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Anti-CD38 therapies, such as daratumumab (dara), have improved clinical outcomes in patients with multiple myeloma (MM). Unlike other currently exploited agents, the novel IgG1λanti-CD38 antibody MOR202 does not induce complement-dependent cytotoxicity (CDC), which has been associated with undesirable infusion-related reactions (IRRs). Alternative approaches to reduce the rate of IRRs include administering the drug as a split infusion, a schedule that was recently approved for daratumumab by the United States Food & Drug Administration (FDA).
MOR202, also known as TJ202, has been granted investigational new drug (IND) clearance by the National Medical Products Administration (NMPA) of China and is also being investigated in late-stage European trials for the treatment of patients with relapsed or refractory (R/R) MM (RRMM).
A first-in-human, multicenter, open-label, phase I-IIa trial (NCT01421186) in patients with RRMM is ongoing in Europe. The aim of the study is to characterize the safety, pharmacokinetic profile, and clinical activity of MOR202 both as a monotherapy and in combination with dexamethasone (dex) alone or dex plus an immunomodulatory drug (iMiD®). At the 23rd Congress of the European Hematology Association (EHA) 2018, Marc S. Raab presented results of MOR202 in combination with dexamethasone (dex), pomalidomide (pom) plus dex, and lenalidomide (len) plus dex.
Raab and colleagues have since published results, based on the primary completion analysis, in The Lancet Hematology; we hereby present a summary.1
Eligible patients were assigned to a dose escalation (1–8; n = 67) or confirmation (n = 24) cohort and received treatment with intravenous (IV) MOR202 in 28-day cycles as per the dosing schedules illustrated in Table 1.
Table 1. MOR202 treatment regimens for dose escalation and confirmation cohort studies1
dex, dexamethasone; len, lenalidomide; pom, pomalidomide *MOR202 was administered on Days 1 and 15. In Cycle 1, an additional loading dose was given on Day 4 †MOR202 was administered on Days 1, 8, 15, and 22. In Cycle 1, an additional loading dose was given on Day 4 ‡Dex (40 mg [≥ 75 years] or 20 mg [< 75 years]) was administered on Days 1, 8, 15, and 22 and on Day 4 of Cycle 1 §Pomalidomide (4 mg) or ¶lenalidomide (25 mg) were administered orally once daily on Days 1–21 of the cycle |
|||||
Regimen |
Patients enrolled, n |
Cohort number |
MOR202 dose, mg/kg |
Treated patients, n |
Patients remaining on treatment, n |
---|---|---|---|---|---|
MOR202 bi-weekly* |
31 |
1 2 3 4 5 6 7 8 |
0.01 0.04 0.15 0.50 1.50 4 8 16 |
4 4 3 3 3 3 3 8 |
0 |
MOR202 weekly† |
4 |
6 |
4 |
4 |
0 |
MOR202 + dex‡ |
18 |
6 7 8 Confirmatory |
4 8 16 16 |
3 4 4 7 |
0 |
MOR202 +dex‡ + pom§ |
21 |
7 8 Confirmatory
|
8 16 16
|
5 8 8
|
10 |
MOR202§ + dex‡ + len¶ |
17 |
7 8 Confirmatory |
8 16 16 |
5 3 9
|
6 |
Table 2. Patient characteristics by treatment regimen1
auto-SCT, autologous stem cell transplant; dex, dexamethasone; ISS, International Stating System; IQR, interquartile range; KPS, Karnofsky performance status; len, lenalidomide; pom, pomalidomide; TEAE, treatment-emergent adverse event |
|||||
Characteristic |
MOR202 biweekly (n = 31) |
MOR202 weekly (n = 4) |
MOR202 + dex |
MOR202 + dex + pom (n = 21) |
MOR202 + dex + len (n = 17) |
---|---|---|---|---|---|
Sex, % male
|
61 |
100 |
56 |
62 |
71 |
Median age, years (IQR) ≥ 65 years, % |
71.0 (64.0–74.0)
26 |
68.5 (55.5–72.0) 25 |
67.0 (56.0–72.0) 39 |
65.0 (58.0–77.0)
48 |
66.0 (57.0–75.0) 47 |
High-risk cytogenetic status, % |
26 |
50 |
28 |
38 |
35 |
Previous auto-SCT, % |
81 |
100 |
83 |
81 |
88 |
Median number of previous treatment lines (IQR) |
3.0 (2.0–4.0) |
4.5 (2.5–8.5) |
3.0 (2.0–4.0) |
3.0 (2.0–3.0) |
2.0 (1.0–2.0) |
ISS Stage III |
16 |
50 |
22 |
24 |
35 |
KPS 60–70%, % |
13 |
0 |
6 |
14 |
12 |
Table 3. Grade ≥ 3 TEAEs reported by ≥ 10% of patients, by treatment regimen1
dex, dexamethasone; len, lenalidomide; pom, pomalidomide; TEAE, treatment-emergent adverse event |
|||||
Grade ≥ 3 TEAE, % |
MOR202 biweekly (n = 31) |
MOR202 weekly (n = 4) |
MOR202 + dex (n = 18) |
MOR202 + dex + pom (n = 21) |
MOR202 + dex + len (n = 17) |
---|---|---|---|---|---|
Any
|
52 |
100 |
83 |
95 |
100 |
Blood and lymphatic Leukopenia Neutropenia Lymphopenia Anemia Thrombocytopenia |
6 0 16 6 3 |
75 50 50 0 25 |
11 22 39 17 17 |
57 71 52 14 24 |
47 53 59 18 18 |
Diarrhea |
0 |
0 |
0 |
10 |
6 |
Pneumonia |
0 |
0 |
6 |
24 |
6
|
Respiratory tract infection |
0 |
0 |
0 |
14 |
0 |
Hypophosphatemia |
0 |
0 |
0 |
5 |
12 |
Plasma cell myeloma |
6 |
25 |
6 |
0 |
0 |
Hypertension |
10 |
0 |
11 |
19 |
12 |
Pericarditis |
0 |
25 |
0 |
0 |
0 |
Supraventricular tachycardia |
0 |
25 |
0 |
0 |
0 |
Cataract operation |
0 |
25 |
0 |
0 |
0 |
Withdrawal due to TEAEs, % |
13 |
50 |
6 |
14 |
18 |
Table 4. Patient responses to different MOR202 regimens1
CI, confidence interval; CR, complete response; Dex, dexamethasone; DoR, duration of response; len, lenalidomide; NA, not applicable; NE, not evaluable; NR, not reached; ORR, overall response rate; PD, partial disease; PFS, progression-free survival; pom, pomalidomide; PR, partial response; sCR, stringent complete response; SD, stable disease; TEAE, treatment-emergent adverse event; VGPR, very good partial response |
|||||
Patient response |
MOR202 biweekly |
MOR202 weekly |
MOR202 + dex |
MOR202 + dex + pom |
MOR202 + dex + len |
---|---|---|---|---|---|
ORR, % (95% CI) |
0 (0.0–11.2) |
0 (0.0–60.2) |
28 (9.7–53.5) |
48 (25.7–70.2) |
65 (38.3–85.8) |
Best overall response, % sCR CR VGPR PR Minimal SD PD NE |
0 0 0 0 0 19 74 6 |
0 0 0 0 0 75 25 0 |
0 0 11 17 11 39 22 0 |
5 5 14 24 19 10 10 14 |
6 6 12 41 6 6 6 18 |
Median DoR, months (95% CI) |
NA |
NA |
16.7 (1.9–24.9) |
16.6 (12.1–NR) |
NR (4.2–NR) |
Median time to progression, months (95% CI) |
1.1 (1.0–1.4) |
2.1 (0.7–9.9) |
8.4 (1.4–11.1) |
17.5 (4.1–NR) |
NR (5.1–NR) |
Median PFS, months (95% CI) |
1.1 (1.0–1.4) |
2.1 (0.7–9.9) |
8.4 (1.4–11.1) |
17.5 (3.0–NR) |
NR (5.1–NR) |
Results from this study suggest that MOR202 is safe and tolerable in heavily pre-treated patients with RRMM. Dex successfully reduced the frequency of infusion-related AEs compared to MOR202 alone, and a recommended treatment regimen for use in future trials was identified. Promising clinical activity and disease control were apparent in patients treated with MOR202 in combination with both dex alone and dex with pom or len.
Due to the stringent inclusion criteria for this study, there was some patient selection bias. Additionally, patients involved in clinical trials investigating alternative anti-CD38 therapies have generally received a greater number of previous lines of therapy than those enrolled in this study. These limitations should be considered with regard to real-world practice.
Raab MS, Engelhardt M, Blank A, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol.2020;S2352-3026(19)30249-2. DOI: 1016/S2352-3026(19)30249-2
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