General MM

IMW 2019 | Results from the phase II PLEIADES trial (MMY2040): dara SC combination therapy

During the 17th International Myeloma Workshop (IMW), Ajai Chari from Icahn School of Medicine at Mount Sinai, New York, NY, US, presented the latest results of the phase II PLEIADES trial (NCT03412565).1

Daratumumab (dara) is known to be efficacious in patients with multiple myeloma (MM) when administered intravenously and is licensed as a monotherapy or for use in combination with other treatments for MM both in Europe and the US.2 A highly permeable subcutaneous formulation of dara (dara SC) is currently being assessed as an alternative to intravenous dara. In the phase III COMLUMBA trial,3 dara SC monotherapy showed similar activity and safety to intravenous DARA but with fewer infusion-related reactions (IRRs). The phase II PLEIADES trial sought to investigate the efficacy and safety of dara SC when combined with standard MM regimens like bortezomib (V), lenalidomide (R) and dexamethasone (d, VRd), Rd or V, melphalan, and prednisone (VMP), in both newly-diagnosed MM (NDMM) and relapsed/refractory MM (RRMM).

Study design & baseline characteristics

This trial enrolled and separately assessed three distinct patient populations:

This trial enrolled and separately assessed three distinct patient populations who received therapies as below:

  • Transplant-eligible NDMM (n=67): dara SC + VRd; 21-day cycles for four cycles:
    • dara SC: 1800mg once a week in cycles one to three and day one of cycle four
    • V: on days one, four, eight, and 11
    • R: 25mg daily on days one to 14
    • d: 20mg on days one, two, eight, nine, 15, and 16
    • Primary endpoint: ≥very good partial response (VGPR)
  • Transplant-ineligible NDMM patients (n=67): dara SC + VMP; 42-day cycles for cycles one to nine, 28-day cycles until disease progression (PD):
    • dara SC: 1800mg once a week in cycle one, once every three weeks in cycles two to nine, and once every four weeks from cycle nine onwards
    • V: on day one, four, eight, 11, 22, 25, 29, and 32 in cycle oneand day one, eight, 22, 29 in cycle two
    • M: 9mg/m2 daily on days one to four of cycles one to nine
    • P: 60mg/m2 daily on days one to four from cycles one to nine
    • Primary endpoint: overall response rate (ORR)
  • RRMM following ≥1 prior therapy (n=65): dara SC + Rd; 28-day cycles until PD:
    • R: 25mg daily on days one to 21
    • d: 40mg weekly
    • Primary endpoint: ORR

Table 1. Baseline characteristics1

 

Transplant-eligible NDMM

dara SC + VRd

(n= 67)

Transplant-ineligible NDMM

dara SC + VMP

(n= 67)

RRMM

dara SC + Rd

(n= 65)

Median age (range), years

59 (33-76)

75 (66-86)

69 (33-82)

Male patients

71.6%

46.3%

69.2%

ECOG score:

0

1

2

 

59.7%

38.8%

1.5%

 

37.3%

56.7%

6.0%

 

55.4%

44.6%

0

Median number of prior lines of therapy (range)

Not applicable (N/A)

N/A

1 (1-5)

Cytogenetic risk:

Standard

High

 

75.5%

24.5%

 

80.5%

19.5%

 

64.5%

35.5%

ISS stage:

I

II

III

 

44.8%

34.3%

20.9%

 

32.8%

44.8%

22.4%

 

42.2%

29.7%

28.1%

* ECOG; Eastern Cooperative Oncology Group, ISS; international staging system

Key findings

 All primary endpoints were met for all cohorts (Table 2)

  • Responses to dara SC combination treatments were similar to intravenous DARA studies with the same combination regimens (VRd: GRIFFIN, VMP: ALCYONE, Rd: POLLUX)

 Table 2. Response outcomes with dara SC combination treatments1

 

Transplant-eligible NDMM

dara SC + VRd

(n= 67)

 

Post-induction cycle four

Transplant-ineligible NDMM

dara SC + VMP

(n= 67)

 

At 11 months

RRMM

dara SC + Rd

(n= 65)

 

At 11.2 months

ORR

97.0%

89.6%

93.8%

Complete response (CR)

7.5%

16.4%

21.5%

Stringent CR (sCR)

9.0%

16.4%

10.8%

VGPR

71.6%

43.3%

43.1%

Partial response (PR)

25.4%

13.4%

18.5%

  • The pharmacokinetics and immunogenicity of dara SC was similar to the intravenous formulation
Safety
  • Across all cohorts, IRRs were observed in 7.5% of patients (15/199):
    • Most were grade I-II (93.3%) with 14/15 patients experiencing IRRs on first treatment administration
    • One patient discontinued dara SC due to grade III IRR
    • No grade IV IRRs were reported
    • Median time to IRR onset: 3.3 hours
  • Table 3 provides a summary of the treatment-related adverse events (TEAEs) that occurred across the treatment cohort

Table 3. Safety summary1

 

Transplant-eligible NDMM

dara SC + VRd

(n= 67)

 

Transplant-ineligible NDMM

dara SC + VMP

(n= 67)

RRMM

dara SC + Rd

(n= 65)

Any TEAE

100%

100%

100%

Serious TEAE

28.4%

38.8%

47.7%

Grade 3-4 TEAE

56.7%

68.7%

83.1%

TEAEs leading to treatment discontinuation

1.5%

3.0%

7.7%

Fatal TEAE

1.5%

3.0%

3.1%

Conclusions

The investigators concluded that dara SC in combination with VRd, VMP, or Rd leads to similar efficacy and safety outcomes in patients with NDMM or RRMM, as intravenous dara in the same patient populations and treatment combinations, respectively. However, dara SC was associated with lower rates of IRRs than its intravenous formulation, making it a more favorable option for patients with MM.

References
  1. Chari A. et al., Subcutaneous (SC) Daratumumab (DARA) in Combination With Standard Multiple Myeloma (MM) Treatment Regimens: An Open-label, Multicenter Phase 2 Study (PLEIADES); 2019 September 13. Oral Abstract #AB698: 17th International Myeloma Workshop, Boston, MA, US
  2. Genmab 2019; Daratumumab for Multiple Myeloma.  http://www.genmab.com/product-pipeline/products-in-development/daratumumab [Accessed 2019 Oct 16]
  3. Mateos M.V. et al., Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.J Clin Oncol. 2019 May 29. DOI: 10.1200/JCO.2019.37.15_suppl.8005
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!