Relapsed/refractory patients

ASCO 2019 | ICARIA MM: Isatuximab + pomalidomide + dexamethasone for relapsed/refractory multiple myeloma: phase III results

During the Hematologic Malignancies — Plasma Cell Dyscrasia oral abstract session on Sunday, 02 June, 2019, at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, US, our Steering Committee member, Paul Richardson from Dana-Farber Cancer Institute, Boston, US, presented phase III data from the ICARIA MM study group trial, which investigated the safety and efficacy of isatuximab (Isa), pomalidomide (P) and low-dose dexamethasone (d) (Isa-Pd) in relapsed/refractory multiple myeloma (RRMM).1

Data given as Isa-Pd versus Pd unless otherwise stated

Background

Isa is an IgG1 monoclonal antibody that targets the CD38 transmembrane glycoprotein in multiple myeloma (MM), with many modes of action. Isa-Pd was investigated in a phase Ib dose-escalation study which identified a 10mg/kg once/twice weekly dose for future studies. These results demonstrated an overall response rate (ORR) of 62% and median progression-free survival (PFS) of 17.6 months.2

Study design and patient characteristics
  • Open-label, multicenter, randomized phase III study
  • Patients with RRMM (intention-to-treat [ITT] population, N= 307)
    • Two or more prior lines of therapy including lenalidomide and a proteasome inhibitor (PI)
    • No prior P exposure (Table 1)
    • Patients were representative of the wider RRMM population (Table 2)
  • Randomized 1:1 to either;
    • Isa-Pd administered as:
      • Isa: 10 mg/kg on days 1, 8, 15 and 22 in cycle 1, and days 1 and 15 in subsequent cycles
      • P: 4 mg on days 1–21 of a 28-day cycle
      • d: 40 mg on days 1, 8, 15 and 22
        • Dose adjusted to 20 mg for patients ≥75 years
    • Pd administered as above, with the exclusion of isatuximab
  • Treatment given until progressive disease (PD) or unacceptable adverse events (AEs)
  • Primary endpoint: PFS
  • Secondary endpoints: ORR and overall survival (OS)
  • Median follow-up: 11.6 months (95% CI, 11.4–12.2)

Table 1: Prior anti-myeloma treatments by treatment group

 

Isa-Pd (n= 154)

Pd (n= 153)

Median prior lines of therapy

3 (2–11)

3 (2–10)

Prior PI

100%

100%

Prior immunomodulatory drug (IMiD)

100%

100%

Prior alkylating agent

90.3%

96.7%

Prior autologous stem cell transplant (ASCT)

53.9%

58.8%

Refractory to lenalidomide

93.5%

91.5%

Refractory to IMid and PI

73.4%

71.9%

Table 2: Patient characteristics of note in the ITT population

 

ITT population (N= 307)

Median age (years)

67 (36–86)

Age ≥75 years

19.9%

Estimated glomerular filtration rate (eGFR, n= 287) of <50 mL/min/1.73m2

19.9%

Median time from diagnosis (years)

4.23 (0.5–20.5)

ISS stage III at diagnosis

28.0%

High-risk cytogenetics

19.5%

Efficacy
  • PFS by independent review committee (IRC) assessment: 11.53 vs47 months, P = 0.001, HR: 0.596 (95% CI, 0.436–0.814)
    • Isa-Pd provided a statistically significant improvement in PFS
    • Subgroup analysis showed the PFS benefit was maintained in subgroups based on baseline eGFR, cytogenetic risk and lenalidomide-refractory status
  • Response data is shown in Table 3
    • Data cut-off: October 2018
    • It was noted that the true CR rate is underestimated due to isatuximab interfering with M-protein measurement; see Table 3 for the of near CR (nCR)
  • OS: 72% vs 63% with HR: 0.687 (95% CI, 0.461–1.023)
    • Median OS not reached in either arm
  • Time to next treatment (TNT): not reached vs 9.1 months (HR 0.538 [95% CI, 0.381–0.758])
    • Isa-Pd delayed TNT
    • Table 4 shows subsequent myeloma therapies
  • Renal function was improved in the Isa-Pd arm
    • Patients with eGFR <50 ml/min/1.73 m2 at baseline: 32 vs 21
      • Complete renal response: 71.9% vs 38.1%
      • Sustained renal response: 31.3% vs 19.0%
  • Median treatment duration: 41.0 weeks (1.3–76.7) vs 24.0 weeks (1.0–73.7)
  • Dose reductions:
    • P: 42.8% (n = 65) vs 24.2% (n = 36)
    • d: 32.9% (n = 50) vs 25.5% (n = 38)
  • Infusion time of isatuximab:
    • First: 3.3 hours
    • Second: 2.8 hours

Table 3: Response data for Isa-Pd versus Pd

 

Isa-Pd (n= 154)

Pd (n= 153)

ORR

60.4%

35.3%

Complete response (CR)/ stringent CR (sCR)

4.5%

2.0%

Very good partial response (VGPR) or better

31.8%

8.5%

Partial response (PR)

28.6%

26.8%

MRD negativity (10-5) in ITT population

5.2%

0%

Median time to first response (days)

35

58

nCR

15.6%

3.3%

Table 4: Subsequent anti-myeloma therapies received by patients

 

Isa-Pd (n = 154)

Pd (n = 153)

Subsequent therapy given

39.0%

54.2%

Type of subsequent therapy

 

 

Alkylating agent

66.7%

39.8%

PI

56.7%

47.0%

IMiD

23.3%

22.9%

Monoclonal antibody (daratumumab)

10.0%

54.2%

Safety
  • Discontinuations: 56.5% (n= 87) vs 74.5% (n= 114)
  • Main reasons for discontinuation:
    • PD: 42.9% (n= 66) vs 57.5% (n= 88)
    • AE: 7.2% (n= 11) vs 12.8% (n= 19)
  • AEs are shown in Table 5 and Table 6
    • There were more TEAEs in the Isa-Pd arm but these did not lead to a higher rate of fatal events or discontinuations
    • There was a higher rate of neutropenia in the Isa-Pd arm, but otherwise the safety profile was similar between groups
  • Treatment is ongoing in: 42.4% (n= 65) vs 22.9% (n= 35)
  • Infusion reactions in Isa-Pd group:
    • All grades: 38.2%
    • Grade ≥3: 2.6%
    • Most were during the first infusion

Table 5: Treatment-emergent adverse events (TEAEs)

 

Isa-Pd (n= 152)

Pd (n= 149)

Grade ≥3 TEAE

86.8%

70.5%

Serious TEAE

61.8%

53.7%

TEAE causing discontinuation

7.2%

12.8%

Fatal TEAE during treatment

7.9%

9.4%

Table 6: TEAEs grade 3– 4 by type in each subgroup

 

Isa-Pd (n= 152)

Pd (n= 149)

Anemia

69.8%

68.0%

Neutropenia

84.8%

70.1%

Thrombocytopenia

30.9%

24.5%

Pneumonia

16.4%

14.7%

Fatigue

3.9%

0.0%

Dyspnea

3.9%

1.3%

Asthenia

3.3%

2.7%

Bronchitis

3.3%

0.7%

Urinary tract infection

3.3%

0.7%

Conclusion

This is the first phase III study to demonstrate that adding an antibody to a standard doublet therapy can provide a significant and sustained PFS benefit in the RRMM setting. The Isa-Pd regimen had a manageable safety profile and should be considered a new option for treating patients with RRMM.

References
  1. Richardson P.G. et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Abstract #8004. American Society of Clinical Oncology meeting, Chicago, US. 2019 Jun 02
  2. Mikhael J. et al. A Phase Ib study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Blood. 2019 Mar 12. DOI: 10.1182/blood-2019-02-895193

Expert Opinion

This is a particularly important study, in that it demonstrates the efficacy and excellent tolerability of another anti-CD38 antibody, isatuximab. My personal opinion is that this study is particularly important in demonstrating how easily isatuximab can be combined with pomalidomide.

Like the POLLUX study, this trial combined an anti-CD38 antibody with an immunomodulatory agent (IMiD) with clear efficacy over the IMiD alone.  However, unlike the POLLUX study, which combined daratumumab with lenalidomide, the ICARIA study targeted patients with more advanced disease, a population where pomalidomide is generally utilized. For this reason, one should not directly compare the ICARIA and POLLUX study outcomes as the patient populations are quite different.

It will be very interesting to see how this impacts on clinical practice in the future; specifically how clinicians choose between daratumumab and isatuximab and which drug partner is chosen for each. Moreover, it will be of interest to see if regulatory authorities around the world will specify what partners are to be matched with what anti-CD38 antibody.

In the end, it is great news for myeloma patients as we have yet another treatment option.

 

Expert Opinion

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