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

During the 17^th 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

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

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

Dara, daratumumab; NDMM, newly diagnosed multiple myeloma; RR, relapsed/refractory; SC, subcutaneous; VMP, bortezomib, melphalan and prednisolone; VRd, bortezomib, lenalidomide and dexamethasone
	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

Dara, daratumumab; NDMM, newly diagnosed multiple myeloma; RR, relapsed/refractory; SC, subcutaneous; VMP, bortezomib, melphalan and prednisolone; VRd, bortezomib, lenalidomide and dexamethasone;  TEAE, treatment-related adverse event
	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.