All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.

The Multiple Myeloma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your Multiple Myeloma Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.

The Multiple Myeloma Hub is an independent medical education platform, sponsored by Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, Roche and Sanofi. The levels of sponsorship listed are reflective of the amount of funding given. Digital educational resources delivered on the Multiple Myeloma Hub are supported by an educational grant from Janssen Biotech, Inc. View funders.

2021-02-24T12:00:32.000Z

Preliminary results of phase I trials on safety and tolerability of bispecific antibodies and BiTEs for RRMM

Feb 24, 2021
Share:

Bookmark this article

The Multiple Myeloma Hub previously conducted a review of the bispecific antibodies that are under clinical evaluation to treat patients with relapsed/refractory multiple myeloma (RRMM). A summary of the available data from these clinical studies was published in October 2020 and is available here. The article described the mechanism of bispecific antibodies, bispecific T-cell engagers (BiTEs), and presented the preliminary results (where available) of several clinical trials.

At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, held in December 2020, data on safety and efficacy were presented for four novel treatments, which have been summarized below. Findings from two other phase I trials evaluating the bispecific antibodies talquetamab and teclistamab in RRMM patients, have been recently reported on the hub.

New bispecific antibodies and BiTEs presented at ASH 2020

Two B-cell maturation antigen (BCMA)-targeting bispecific antibodies, REGN54581 (NCT03761108) and TNB-383B2 (NCT03933735), and one BiTE, AMG 7013 (NCT03287908), were evaluated for safety and efficacy in phase I dose-escalation trials. Additionally, we learned about the initial results of a study with a bispecific antibody targeting a new antigen for MM: the anti-FcRH5 cevostamab (BFCR4350A)4 (NCT03275103).

These trials included patients who have progressed after ≥ 3 prior lines, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD®), and an anti-CD38 monoclonal antibody (mAb) therapy. The baseline characteristics (Table 1) for age, gender, and prior lines of therapy in all trials were similar except for TNB-383B, which reported data for the MM subtype and patient ethnicity (21% Black or African American patients).

Table 1. Baseline characteristics (summary of the four trials)1,2,3,4

BMCA, B-cell maturation antigen; ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; IMiD, immunomodulatory drug; ISS, International Staging System; mAb, monoclonal antibody; MM, multiple myeloma; NR, not reported; PI, proteasome inhibitor; R-ISS, Revised International Staging System.

Characteristic

BCMA-directed therapies

Anti-FcRH5 bsAb

AMG 701
(N = 85)

REGN5458
(N = 49)

TNB-383B
(N = 58)

BFCR4350A
(N = 53)

Male/Female, n (%)

44/41 (52/48)

25/24 (51/49)

35/23 (60/40)

31/22 (59/41)

Age, years, median (range)

64 (34–83)

64 (41–81)

66 (37–88)

62 (33–80)

Race

Black or African American, n (%)

NR

NR

12 (21)

NR

White, n (%)

45 (78)

Not reported, n (%)

1 (2)

ECOG performance status, n (%)

0

NR

14 (29)

15 (26)

NR

1

34 (69)

33 (57)

2

1 (2)

9 (16)

ISS or R-ISS, n (%)

I

18 (21)

8 (16)

NR

NR

II

41 (48)

31 (63)

NR

III

22 (26)

10 (20)

19 (33)

unknown

4 (5)

0

NR

Prior lines of therapy, median (range)

6 (2–25)

5 (2–17)

6 (3–15)

6 (2–15)

Triple exposed, n (%)

Triple refractory (PI, IMiD, and anti-CD38 mAb), n (%)

79 (93)

53 (62)

NR

49 (100)

58 (100)

37 (64)

NR

38 (72)

Penta-drug exposed, n (%)

Penta-refractory, n (%)

NR

NR

NR

28 (57)

44 (76)

20 (34)

NR

24 (45)

MM subtype, n (%)

IgG

NR

NR

30 (52)

NR

IgA

12 (21)

Light chain

13 (22)

Other

3 (5)

Safety

Table 2 summarizes the adverse events from the four trials.

AMG 701

Twenty-one patients continued treatment with AMG 701, while the remaining discontinued mainly due to progressive disease (n = 51), and five due to adverse events (AEs). There were four deaths from AEs, none related to AMG 701: sepsis (n = 2), retroperitoneal bleeding (n = 1), and subdural hematoma (n = 1). The most common serious adverse events (SAEs) were infections (17%) and cytokine release syndrome (CRS; 9%). Grade III CRS dose-limiting toxicities (DLTs) were seen in eight patients and non-CRS Grade III/IV in three patients.

REGN5458

The most common Grade ≥ 3 AEs were hematologic. DLTs occurred in two patients but were resolved with supportive care. No Grade ≥ 3 CRS was reported, while Grade I and II CRS were reported in 84% and 16%, respectively. The median duration of CRS onset was 18.7 hours (range, 6–382), and the median duration of CRS was 11.7 hours (range, 0–77). There was no correlation between CRS, dose level, and response to treatment.

TNB-383B

Thirty-three patients discontinued treatment, mainly due to progressive disease (n = 30), DLT (n = 1), and COVID-19 (n = 2). The most common AEs were CRS (45%) and hematologic toxicities (≈20%). Despite the increase in AEs (80%) due to CRS (Grade I and II) at doses ≥ 40 mg, non-CRS AEs, including Grade III/IV, remained stable at any given dose. Grade ≥ 3 treatment-emergent AEs were seen in 57% of patients.

Grade I/II CRS was seen in 26% of patients, with no Grade III CRS being observed. The median onset time of CRS was ≤ 1 day (range, 0–7), and the median duration of CRS was 1 day (range, 1–7).

BFCR4350A

The most common AE was CRS (76%) but of Grade I or II. Infusion-related reactions were observed in 23% of patients. Twenty-eight patients had serious AEs with treatment-related events seen in 13 patients. Five patients had AEs leading to withdrawal, with treatment-related events seen in two patients: pneumonitis and meningitis seen in one patient each. There were no treatment-related Grade V events, and only one patient with DLT of Grade III pneumonia was seen in the 3.6/90 mg group.

Table 2. Adverse events (summary of the four trials )1,2,3,4

AST, aspartate aminotransferase test; CRS, cytokine release syndrome; NR, not reported; SAEs, serious adverse events.

Event

AMG 701

REGN5458

TNB-383B

BFCR4350A

Any grade

Grade ≥ 3

Any grade

Grade ≥ 3

Any grade

Grade ≥ 3

CRS grade, n (%)

Grade I

23 (27)

16/19 (84)

NR

NR

0 (0)

18 (34)

NR

Grade II

24 (28)

3/19 (16)

21 (40)

Grade III

8 (9)

0 (0)

1 (2)

Hematologic (%)

Anemia

42

37

22

21

17

28

19

Neutropenia

25

16

14

19

16

17

15

Thrombocytopenia

21

18

6

17

14

32

25

Lymphopenia

NR

18

12

NR

NR

15

15

Nonhematologic (%)

CRS

65

39

0

45

0

76

2

Diarrhea

31

NR

NR

12

0

28

2

Hypophosphatemia

31

NR

NR

NR

NR

19

9

Fatigue

NR

35

6

24

2

17

4

Nausea

NR

31

0

21

0

19

0

Pyrexia

NR

31

2

16

2

74

NR

Back pain

NR

27

4

NR

NR

NR

NR

Headache

NR

NR

NR

22

2

8

NR

Infection

17

47

18

21

14

NR

NR

Vomiting

NR

NR

NR

14

0

NR

NR

Chills

NR

NR

NR

12

0

15

NR

Hypomagnesemia

NR

NR

NR

12

0

28

0

Infusion-related reaction

NR

NR

NR

NR

NR

23

0

Hypokalemia

NR

NR

NR

NR

NR

21

4

AST increased

NR

NR

2

NR

NR

15

2

SAEs (%)

38

NR

NR

33

NR

53

NR

Efficacy

Table 3 summarizes the overall response rate (ORR) from trials with AMG 701, REGN5458, TNB-383B, and BFCR4350A.

AMG 701

Data cutoff: July 2020

Median duration for treatment was 7.6 weeks (range, 4.1–15.1). The ORR to the treatment was highest (83%) in the recent cohort of six patients, with 50% ≥ very good partial response (VGPR). Six out of seven patients were minimal residual disease (MRD)-negative with stringent complete response (sCR; n = 3), complete response (CR; n = 3), and VGPR (n = 1). All six patients have ongoing responses, and the median duration of response in one patient is 22 months.

The median response to treatment was 5.6 months, and the median follow-up time for responding patients was 6.5 months (range 1–27). The study did not assess median duration of response as they are still ongoing in 17/21 patients. AMG 701 indicated a good pharmacokinetics (PK) profile in its target patient population of RRMM, with AMG 701 exposures increasing in a dose-related manner and supporting the once-weekly dosing regimen.

REGN5458

Data cutoff: June 2020

The median duration of follow-up was 2.6 months (range 0.5–13.4). The ORR was 39% with 95% (18/19) of responders achieving VGPR. A CR or sCR was observed in 42% (8/19) of patients. The median duration of response was 6 months (range 1.0–13.1) and 37% of responders have maintained response for ≥ 8 months. 74% of the responders are currently continuing treatment. MRD negativity was achieved in 57% (4/7) patients. Treatment with REGN5458 showed early, consistent, and durable responses in RRMM patients.  

TNB-383B

Data cutoff: October 2020

The ORR was 80% at doses ≥ 40 mg of TNB-383B with 60% of patients attaining VGPR, and 13.3% CR. MRD-negativity was seen in three out of four patients. Response to treatment continued to improve with ongoing treatment in 22/27 patients. Median duration of response was up to 18 weeks.

The PK profile of TNB-383B was proportionate with 5.4 mg onwards, and supportive of doses ≥ 20 mg once every three-week schedule.

BFCR4350A

Data cutoff: April 2020

A 53% ORR was observed in the ≥ 3.6 mg/20 mg group and no response was seen in the ≤ 3.6/10.8 mg group. The median time to first response was 29.5 days (range, 21–105), and to best response was 57.5 days (range, 21–272). MRD-negativity was seen in 6/7 patients, and 32% of patients showed ≥ VGPR in the ≥ 3.6 mg/20 mg group. Median follow-up in patients responding to treatment was 10.3 months (range, 2.7–19.5). Eight patients showed durable response to treatment with a response duration of ≥ 6 months, and four patients continued to respond despite treatment discontinuation. The PK profile with BFCR4350A exposures increased in a dose-related manner and was supportive of the dosing regimen.

Table 3. Overall response rate (summary of the four trials)1,2,3,4

Therapy

       ORR (%)

BiTE, bispecific T-cell engager; DL, dose levels; ORR, overall response rate.

AMG 701

All patients (n = 82)

26

Dose 0.015–1.6 mg (n = 27)

4

Dose 3–18 mg (n = 55)

36

Most recent cohort (n = 6)

83

REGN5458

All patients (N = 49)

 

DL 1–3 (n = 24)

29.2

DL 4–5 (n = 17)

41.2

DL 6 (n = 8)

62.5

TNB-383B

0.025–1.8 mg (n = 15)

20

5.4–30 mg (n = 28)

43

40–60 mg (n = 15)

80

BFCR4350A

≥ 3.6/20 mg (n = 34)

53

3.6/20 mg–3.6/60 mg (n = 16)

44

3.6/90 mg–3.6/132 mg (n = 18)

61


 Conclusion

The preliminary findings from these clinical trials indicate that AMG 701, REGN5458, TNB-383B, and BFCR4350A have a good safety profile and show a durable efficacy in heavily pretreated RRMM patients. ORRs were encouraging across all patients, and responses improved over time. The dose-escalation studies for all four treatments are ongoing.

  1. Madduri D, Rosko A, Brayer J, et al. REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):41-42. DOI: 10.1182/blood-2020-139192
  2. Rodriguez C, D’Souza A, Shah N, et al. Initial Results of a phase I study of TNB-383B, a BCMA x CD3 bispecific T-cell redirecting antibody, in relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):43-44. DOI: 1182/blood-2020-139893
  3. Harrison S, Minnema M, Lee HC, et al. A phase 1 first in human (FIH) study of AMG 701, an anti-B-cell maturation antigen (BCMA) half-life extended (HLE) BiTE® (bispecific T-cell engager) molecule, in relapsed/refractory (RR) multiple myeloma (MM). Blood. 2020;136(Supplement 1):28-29. DOI: 1182/blood-2020-134063
  4. Cohen AD, Harrison SJ, Krishnan A, et al. Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):42-43. DOI: 1182/blood-2020-136985

Your opinion matters

Which dosing schedule for belantamab mafodotin do you think is optimal for providing an efficacy benefit while managing toxicities?
2 votes - 41 days left ...

Newsletter

Subscribe to get the best content related to multiple myeloma delivered to your inbox