Relapsed/refractory patients

ASCO 2019 | Phase I study of iberdomide (IBER) in relapsed/refractory multiple myeloma 

At the 2019 meeting of the American Society of Clinical Oncology, Sagar Lonial, Winship Cancer Institute of Emory University, presented the phase Ib/IIa results (NCT02773030) of iberdomide (IBER, CC 220) for the treatment of relapsed/refractory multiple myeloma (RRMM).1

IBER, a novel cereblon E3 ligase modulator (CELMoD) has shown preclinical activity and an ability to overcome immunomodulatory drug (IMiD) resistance. It also has a synergistic mechanism of action with daratumumab, bortezomib and dexamethasone (dex).

Study design and patient characteristics

This study aimed to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and obtain preliminary safety data for IBER. The patient population were RRMM patients who had disease progression despite more than two prior anti-myeloma treatments, including lenalidomide and/or pomalidomide, and a proteasome inhibitor (PI).

Dosing schedule for cohort B (N= 66, as per April 2019 data cut);

  • IBER on days 1-21
    • Escalating doses from 0.3mg to 1.2mg
    • Efficacy seen at low doses, including 0.9mg and 1.1mg, with these cohorts expanded to investigate the effect further
  • Dex: 40mg on days 1, 8, 15 and 22 of a 28-day cycle
    • Dose reduction to 20mg for patients over the age of 75

Patient characteristics:

  • Median age: 64.5 years (33-79)
  • Median prior regimens: 5 (2-12)
    • Autologous stem cell transplant: 79%
    • Lenalidomide: 100%
    • Pomalidomide: 69%
    • PIs: 100%
    • Daratumumab: 66%
Results
  • Median duration of treatment; 3 cycles (1-31)
  • Current status of treatment:
    • Twenty patients (30.3%) are continuing to receive treatment (2-27+ cycles)
    • Dose reduction of IBER: 13 (19.7%)
    • Discontinued treatment: 46 (69.7%)
      • Progressive disease (PD): 38 (57.6%)
      • Adverse event (AE): 6 (9.1%)
      • Physician decision: 1 (1.5%)
      • Other: 1 (1.5%)
  • Neither MTD nor RP2D were reached
Safety

Treatment emergent AEs (TEAEs) that did occur at grade 3 and grade 4 in this cohort are shown in Table 1.

Table 1: Grade 3 and 4 TEAEs in, cycle 1, occurring in ≥1 patient

 

Grade 3

Grade 4

Anemia

10 (15.2%)

0

Neutropenia

6 (9.1%)

6 (9.1%)

Thrombocytopenia

2 (3.0%)

3 (4.5%)

Infection

7 (10.6%)

1 (1.5%)

Pneumonia

2 (3.0%)

0

Dose-limiting toxicities (DLTs):

  • No DLTs were experienced by patients receiving doses between 0.3mg and 1.1mg
  • Eight patients received a dose of 1.2 mg of IBER
    • One patient experienced grade 4 sepsis
  • Three patients received a dose of 1.3mg of IBER
    • One patient experienced grade 3 pneumonia
  • Professor Lonial stated that whilst the DLTs were not always associated with neutropenia, it was not possible to exclude the drug as the cause, so these cohorts are being expanded to further investigate this
Efficacy

The responses are shown in Table 2 with Professor Lonial stating that these deepened over time.

Table 2: responses to IBER in total cohort, and by refractory status

 

All evaluable

(n = 59)

IMiD refractory

(n = 51)

Daratumumab + pomalidomide refractory

(n = 27)

Overall response rate (ORR)

32.2%

35.3%

29.6%

Very good partial response (VGPR)

3.4%

2.0%

3.7%

Partial response (PR)

28.8%

33.3%

25.9%

Minimal response (MR)

16.9%

17.7%

14.8%

Stable disease (SD)

35.6%

33.3%

37.0%

PD

15.3%

13.7%

18.5%

Clinical benefit rate (CBR)

49.2%

-

-

Disease control rate (DCR)

84.7%

-

-

Conclusion

This study indicates that IBER has activity in heavily pretreated patients with RRMM and has a manageable safety profile. The ORR was similar across the cohort, irrespective of lenalidomide, pomalidomide and anti-CD38 antibody refractory status. Enrollment is ongoing for cohorts looking at IBER in combination with other agents such as bortezomib and daratumumab.

Professor Lonial highlighted his key take-home messages:

  • The traditional AEs experienced with IMiD usage in the first cycle, were not seen at the grade 3/4 level with IBER
  • IBER was well-tolerated overall
  • IBER appears to be able to overcome resistance to lenalidomide and pomalidomide
  • Responses to IBER deepen over time
  • At higher doses of IBER, more patients developed VGPRs
  • A continued dose escalation is warranted, based on the lack of DLTs
  • These results are promising in such a heavily pre-treated population, who received a median of 5 prior lines of therapy
References
  1. Lonial S. et al. First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Abstract #8006. American Society of Clinical Oncology meeting, Chicago, US. 2019 Jun 02.

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