MOR202 for patients with R/R multiple myeloma — results from a phase I–IIa trial

Anti-CD38 therapies, such as daratumumab (dara), have improved clinical outcomes in patients with multiple myeloma (MM). Unlike other currently exploited agents, the novel IgG1_λanti-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

Study design

• Primary endpoints:
  • Maximum tolerated dose (MTD) of MOR202 as a monotherapy or in combination with dex ± an iMiD®
  • Recommended MOR202 dosing regimen
  • Adverse events (AEs)
• Secondary endpoints (with sufficient data to be reported here) were overall response rate (ORR), proportion of patients with stable disease, duration of response (DoR), time to progression, and progression-free survival (PFS)
• Data collection cut-off: December 31, 2017

Patient eligibility

• Adult patients with RRMM (N = 91), were enrolled from nine hospitals in Germany and one in Austria. Definitions for RRMM varied by treatment subgroup:
  • MOR202 monotherapy or MOR202 + dex: ≥ 2 prior therapies including an IMiD and a proteasome inhibitor (PI)
  • MOR202 + pom + dex: ≥ 2 prior therapies including lenalidomide and a PI, with disease progression within 60 days of most recent therapy, and non-refractory/intolerant to pom
  • MOR202 + len + dex: ≥ 1 prior therapy
• Patients had a Karnofsky performance status of ≥ 60%, adequate organ function, documented progression to most recent anti-myeloma therapy, and measurable disease defined as ≥ 1 of
  • serum monoclonal protein ≥ 0.5 g/100 mL and/or
  • urine monoclonal protein ≥ 200 mg per 24-hour period
  • bone marrow clonal plasma cell population
  • abnormal FLC ratio
• Patients with primary refractory MM and those that had previously received an allogenic stem cell transplant (allo-SCT) and/or prior anti-CD38 therapy were excluded

Treatment

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

Results

Patient characteristics

• At the time of enrollment, the majority (> 80%) of patients had received
  • autologous SCT (auto-SCT)
  • ≥ 2 lines of anti-MM treatment
• Baseline patient characteristics are shown in Table 2

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 (n = 18)	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

 Safety

• Treatment-emergent AEs (TEAEs) were observed in 100% of patients
  • The most common Grade ≥ 3 TEAEs are shown in Table 3
• MOR202-related serious AEs were predominantly IRRs (10%) and pneumonia (4%)
• Infusion-related reactions were observed in
  • 40% of patients receiving MOR202 monotherapy
  • 7% of patients receiving MOR202 as a combination treatment
• MOR202 MTD was not reached in any cohort
• No DLTs were observed at doses up to 8 mg/kg, but four DLTs were reported at 16 mg/kg
  • The main reason for discontinuation was disease progression in all cohorts, followed by AEs
  • Withdrawal due to MOR202-related, or suspected MOR202-related, TEAEs occurred in three patients in the MOR202 monotherapy cohorts and in two patients in the MOR202 combination cohorts
• Five treatment-emergent deaths were observed, none of which were associated with MOR202
  • One death due to cardiovascular disorder in the MOR202 + dex + pom group was attributed to treatment with pom

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

Efficacy

• Patient responses to MOR202 dosing schedules are illustrated in Table 4
• Upon analysis of the results from this study, the suggested MOR202 treatment regimen for the treatment of adult patients with RRMM is
  • IV infusion of MOR202 for 30 minutes at doses up to 16 mg/kg + dex (40 mg) ± len (25 mg) or pom (4 mg)

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 (n = 31)	MOR202 weekly (n = 4)	MOR202 + dex (n = 18)	MOR202 + dex + pom (n = 21)	MOR202 + dex + len (n = 17)
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)

Conclusion

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.

Future directions

• Two confirmatory clinical trials are underway further investigating the efficacy of MOR202:
  • NCT03860038: single-arm phase II study investigating the combination of MOR202 with dex in patients with RRMM who have received ≥ 2 prior lines of treatment
  • NCT03952091: randomized phase III study investigating MOR202 in combination with dex plus len vs dex plus len in patients with RRMM who received ≥ 1 prior line of treatment