patients in the DARA SC group developed IRR
.
Overall, the primary analysis of the COLUMBA study showed that DARA SC was not inferior to DARA IV, and the final analysis of extended follow-up supported this result
。 In addition, DARA SC has several advantages over DARA IV: DARA SC has significantly shorter dosing times, thereby reducing patient treatment burden, while also leading to more positive views and satisfaction with treatment, and the final analysis of the COLUMBA study provides data on the long-term efficacy and tolerability of daratumumab monotherapy and supports the comparable clinical outcomes of DARA SC to DARA IV, with low IRR incidence, short dosing time, and no need for dose adjustment
。 Based on the above results, dara SC is considered a better treatment option
for patients with MM than DARA IV.
References:
Usmani S Z, Nahi H, Legiec W, et al.
Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma[J].
Haematologica, 2022, 107(10):2408-2417.
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