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Elranatamab, a subcutaneous BCMA/CD3 bispecific antibody, in patients with RRMM: Findings from the MagnetisMM-1 trial

Jul 2, 2021
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Elranatamab (PF-06863135) is a bispecific antibody (IgG2a) targeting the B-cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells, bridging them together to activate an immune response. The binding affinity of elranatamab to BCMA and CD3 has been optimized to potentially prompt more potent T-cell-mediated anti-myeloma activity. Subcutaneous (SC) administration of elranatamab is intended to allow higher doses than intravenous administration without increasing the incidence of adverse events (AEs).

The Multiple Myeloma Hub has previously reported about elranatamab being granted fast track designation by the U.S. Food and Drug Administration (FDA) to aid the rapid development and review, including initial data from the phase I MagnetisMM-1 trial presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. Further results from the MagnetisMM-1 trial were recently presented during the 2021 ASCO Annual Meeting by Nizar Bahlis1, and the 26th Congress of the European Hematology Association (EHA2021) by Caitlin Costello2. This article provides a summary of the presentation.

Study design

MagnetisMM-1 (NCT03269136) is a phase I, open-label, multicenter, dose-escalation trial to assess the safety and efficacy of elranatamab in adult patients with advanced relapsed or refractory multiple myeloma (RRMM), who had received prior treatment with immunomodulatory drugs (IMiDs), protease inhibitors (PIs) and anti-CD38 therapy.

Patients with measurable disease by the International Myeloma Working Group (IMWG) criteria, with an absolute neutrophil count of ≥1.0 × 109/L, platelets ≥25 × 109/L, and hemoglobin ≥8 g/dL were eligible. Of note, prior BCMA-directed therapy was allowed. Elranatamab was administered SC every week, and the dose ranged from 80−1,000 µg/kg (Figure 1).

The primary endpoints were overall response rate (ORR), AEs, cytokine release syndrome (CRS) incidence, dose-limiting toxicity (DLT), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics (PK) and pharmacodynamics.

Figure 1. Dose escalation schema* 

RP2D, recommended phase 2 dose.
*Adapted from Bahlis et al.1 and Costello et al.2

Baseline characteristics

At data cutoff (February 4, 2021), 30 heavily pretreated patients treated with a median of eight prior therapies (range, 3−15), had received elranatamab. More than half the study population was female, and 40% of all patients were ≥65 years (Table1).

 Table 1. Baseline characteristics*

Characteristic

N = 30

Sex, female, %

57

Median age, years (range)

63 (46–80)

≥65 years, %

40

R-ISS stage at initial diagnosis, %

                           I

20

                           II

40

                           III

23

Cytogenic risk, %

                           High

23

                           Standard

63

Prior anti-myeloma therapies, median (range)

8 (3–15)

Prior therapies, %

PIs

100

IMiDs

100

                           Lenalidomide

97

                           Pomalidomide

90

                           Thalidomide

27

Anti-CD38 therapy

97

                           Daratumumab

93

                           Isatuximab

13

BCMA-targeted therapy

23

                           Anti-BCMA ADC

20

                           CAR-T

10

Triple-class refractory disease, %

87

ADC, antibody-drug conjugate; BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T cell; IMiDs, immunomodulatory drugs; PI, protease inhibitor; R-ISS, Revised International Staging System.
*Adapted from Bahlis et al.1 and Costello et al.2

Results

Efficacy

  • Responses were observed starting at a dose of 215 µg/kg, and ORR was 83% at 1,000 µg/kg (RP2D) (Table 2). Complete response (CR) rate, including stringent CR (sCR), was 30%.
  • Median time to response was 22 days (range, 21–50) in 14 patients with confirmed ORR. In 75% of patients (3/4) with prior BCMA-directed therapy, very good partial response (VGPR) was attained in two and sCR in one patient.
  • 75% of patients (total of 4 patients assessed) were also minimal residual disease (MRD)-negative at 10−5 by next-generation sequencing.
  • Median duration of response was not reached in the 14 patients, and the median duration of follow-up for patients treated at doses ≥215 µg was 7.7 months.
  • Probability of being event-free at 6 months was high at 92% (range, 57–99).

Table 2. Investigator-assessed IMWG responses*

IMWG response, %

1,000 µg/kg
(n = 6)

Total ≥215 µg/kg
(n = 20)

Confirmed ORR

83

70

              sCR

0

25

              CR

17

5

              VGPR

50

35

              PR

17

5

MR

0

0

SD

0

15

PD

17

15

CR, complete response; IMWG, International Myeloma Working Group; MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; RP2D, recommended phase 2 dose; sCR, stringent CR; SD, stable disease; VGPR, very good partial response.
*Adapted from Bahlis et al.1 and Costello et al.2

Safety

  • Treatment-emergent AEs (TEAEs) observed in ≥20% of patients are listed in Table 3. Lymphopenia (83%) was the most common hematologic AE, with patients also experiencing neutropenia (53%) and thrombocytopenia (53%).
  • No DLTs were reported.
  • The most common nonhematologic AE was CRS (73%); however, these were limited to Grade 1 or 2 only.
  • At a median time to onset of CRS of 1 day (range, 1–3) and a median duration of CRS of 3 days (range, 1–10), patients did not receive any premedication or step-up dosing to mitigate CRS.
  • CRS was managed in 30% of patients with tocilizumab and in 10% with steroids.
  • CRS did not lead to any permanent treatment discontinuation, dosing interruptions, or dose reduction.

Table 3. TEAEs*

AEs, %

Grade 1

Grade 2

Grade 3

Grade 4

Total
(N = 30)

Hematologic

Lymphopenia

0

0

20

63

83

Anemia

0

10

50

0

60

Neutropenia

0

0

23

30

53

Thrombocytopenia

10

7

17

20

53

Leukopenia

3

10

23

3

40

Nonhematologic

CRS

57

17

0

0

73

Injection site reaction

43

7

0

0

50

Nausea

17

17

3

0

37

Increased AST

17

7

10

0

33

Increased ALT

17

3

10

0

30

Diarrhea

20

7

3

0

30

Vomiting

23

3

0

0

27

Decreased appetite

17

7

0

0

23

Dry skin

17

7

0

0

23

Hypokalemia

3

17

3

0

23

Arthralgia

10

7

3

0

20

ICANS

10

10

0

0

20

Pyrexia

17

3

0

0

20

AEs, adverse events, ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; TEAES, treatment-emergent adverse events.
*Adapted from Bahlis et al.1 and Costello et al.2

PK and pharmacodynamics

  • Elranatamab exposure increased in an approximately dose-proportionate manner. A prolonged absorption phase with Tmax of 3−7 days was observed after a single dose administrated SC.
  • Body weight and BCMA were not significant covariates on total exposure.
  • Serum cytokine increased significantly following the first dose, peaked at 8−24 hours, but demonstrated no notable increases with subsequent doses.

Enrollment paused temporarily on elranatamab trials due to peripheral neuropathy1,3

Part 2 from the MagnetisMM-1 phase I trial evaluates elranatamab combined with other agents (i.e., dexamethasone, lenalidomide, and pomalidomide). On the other hand, elranatamab as monotherapy is further investigated in the MagnetisMM-3 phase II trial (NCT04649359).

By early May 2021, three cases of Grade 3 peripheral neuropathy were reported in the MagnetisMM-1 trial: one receiving elranatamab as a single agent, and two in combination with pomalidomide. These AEs led to the immediate pause of patient recruitment in the phase II trial until more information was gathered.

As reported by Bahlis in the Q&A session at ASCO 2021, they are still studying the details of these events, but the peripheral neuropathy improved from Grade 3 to Grade 2 in all three patients when the treatment was discontinued. By June 2021, the sponsor was able to reinitiate patient recruitment for the pivotal trial MagnetisMM-3 safely.

Conclusion

The findings from the trial support the safety and efficacy of elranatamab at doses up to 1,000 µg/kg SC weekly in patients with RRMM. No DLTs were reported, and all CRS events were either Grade 1 or 2. PK and pharmacodynamics, along with the efficacy data, support the weekly SC dosing of elranatamab. Overall, the initial experience with elranatamab demonstrates that it is effective, achieving deep responses with a manageable safety profile in patients with heavily pretreated disease.

  1. Bahlis NJ, Raje NS, Costello CL, et al. Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM). Oral abstract #8006. 2021 ASCO Annual Meeting; June 8, 2021; Virtual.
  2. Costello CL, Raje NS, Bahlis NJ, et al. MagnetisMM-1: Phase 1 study of elranatamab (PF -06863135), a B-cell maturation antigen (BCMA) targeted CD3-engaging bispecific antibody, for patients with relapsed or refractory multiple myeloma (MM). Oral abstract S192. EHA2021; June 9, 2021; Virtual.
  3. Parson L. Pfizer pauses enrolment for trial evaluating anti-BCMA bispecific antibody. PMLiVE. http://www.pmlive.com/pharma_news/pfizer_pauses_enrolment_for_trial_evaluating_anti-bcma_bispecific_antibody_1369228. Published May 5, 2021. Accessed June 29, 2021.

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