Results from the LYRA study: daratumumab, bortezomib, cyclophosphamide and dexamethasone for newly diagnosed or relapsed multiple myeloma  

The triplet combination of bortezomib, cyclophosphamide and dexamethasone (VCd) has been found to be well-tolerated and provide high response rates in patients with newly diagnosed multiple myeloma (NDMM) making it a suitable option for induction therapy in both transplant eligible and ineligible patients. To date, there has been no standard dosing protocol for VCd due to inconsistent trial results.

Daratumumab, an anti-CD38 monoclonal antibody, shows high efficacy when combined with other regimens. Recently, daratumumab in combination with bortezomib, melphalan and, prednisone (d-VMP) was approved in the frontline setting for patients ineligible for autologous stem cell transplant (ASCT).¹ However, since this is not commonly used it is necessary to establish the efficacy of daratumumab in other combinations, especially for patients with NDMM.

Habte Yimer, Texas Oncology-Tyler/US Oncology Research, Tyler, TX, and colleagues conducted a single-arm, open-label, multicenter, phase II study (LYRA, MMY2012, NCT02951819) investigating the regimen of daratumumab with VCd (D-VCd) in patients with NDMM and relapsed MM (RMM). Additionally, the effect of administering the first dose of daratumumab as a split dose was evaluated.²

Patient characteristics and study design

Data given as NDMM versus RMM

• Adult patients with measurable disease (N = 101):
  • Previously untreated disease (NDMM) regardless of eligibility status for high-dose chemotherapy or ASCT (n = 87)
  • Relapsed disease (1 prior line of therapy) with a partial response (PR) or better to initial therapy prior to progression (RMM) (n = 14)
• Induction cycles (4–8):
  • Subcutaneous bortezomib: 1.5 mg/m² – on days 1, 8 and 15 of a 28-day cycle
  • Oral cyclophosphamide: 300 mg/m² – on days 1, 8, 15 and 22 of a 28-day cycle
  • Oral or intravenous (IV) dexamethasone: 40 mg – weekly
  • IV daratumumab: 16 mg/kg – weekly
• In cycle 1 only:
  • Dexamethasone and daratumumab were administered as split doses
  • Dexamethasone: 20 mg on days 1 and 2
  • Daratumumab: of 8 mg/kg IV on days 1 and 2
  • Median infusion times for daratumumab: 4.5 hours and 3.8 hours
• Patients eligible for transplant then received a conditioning regimen and ASCT
• Maintenance: all received ≤12 daratumumab maintenance doses (16 mg/kg) monthly
• Primary endpoint: complete response + very good partial response (CR + VGPR) after 4-cycles of induction therapy
• Secondary endpoints: overall response rate (ORR), time to VGPR or better, time to PR or better, duration of response (DoR), progression-free survival (PFS) and overall survival (OS)
• Median age: 64 (41–82)
• High-risk cytogenetics (del[17p], t[4;14] or t[14;16]): 35.4% (34/96)
• Median follow-up was 7.9 months vs 8.8 months
• Patients receiving ≥1 treatment dose (n = 100): 86 vs 14
• Median duration of treatment: 225 (50–441) vs 235.5 (71–394) days
• Median treatment cycles: 8 (2–15) vs 9 (3–15)
• Median induction cycles: 6 (2–8) vs 7.5 (3–8)
• At data cut-off, 10 January 2018, 14 patients had discontinued treatment
• Patients with NDMM: 28 proceeded to have an ASCT

Key findings

Efficacy

	NDMM (n = 86):	RMM (n = 14):
After 4 cycles of induction
CR + VGPR	44.2% (95% CI, 33.5–55.3%)	57.1% (95% CI, 28.9–82.3%)
CR	4.7% (n = 4) (95% CI, 1.3–11.5%)	14.3% (n = 2) (95% CI, 1.8–42.8%)
ORR	79.1% (95% CI, 69.0–87.1%)	71.4% (95% CI, 41.9–91.6%)
At the end of induction
CR + VGPR	55.8% (n = 48) (95% CI, 44.7–66.5%)	64.3% (n = 9) (95% CI, 35.1–87.2%)
CR	9.3% (n = 8) (95% CI, 4.1–17.5%)	21.4% (n = 3) (95% CI, 4.7–50.8%)
ORR	81.4% (95% CI, 71.6–89.0%)	71.4% (95% CI, 41.9–91.6%)

Table 1: Rates of CR + VGPR, CR and ORR 

	NDMM (n = 86):	RMM (n = 14):
Median time to PR or better	1.0 month (95% CI, 1.0–1.0)	1.0 month (95% CI, 0.9–not evaluable [NE])
Median time to VGPR or better	4.6 months (95% CI, 2.8–6.4)	1.8 months (95% CI, 1.0–NE)
Median DoR	Not reached (NR)	12.4 months (95% CI, 3.7–12.4)
Median PFS (n = 87)	NR	13.3 months (95% CI, 6.8–13.3)
Twelve-month PFS	87.0% (95% CI, 57.1–96.6%)	66.2% (95% CI, 32.4–86.0%)
Twelve-month OS	98.8% (95% CI, 92.0–99.8%)	54.5% (95% CI, 8.6–86.1%)

Table 2: Efficacy results; time to PR or >VGPR, DoR, PFS and OS

Safety

	NDMM (n = 86)	RMM (n = 14)
Most frequent treatment-emergent adverse event (TEAE) of any grade	Fatigue (61.6%)	Fatigue, diarrhea and upper respiratory tract infection (42.9% each)
Most frequent TEAE grade 3/4	Neutropenia (11.6%)	Neutropenia (21.4%)
Serious TEAEs	19 patients	2 patients
Most frequent serious TEAE (occurred in ≥2 patients)	Atrial fibrillation (3.5%) Pulmonary embolism (2.3%) Bacteraemia (2.3%) Mental status changes (2.3%)	NR
Serious TEAEs related to daratumumab	3 patients Bacteraemia (n = 1) Viral upper respiratory tract infection (n = 1) Vomiting (n = 1)	None

Table 3: Safety results 

Infusion reactions (IRs) (n = 100):

• In total: 54%
• Most were during cycle 1 with 49% occurring on day 1 and 4% on day 2
• Most frequent were: chills (13%), cough (9%), dyspnoea (8%), pruritus (7%) and nausea (7%)
• Grade 3 IRs occurred in 2 patients, both with NDMM
  • Hypertension
  • Anaphylactic reaction
• No patients discontinued due to IRs

Discontinuations and deaths:

• Three patients with TEAEs discontinued treatment
  • Two subsequently died due to adverse events unrelated to study
• Two other patients RMM died due to progressive disease

Conclusion

• The D-VCd regimen can be safely administered and that the first dose of daratumumab can be split without causing additional safety concerns or IRs
• Additionally, D-VCd provides good VGPR rates in patients with NDMM regardless of transplant eligibility status
• D-VDd offers an alternative to IMid treatments and weekly dosing is more convenient for patients.
• Three patients discontinued treatment due to TEAEs
• Generally, TEAEs were deemed manageable
• No adverse impact on stem cell collection or engraftment was seen in patients who continued to ASCT showing daratumumab combination therapy is a feasible option for induction therapy in the transplant-eligible NDMM population
• Since the depth of response increased with longer daratumumab treatment, the prolonged administration of daratumumab is recommended
• Splitting the first daratumumab dose did not result in more IRs and reduced the infusion time
• Limitations of the study:
  • Small population size
  • No control or active-comparator arm
  • Primary endpoint may not allow for deep responses to develop