ASCO 2019 | CASSIOPEIA part 1 trial results

On Sunday June 02, 2019, during the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, US, the Multiple Myeloma Hub Co-Chair, Philippe Moreau, presented part 1 of the CASSIOPEIA trial results. This study, conducted on behalf of the Intergroupe Francophone du Myelome (IFM) and Hemato-Oncologie voor Volwassenen Nederland (HOVON), was a phase III, randomized study in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). It compared daratumumab, an anti-CD38 antibody, in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to bortezomib, thalidomide and dexamethasone (VTd) alone. The results were published on the same day in The Lancet with a median follow-up of 18.8 months.

Results given as D-VTd versus VTd unless otherwise stated

Study design (part 1)

• Induction therapy of four 28-day cycles. Patients were randomized 1:1 to either:
  • D-VTd consisting of:
    • Intravenous (IV) daratumumab: 16mg/kg weekly for cycles 1-2 and every 2 weeks in cycles 3 and 4
    • Subcutaneous bortezomib: 1.3mg/m² on days 1, 4, 8 and 11
    • Oral thalidomide: 100 mg/day
    • Oral or IV dexamethasone: 20-40mg
  • VTd, as above, without daratumumab
• Autologous stem cell transplant (ASCT)
• Consolidation (two 28-day cycles):
  • D-VTd, as in induction with the following exceptions:
    • Daratumumab administered once per two weeks
    • Oral or IV dexamethasone: 20 mg
  • VTd alone, as per D-VTd consolidation, without daratumumab
• Maintenance: in case of partial response (PR) or better, patients randomized to receive:,
  • Daratumumab monotherapy (maximum 2 years) followed by observation until progressive disease (PD)
  • Observation until PD

Patient characteristics

Table 1: Patient characteristics 

	D-VTd (n = 543)	VTd (n = 542)
Median age (years)	59	58
ISS stage III disease	84 (16%)	81 (15%)
High-risk cytogenetics	82 (15%	86 (16%)
Completion of induction and consolidation	85%	81%
ASCT conducted	90%	89%
Discontinuations	75 (14%)	101 (19%)
Main reasons for discontinuation:  Adverse event (AE) or serious AE PD	49 (9%) 19 (4%)	55 (10%) 21 (4%)
Deaths	7	0

Efficacy

• The primary endpoint of post-consolidation stringent complete response (sCR) was significantly better in the D-VTd group: 29% vs 20% (odds ratio: 1.60, 95% CI, 1.21-2.12, P = 0.001). Further details are shown in Table 2.
• Adding daratumumab to the VTd regimen improved depth of response as measured by measurable residual disease (MRD) negativity (10^-5): 64% vs 44% (P < 0.0001)
• The benefit in sCR was seen in all subgroups, with the exception of patients with:
  • High-risk cytogenetics
  • ISS stage III disease
• Progression-free survival (PFS) at 18 months was significantly better in the D-VTd cohort compared to VTd: 93% vs 85% (HR 0.47 (0.33-0.67), P < 0.0001) providing a 53% reduction in the risk of progression or death
  • This benefit was conferred mostly in the induction and consolidation phase
• Median overall survival (OS): not reached in both arms with a trend in favor for D-VTd (24-month OS rate: 97% vs 93%)

Table 2: Responses over time to D-VTd and VTd

* Stable disease (SD), or not available (NE)
	sCR	CR	VGPR	PR	SD/PD/NE*
D-VTd
Post-induction	7%	7%	51%	28%	7%
Post-ASCT	13%	9%	54%	16%	8%
Post-consolidation	29%	10%	45%	9%	7%
VTd
Post-induction	7%	2%	47%	34%	10%
Post-ASCT	9%	5%	53%	23%	10%
Post-consolidation	20%	6%	52%	12%	10%

Safety

Table 3: Safety data for D-VTd compared to VTd in relation to AEs, infusion related reactions (IRRs), secondary primary malignancies (SPMs) and data surrounding ASCT

	D-VTd	VTd
Treatment-emergent (TE) hematologic AEs grade ≥3: -          Neutropenia -          Thrombocytopenia -          Lymphopenia	148 (28% 59 (11%) 91 (17%)	79 (15%) 40 (7%) 52 (10%)
Treatment-emergent non-hematologic AEs grade ≥3: -          Peripheral sensory neuropathy -          Stomatitis -          Nausea -          Pyrexia	47 (9%) 68 (13%) 21 (4%) 14 (3%)	46 (9%) 88 (16%) 12 (2%) 12 (2%)
IRRs of any grade	190 (35%)	0 (0%)
Infections grade ≥3	118 (22%)	105 (20%)
Most common serious infection: pneumonia	19 (4%)	9 (2%)
SPMs	2%	2%
ASCT -          Plerixafor usage -          Median number CD34+ cells (106/kg) -          Hematopoietic reconstitution	110 (22%) 6.3                   100%	39 (8%) 8.9                 100%

Conclusion

Professor Moreau concluded that D-VTd provided a significant clinical benefit compared to VTd, in TE patients with NDMM. The patient responses deepened over time, and the D-VTd regimen gave a 53% reduction in the risk of progression or death. The new quadruplet was well-tolerated, with a safety profile consistent with that of the drugs already known (daratumumab as a single agent and VTd as a triplet combination). D-VTd can be considered a viable treatment option in this population.