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DARZALEX® (daratumumab)

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DARZALEX - MMY3007 (ALCYONE) Study

Last Updated: 12/02/2024

SUMMARY

  • ALCYONE is a phase 3 study evaluating the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (DVMP) in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation (ASCT).1
    • Mateos et al (2018)1 reported the results of a planned interim analysis, at a median follow-up of 16.5 months, in which the combination of DVMP provided a 50% reduction in the risk of disease progression or death compared with VMP alone (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P<0.001), with 18-month progression-free survival (PFS) rates of 71.6% vs 50.2%, respectively. Refer to Table: Most Common On-Treatment Adverse Events of Any Grade and Grade 3/4 (Safety Population; Planned Interim Analysis) for reported adverse event (AE) information.
    • Mateos et al (2022)2 presented (at the 64th American Society of Hematology [ASH] Annual Meeting and Exposition) an updated efficacy and safety analysis of the ALCYONE study (median follow-up, 78.8 months). In the DVMP vs VMP arm, the median PFS was 37.3 vs 19.7 months (HR, 0.43; 95% CI, 0.36-0.52; P<0.0001), and the median overall survival (OS) was 82.7 vs 53.6 months (HR, 0.64; 95% CI, 0.52-0.79; P<0.0001). The rate of minimal residual disease (MRD)-negativity and sustained MRD-negativity lasting both for ≥12 and ≥18 months were higher in the DVMP vs VMP arm. Grade 3 or 4 treatment-emergent adverse events (TEAEs) in the DVMP vs VMP arm were reported in 82.9% vs 77.4% of patients. The most common serious TEAE in both treatment arms was pneumonia (DVMP, 14.7%; VMP, 3.7%).
  • Fu et al (2023)3 evaluated PFS by MRD status in a pooled population of Asian and global patients from the OCTANS and ALCYONE studies. For both OCTANS and ALCYONE, the rates of overall MRD-negativity and sustained MRD-negativity were higher with
    D-VMP vs VMP and is detailed in Table: Overall MRD-negativity and Sustained MRD-negativity Rates. In a pooled analysis of OCTANS and ALCYONE, D-VMP vs VMP alone was associated with prolonged PFS across most of the high-risk subgroups evaluated. PFS in the high-risk subgroups of the OCTANS and ALCYONE studies is noted in Table: PFS by High-Risk Subgroups in Pooled Data from the OCTANS and ALCYONE Studies.
  • San-Miguel et al (2022)4 evaluated the predictive and prognostic role of MRD-negativity and durability in patients treated in the MAIA and ALCYONE studies. In the intention-to-treat (ITT) population and among patients with complete response or better (≥CR), patients receiving the DVMP regimen achieved higher rates of MRD-negativity and durability compared with VMP. Results regarding the ALCYONE study have been summarized below.
  • Jakubowiak et al (2022)5 conducted a pooled analysis of patient-level data from the MAIA and ALCYONE studies analyzing PFS and best response in transplant-ineligible NDMM patients with high-risk cytogenetic abnormalities. The median PFS was 21.2 months in the pooled DARZALEX cohort vs 19.3 months in the control cohort (HR, 0.59; 95% CI, 0.41-0.85; P=0.0046), representing a 41% reduction in risk of disease progression or death. Best response of ≥CR was achieved in 41.6% (n=42) of patients in the pooled DARZALEX cohort vs 22.5% (n=20) of patients in the control cohort (odds ratio [OR], 2.63; 95% CI, 1.34-5.16; P=0.0051). Results regarding the ALCYONE study have been summarized below.
  • Cavo et al (2022)6 conducted a pooled analysis of data from the POLLUX, CASTOR, ALCYONE, and MAIA studies to evaluate the association between patients achieving ≥CR with MRD-negative status and PFS. Achievement of ≥CR with MRD-negative status was strongly associated with improved PFS, regardless of therapy or disease setting. In the ITT population and among patients with ≥CR, MRD-negativity rate was higher in the DVMP vs VMP arm. Results regarding the ALCYONE study have been summarized below.
  • Mateos et al (2021)7 conducted a subgroup analysis of frailty status in patients enrolled in the ALCYONE study. The overall response rate (ORR) was higher in the DVMP arm vs VMP arm across frailty subgroups. For frail patients, ORR was achieved by 88.3% (n=144) in the DVMP arm vs 72.4% (n=110) patients in the VMP arm (P=0.0003). The most common grade 3/4 TEAEs across all frailty subgroups are presented in the Table: Most Common Grade 3/4 (≥10%) TEAEs in the Safety Population (ALCYONE).
  • Knop et al (2021)8 evaluated the treatment effect of DVMP on patient-reported outcomes (PROs) in the ALCYONE study.
  • Rodriguez-Otero et al (2020)9 presented long-term efficacy outcomes and health-related quality of life (HRQoL) based on response status in patients treated in the ALCYONE study.
  • Cavo et al (2018)10 presented a safety and efficacy analysis of elderly patients (aged ≥75 years vs <75 years) enrolled in the ALCYONE study.
  • Cavo et al (2018)11 presented data on the impact of baseline renal function on efficacy and safety of DVMP from the ALCYONE study.

PRODUCT LABELING

CLINICAL DATA

ALCYONE is an ongoing, open-label, active controlled, multicenter, randomized, phase 3 study evaluating the safety and efficacy of DVMP vs VMP in patients with NDMM who were ineligible for high-dose chemotherapy with ASCT.1 Mateos et al (2018)1 reported results of a planned interim analysis of data from ALCYONE study. Dimopoulos et al (2018)12 presented additional safety and efficacy results of a continuing 1-year follow-up in the ALCYONE study. Mateos et al (2020)13 published additional safety and efficacy results of a continuing >3 year follow up in the ALCYONE study. Mateos et al (2022)2 presented an updated efficacy and safety analysis of the ALCYONE study at a median follow-up of almost 7 years.

Study Design/Methods

  • Patients were randomly assigned 1:1 to receive either VMP alone or DVMP as follows (randomization was stratified according to disease stage [I, II, or III], geographic region [Europe vs other], and age [<75 vs ≥75 years]):
    • VMP: up to 9 cycles (each 42-day) of:
      • Bortezomib 1.3 mg/m2 subcutaneously (SC) twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9
      • Melphalan 9 mg/m2 orally once daily on days 1-4 of each cycle
      • Prednisone 60 mg/m2 orally once daily on days 1-4 of each cycle
    • DVMP:
      • Up to 9 cycles (each 42-day) of VMP as described above plus:
      • DARZALEX 16 mg/kg intravenously (IV) once weekly in cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until there was disease progression or unacceptable toxicity
      • Patients in this arm also received dexamethasone 20 mg orally or IV and other pre-infusion medications (approximately 1 hour before DARZALEX infusion) for management of infusion reactions. On day 1 of each cycle, the dexamethasone 20 mg dose was substituted for the prednisone dose in the VMP regimen.
  • Patients with documented NDMM and who were not candidates for high-dose chemotherapy with ASCT because of coexisting conditions or older age (≥65 years) were included.
  • Primary endpoint: PFS
  • Key secondary endpoints: ORR, rates of very good partial response or better (≥VGPR), ≥CR, MRD-negative status, and OS
  • Other endpoints: safety, side-effect profile, time to response (TTR), and duration of response (DOR)

Results

Patient Characteristics
  • A total of 706 patients (DVMP, n=350; VMP, n=356) were randomly assigned to treatment, of whom 700 patients received study treatment (DVMP, n=346; VMP, n=354).
  • At the planned interim analysis:
    • 276 (79.8%) patients in the DVMP arm and 220 (62.1%) patients in the VMP arm had received all 9 cycles of VMP; 17 patients in each arm were still receiving VMP.
    • 19.4% of patients in the DVMP arm vs 33.1% of patients in the VMP arm discontinued treatment.
      • A higher proportion of patients in the VMP arm than in the DVMP arm discontinued for reasons of disease progression (13.3% vs 6.6%) and AEs (9.3% vs 4.9%); rates of discontinuation because of death were 3.2% in the DVMP and 2.3% in the VMP arm.
    • Among patients in the DARZALEX arm, the most frequent reasons for treatment discontinuation after cycle 9 were disease progression (8.7%) and death (0.6%).
  • Baseline characteristics were similar between the two arms for the following: age, Eastern Cooperative Oncology Group performance status (ECOG PS), International Staging System (ISS) disease stage, high-risk cytogenic profile, and median (range) time from initial diagnosis.
Efficacy
  • Patients were followed up for a median of 16.5 months in the planned interim analysis.
  • The median duration of treatment was 14.7 months in the DVMP arm and 12.0 months in the VMP arm.
  • For the primary endpoint of PFS, events of disease progression or death occurred in 88 (25.1%) patients in the DVMP arm vs 143 (40.2%) patients in the VMP arm.
  • DVMP provided a 50% reduction in the risk of disease progression or death compared with VMP, with an HR of 0.50 (95% CI, 0.38-0.65; P<0.001). In the DVMP and VMP arms, respectively:
    • 12-month PFS rates were 86.7% (95% CI, 82.6%-89.9%) and 76.0% (95% CI, 71.0%-80.2%).
    • 18-month PFS rates were 71.6% (95% CI, 65.5%-76.8%) and 50.2% (95% CI, 43.2%-56.7%).
  • Median PFS was not reached (95% CI, not estimable [NE]) in the DVMP arm and was 18.1 months (95% CI, 16.5-19.9 months) in the VMP arm (P<0.001).
  • In prespecified subgroup analyses of PFS, superiority of DVMP over VMP alone was generally consistent across the subgroups analyzed. Results are summarized in Table: Prespecified Subgroup Analyses of PFS (Planned Interim Analysis).
  • Secondary endpoints are summarized in Table: Secondary Endpoints (ITT Population; Planned Interim Analysis).

Prespecified Subgroup Analyses of PFS (Planned Interim Analysis)1
Subgroup
DVMP
VMP
HR (95% CI)
Number of PFS Events, n/N
Age, years
 
<75 years
60/246
101/249
0.49 (0.36-0.68)
 
≥75 years
28/104
42/107
0.53 (0.32-0.85)
Baseline creatinine clearance
≤60 mL/min
32/150
63/145
0.36 (0.24-0.56)
>60 mL/min
56/200
80/211
0.63 (0.45-0.88)
Baseline hepatic function
Normal
73/301
115/303
0.53 (0.40-0.71)
Impaired
15/46
28/52
0.42 (0.22-0.80)
ISS disease stage
I
12/69
18/67
0.50 (0.24-1.05)
II
35/139
70/160
0.49 (0.32-0.73)
III
41/142
55/129
0.53 (0.35-0.79)
Type of multiple myelomaa
 
IgG
51/207
93/218
0.45 (0.32-0.64)
 
Non-IgG
26/82
29/83
0.81 (0.48-1.37)
Cytogenetic profile at study entry
Standard risk
54/261
108/257
0.39 (0.28-0.55)
High riskb
24/53
19/45
0.78 (0.43-1.43)
ECOG performance status
0
14/78
35/99
0.40 (0.21-0.74)
1 or 2
74/272
108/257
0.52 (0.39-0.70)
Abbreviations: CI, confidence interval; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Ig, immunoglobulin; ISS, International Staging System; PFS, progression-free survival; VMP, bortezomib + melphalan + prednisone.
aAnalysis was conducted based on data obtained from patients with measurable disease in serum.
bPatients with presence of del17p, t(4;14), or t(14;16) on fluorescence in situ hybridization testing or presence of t(4;14) or del17p on karyotype testing.

Secondary Endpoints (ITT Population; Planned Interim Analysis)1
 Endpoint
DVMP
VMP
P-value
ORa, n (%) [95% CI]
318 (90.9)
[87.3-93.7]
263 (73.9)
[69.0-78.4]
<0.001
≥VGPRa, n (%)
249 (71.1)
177 (49.7)
<0.001
≥CRa n (%)
149 (42.6)
87 (24.4)
<0.001
MRD negativitya,b, n (%)
78 (22.3)
22 (6.2)
<0.001
Median overall survivalc
not reached
not reached
—
Abbreviations: CI, confidence interval; CR, complete response; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intent-to-treat; MRD, minimal residue disease; OR, overall response; VGPR, very good partial response; VMP, bortezomib + melphalan + prednisone.
aThese secondary endpoints were sequentially tested (each with an overall 2-sided α level of 0.05), with a hierarchical testing approach, in the following order: overall response rate; rate of very good partial response or better; rate of complete response or better; and rate of negative status for MRD.
bThe threshold for MRD was 1 tumor cell per 105 white cells.
cFollow-up of patients for long-term survival is ongoing.
  • Regardless of study treatment, negative status for MRD was associated with longer PFS than positive status for MRD; among patients with persistent MRD, a longer PFS was observed in the DVMP than in the VMP arm.
  • Among other endpoints, in the DVMP and VMP arms, respectively:
    • Median TTR: 0.79 months and 0.82 months
    • Median DOR: not reached (95% CI, NE) and 21.3 months (95% CI, 18.4-NE)
Safety
  • The most common on-treatment AEs (≥20% for any grade and ≥10% for grade 3/4 in either treatment arm) are summarized in Table: Most Common On-Treatment Adverse Events of Any Grade and Grade 3-4 (Safety Population; Planned Interim Analysis).
  • Grade 3/4 infections were more frequent in the DVMP arm than in the VMP arm (23.1% vs 14.7%), with pneumonia being the most common grade 3/4 infection (11.3% vs 4.0%). In the DVMP and VMP arms, respectively:
    • Infections, including pneumonia, resolved in 87.9% and 86.5% of patients.
    • Rates of treatment discontinuation because of infections were 0.9% and 1.4%.
    • Infection-related deaths occurred in 5 (1.4%) patients and 4 (1.1%) patients.
  • Rates of serious AEs were 41.6% in the DVMP arm and in 32.5% in the VMP arm, with pneumonia being the most common serious AE (10.1% and 3.1%, respectively).
  • Tumor lysis syndrome occurred in 2 (0.6%) patients in each treatment arm.
  • Second primary malignancy occurred in 8 (2.3%) patients in the DVMP arm and in 9 (2.5%) in the VMP arm.
  • Fatal AEs within a month after the last study treatment occurred in 14 (4.0%) patients in the DVMP arm and in 16 (4.5%) in the VMP arm.

Most Common On-Treatment Adverse Events of Any Grade and Grade 3/4 (Safety Population; Planned Interim Analysis)1
Event, n (%)
DVMP
(n=346)
VMP
(n=354)
Any Gradea
Grade 3/4b
Any Gradea
Grade 3/4b
Neutropenia
172 (49.7)
138 (39.9)
186 (52.5)
137 (38.7)
Thrombocytopenia
169 (48.8)
119 (34.4)
190 (53.7)
133 (37.6)
Anemia
97 (28.0)
55 (15.9)
133 (37.6)
70 (19.8)
Infections
231 (66.8)
80 (23.1)
170 (48.0)
52 (14.7)
Upper respiratory tract infection
91 (26.3)
7 (2.0)
49 (13.8)
5 (1.4)
Pneumonia
53 (15.3)
39 (11.3)
17 (4.8)
14 (4.0)
Any infusion-related reaction
96 (27.7)
17 (4.9)
NA
NA
Peripheral sensory neuropathy
98 (28.3)
5 (1.4)
121 (34.2)
14 (4.0)
Diarrhea
82 (23.7)
9 (2.6)
87 (24.6)
11 (3.1)
Pyrexia
80 (23.1)
2 (0.6)
74 (20.9)
2 (0.6)
Nausea
72 (20.8)
3 (0.9)
76 (21.5)
4 (1.1)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; NA, not applicable; VMP, bortezomib + melphalan + prednisone.
aReported in ≥20% of patients in either treatment arm.
bReported in ≥10% of patients in either treatment arm.

Updated Analysis of ALCYONE Study (Median Follow-up 78.8 Months)

Mateos et al (2022)2 presented an updated analysis of ALCYONE at a median follow-up of almost 7 years (78.8 months). Follow-up results are summarized below.

Results

Patient Disposition
  • At data cutoff, all patients had either discontinued or completed 9 cycles of VMP therapy.
  • Patient disposition in the ITT population is summarized in the Table: Summary of Patient Disposition (ALCYONE).

Summary of Patient Disposition (ALCYONE)2
Parameter
DVMP (n=350)
VMP (n=356)
Patients treated, n (%)a
346 (98.9)
354 (99.4)
Patients still on treatment, n (%)b
86 (24.9)
0 (0.0)
Patients who discontinued treatment, n (%)b
260 (75.1)
118 (33.3)
Reason for discontinuation, n (%)
Progressive disease
164 (47.4)
47 (13.3)
Adverse event
32 (9.2)
34 (9.6)
Death
26 (7.5)
8 (2.3)
Noncompliance with study drug
16 (4.6)
15 (4.2)
Patient withdrawal
10 (2.9)
6 (1.7)
Physician decision
4 (1.2)
7 (2.0)
Lost to follow-up
2 (0.6)
0 (0.0)
Other
6 (1.7)
1 (0.3)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisoneaPercentages are based on the number of patients randomized.bPercentages are based on the number of patients treated.
Efficacy
  • In the DVMP vs VMP arm, the median PFS was 37.3 vs 19.7 months (HR, 0.43; 95% CI, 0.36-0.52; P<0.0001) and the 72-month PFS rate was 31.9% vs 7.0%.
  • In the DVMP vs VMP arm, the median OS was 82.7 vs 53.6 months (HR, 0.64; 95% CI, 0.52-0.79; P<0.0001) and the 72-month OS rate was 55.7% vs 39.7%.
  • The OS benefit in the DVMP vs VMP arm was generally consistent across the prespecified patient subgroups. See Table: OS in Prespecified Subgroups (ALCYONE).

OS in Prespecified Subgroups (ALCYONE)2
Subgroup
DVMP
VMP
HR (95% CI)a
n/N
Median OS (months)
n/N
Median OS (months)
Sex
Male
78/160
72.7
94/167
50.7
0.70 (0.52-0.95)
Female
82/190
83.0
113/189
55.1
0.60 (0.45-0.79)
Age
<75 years
105/246
85.5
137/249
56.6
0.62 (0.48-0.80)
≥75 years
55/104
59.1
70/107
49.7
0.71 (0.50-1.01)
Race
White
142/297
81.0
182/304
52.9
0.66 (0.53-0.82)
Other
18/53
NE
25/52
78.1
0.55 (0.30-1.01)
Region
Europe
137/289
82.2
177/295
53.6
0.66 (0.53-0.83)
Other
23/61
NE
30/61
57.9
0.57 (0.33-0.98)
Baseline renal function (CrCl)
>60 mL/min
92/200
83.0
113/211
57.9
0.71 (0.54-0.94)
≤60 mL/min
68/150
79.2
94/145
48.1
0.55 (0.40-0.76)
Baseline hepatic function
Normal
140/301
82.2
173/303
55.7
0.68 (0.54-0.85)
Impaired
20/46
NE
34/52
40.7
0.51 (0.29-0.89)
ISS disease stage
I
18/69
NE
26/67
NE
0.52 (0.29-0.96)
II
63/139
83.0
88/160
61.3
0.72 (0.52-1.00)
III
79/142
63.0
93/129
42.3
0.57 (0.42-0.78)
Type of MM
IgG
98/207
81.0
124/218
58.2
0.71 (0.54-0.92)
Non-IgG
43/82
72.5
51/83
46.2
0.67 (0.45-1.01)
Cytogenetic risk at study entry
High riskb
33/53
46.2
31/45
39.5
0.85 (0.52-1.38)
Standard risk
113/261
83.0
149/257
55.1
0.58 (0.45-0.74)
ECOG PS score
0
22/78
NE
55/99
53.7
0.35 (0.21-0.57)
1-2
138/272
72.5
152/257
52.9
0.73 (0.58-0.92)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ISS, International Staging System; MM, multiple myeloma; NE, not estimable; OS, overall survival; VMP, bortezomib + melphalan + prednisoneaHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for DVMP.bPatients with high cytogenetic risk were positive by fluorescence in situ hybridization or karyotype testing for ≥1 of the following cytogenetic abnormalities: t(4;14), t(14;16), or del(17p).

Summary of MRD-Negativity Rates and Sustained MRD-Negativity Rates in ITT Population (ALCYONE)2
Parameter
DVMP (n=350)
VMP (n=356)
P value
MRD negative, n (%)
99 (28.3)
25 (7.0)
<0.0001
Sustained MRD negativity, n (%)
Lasting ≥12 months
49 (14.0)
10 (2.8)
<0.0001
Lasting ≥18 months
31 (8.9)
6 (1.7)
<0.0001
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intent to treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone
  • A total of 139 patients in the DVMP arm, and 235 patients in the VMP arm received subsequent treatment.
  • In the DVMP vs VMP arm, 5.8% vs 35.3% of patients received DARZALEX-containing treatment in a subsequent line of therapy.

Safety

  • The most common TEAEs are summarized in the Table: Summary of Any Grade (≥15%) and Grade 3 or 4 (≥5%) TEAEs in the Safety Population (ALCYONE).
  • In the DVMP vs VMP arm, grade 3/4 TEAEs were reported in 82.9% vs 77.4% of patients, and grade 3/4 infections were reported in 30.3% vs 15.0% of patients.
  • The most common serious TEAE in both treatment arms was pneumonia (DVMP, 14.7%; VMP, 3.7%).
  • The rate of treatment discontinuation due to TEAEs in the DVMP vs VMP arm was 9.0% vs 9.3%.

Summary of Any Grade (≥15%) and Grade 3 or 4 (≥5%) TEAEs in the Safety Population (ALCYONE)2
Event, n (%)
DVMP (n=346)
VMP (n=354)
Any Grade
Grade 3 or 4
Any Grade
Grade 3 or 4
Hematologic
Neutropenia
175 (50.6)
140 (40.5)
186 (52.5)
138 (39.0)
Thrombocytopenia
173 (50.0)
120 (34.7)
190 (53.7)
134 (37.9)
Anemia
112 (32.4)
63 (18.2)
131 (37.0)
70 (19.8)
Leukopenia
47 (13.6)
28 (8.1)
53 (15.0)
30 (8.5)
Lymphopenia
39 (11.3)
27 (7.8)
36 (10.2)
22 (6.2)
Nonhematologic
Upper respiratory tract infection
107 (30.9)
8 (2.3)
50 (14.1)
6 (1.7)
Diarrhea
101 (29.2)
9 (2.6)
87 (24.6)
11 (3.1)
Peripheral sensory neuropathy
100 (28.9)
5 (1.4)
122 (34.5)
14 (4.0)
Pyrexia
89 (25.7)
2 (0.6)
74 (20.9)
2 (0.6)
Bronchitis
76 (22.0)
11 (3.2)
27 (7.6)
3 (0.8)
Nausea
75 (21.7)
3 (0.9)
76 (21.5)
4 (1.1)
Pneumonia
74 (21.4)
56 (16.2)
19 (5.4)
16 (4.5)
Back pain
71 (20.5)
8 (2.3)
42 (11.9)
4 (1.1)
Cough
71 (20.5)
1 (0.3)
27 (7.6)
1 (0.3)
Constipation
64 (18.5)
3 (0.9)
65 (18.4)
1 (0.3)
Peripheral edema
68 (19.7)
3 (0.9)
39 (11.0)
1 (0.3)
Vomiting
62 (17.9)
5 (1.4)
55 (15.5)
6 (1.7)
Fatigue
61 (17.6)
12 (3.5)
51 (14.4)
9 (2.5)
Hypertension
52 (15.0)
23 (6.6)
11 (3.1)
6 (1.7)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone

Pooled Analysis of OCTANS and ALCYONE: PFS Outcomes by MRD and Cytogenetic Risk Status

Fu et al (2023)3 reported the subgroup analysis results of PFS by MRD status using data from the OCTANS and ALCYONE studies.

Study Design/Methods

  • The data cutoff date for the OCTANS analysis was December 23, 2022, and the data cutoff date for the ALCYONE analysis was June 24, 2019.

Results

Patient Characteristics

A total of 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74) in the OCTANS study, and 706 global patients were randomized (D-VMP, n=350; VMP, n=356) in the ALCYONE study. See Table: Demographic and Baseline Characteristics in the ITT Population.


Demographic and Baseline Characteristics in the ITT Population3
OCTANS
ALCYONE
D-VMP
(n=146)
VMP
(n=74)
D-VMP
(n=350)
VMP
(n=356)
Median age (range), years
69 (58-81)
69 (57-84)
71 (40-93)
71 (50-91)
Female, n (%)
61 (41.8)
28 (37.8)
190 (54.3)
189 (53.1)
ECGO PS score, n (%)
0
50 (34.2)
21 (28.4)
78 (22.3)
99 (27.8)
1
71 (48.6)
40 (54.1)
182 (52.0)
173 (48.6)
2
25 (17.1)
13 (17.6)
90 (25.7)
84 (23.6)
ISS disease stage, n (%)a
   I
37 (25.3)
19 (25.7)
69 (19.7)
67 (18.8)
   II
68 (46.6)
32 (43.2)
139 (39.7)
160 (44.9)
   III
41 (28.1)
23 (31.1)
142 (40.6)
129 (36.2)
Median (range) time from MM diagnosis to randomization, months
0.66
(0.1-14.6)
0.61
(0.1-2.1)
0.76
(0.1-11.4)
0.82
(0.1-25.3)
Cytogenetic profileb
   n
145
74
314
302
   Standard risk, n (%)
117 (80.7)
54 (73.0)
261 (83.1)
257 (85.1)
   High risk, n (%)
28 (19.3)
20 (27.0)
53 (16.9)
45 (14.9)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; VMP, bortezomib + melphalan + prednisone.
aBased on the combination of serum β2-microglobulin and albumin.
bCytogenetic risk was based on local fluorescence in situ hybridization or karyotype analysis. Patients with high-risk cytogenetics had a del17p, t(4;14), and/or t(14;16) abnormality. Patients with standard-risk cytogenetics had an absence of high-risk cytogenetic abnormalities.
Efficacy
  • For OCTANS, at a median follow-up of 41.2 months (range, 0-59.9), median PFS was 38.7 months with D-VMP vs 19.2 months with VMP alone (HR, 0.35; 95% CI, 0.23-0.52; P<0.0001) in TIE Asian patients with NDMM.
  • For ALCYONE, at a median follow-up of 40.1 months (range, 0-52.1), D-VMP exhibited a greater PFS benefit vs VMP alone (36.4 vs 19.3 months, respectively; HR, 0.42; 95% CI, 0.34-0.51; P<0.0001) in a global population of TIE patients with NDMM.
  • Rates of overall MRD-negativity and sustained MRD-negativity lasting ≥12 and ≥18 months were higher with D-VMP vs VMP alone in both OCTANS and ALCYONE. See Table: Overall MRD-negativity and Sustained MRD-negativity Rates.
    • Patients who achieved MRD-negativity demonstrated prolonged PFS vs those who did not reach MRD-negativity within each treatment group; however, the PFS benefit observed with D-VMP vs VMP was maintained irrespective of MRD status.
    • The achievement of sustained MRD-negativity lasting ≥12 months was associated with longer PFS vs MRD-negativity lasting <12 months in both OCTANS and ALCYONE.
  • In a pooled analysis of OCTANS and ALCYONE (D-VMP, n=496; VMP, n=430), D-VMP vs VMP alone was associated with prolonged PFS across most of the high-risk subgroups evaluated. See Table: PFS by High-Risk Subgroups in Pooled Data from the OCTANS and ALCYONE Studies.
    • D-VMP vs VMP alone prolonged PFS both in patients with revised standard cytogenetic risk (NE vs 18.9 months; HR, 0.33; 95% CI, 0.26-0.42) and in those with revised high cytogenetic risk (25.6 vs 18.9 months; HR, 0.54; 95% CI, 0.41-0.71).
    • Prolonged PFS was also observed for D-VMP vs VMP alone in patients with gain(1q21) and/or amp(1q21), 1 HRCA, and ≥2 HRCAs.

Overall MRD-negativity and Sustained MRD-negativity rates3
OCTANS
ALCYONE
D-VMP
(n=146)
VMP
(n=74)
P valuea
D-VMP
(n=350)
VMP
(n=356)
P valuea
Overall MRD-negativity rate (10-5), n (%)
59 (40.4)
8 (10.8)
<0.0001
99 (28.3
25 (7.0)
<0.0001
Sustained MRD-negativity rate (10-5), n (%)b
Lasting ≥12 months
36 (24.7)
1 (1.4)
<0.0001
49 (14.0)
10 (2.8)
<0.0001
Lasting ≥18 months
22 (15.1)
1 (1.4)
0.0008
31 (8.9)
6 (1.7)
<0.0001
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.
aP value was calculated using Fisher’s exact test.
bSustained MRD-negativity was defined as MRD-negative and confirmed ≥1 year later without an MRD-positive result in between.

PFS by High-Risk Subgroups in Pooled Data from the OCTANS and ALCYONE Studies3
Subgroups
OCTANS
ALCYONE
HR
(95% CI)
n/N
Median PFS, Months
n/N
Median PFS, Months
Baseline characteristic
   Age ≥75 years
61/127
37.3
77/117
20.4
0.50 (0.35-0.70)
   ISS stage lll disease
95/183
33.0
113/152
18.2
0.42 (0.32-0.56)
   Renal insufficiency
102/213
40.5
130/178
19.3
0.40 (0.30-0.52)
   Extramedullary plasmacytomas
25/36
20.7
25/29
14.6
0.50 (0.28-0.88)
   Cytogenetic risk
      Standard cytogenetic risk
172/378
43.0
222/311
19.1
0.37 (0.30-0.45)
      High cytogenetic risk
57/81
21.1
49/65
18.1
0.61 (0.41-0.89)
      Revised standard cytogenetic risk
120/291
NE
177/251
18.9
0.33 (0.26-0.42)
      Revised high cytogenetic risk
109/168
25.6
94/125
18.9
0.54 (0.41-0.71)
      Gain(1q21)
4/8
38.9
9/11
17.5
0.31 (0.08-1.18)
      Amp(1q21)
69/114
31.3
64/84
18.9
0.46 (0.32-0.65)
      Gain(1q21) or amp(1q21)
70/118
31.9
69/90
18.9
0.45 (0.32-0.63)
      1 HRCA
87/131
24.4
64/88
19.3
0.62 (0.44-0.86)
      ≥2 HRCAs
22/37
28.2
30/37
17.5
0.36 (0.20-0.63)
      Isolated gain(1q21)
1/3
NE
4/4
18.4
0.27 (0.03-2.52)
      Isolated amp(1q21)
50/83
31.6
38/53
19.4
0.53 (0.34-0.82)
      Isolated gain(1q21) or amp(1q21)
52/87
32.0
45/60
19.4
0.49 (0.32-0.73)
      Gain(1q21) or amp(1q21) plus
      ≥1 HRCA
18/31
28.2
24/30
15.6
0.37 (0.20-0.71)
Abbreviations: CI, confidence interval; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; NE, not estimable; PFS, progression-free survival.

Predictive and Prognostic Role of MRD Negativity and Durability

San-Miguel et al (2022)4 evaluated the predictive and prognostic role of MRD negativity and durability in patients with NDMM ineligible for transplant. Results regarding the ALCYONE study have been summarized below.

Results

Patient Characteristics

Demographics and Baseline Characteristics by MRD Durability14
Characteristic
DVMP
VMP
ITT
(n=350)
MRD-negative patients
ITT
(n=356)
MRD-negative patients
At any time
(n=94)
≥12 months
(n=49)
Not ≥12 months
(n=45)
At any time
(n=25)
≥12 months
(n=10)
Not ≥12 months
(n=15)
Age, years
Median (range)
71.0 (40-93)
71.0 (40-93)
71.0 (40-87)
71.0 (56-93)
71.0 (50-91)
73.0 (52-82)
72.0 (52-82)
74.0
(67-82)
Distribution, n (%)
<75
246 (70.3)
68 (72.3)
36 (73.5)
32 (71.1)
249 (69.9)
15 (60.0)
6
(60.0)
9
(60.0)
≥75
104 (29.7)
26 (27.7)
13 (26.5)
13 (28.9)
107 (30.1)
10 (40.0)
4
(40.0)
6
(40.0)
ISS disease stagea, n (%)
I
69 (19.7)
16 (17.0)
9
(18.4)
7
(15.6)
67 (18.8)
5
(20.0)
2
(20.0)
3
(20.0)
II
139 (39.7)
39 (41.5)
23 (46.9)
16 (35.6)
160 (44.9)
10 (40.0)
5
(50.0)
5
(33.3)
III
142 (40.6)
39 (41.5)
17 (34.7)
22 (48.9)
129 (36.2)
10 (40.0)
3
(30.0)
7
(46.7)
Cytogenetic profileb, n (%)
Patients evaluated
314
88
46
42
302
23
9
14
Standard-risk cytogenetic abnormality
261 (83.1)
74 (84.1)
40 (87.0)
34 (81.0)
257 (85.1)
19 (82.6)
7
(77.8)
12
(85.7)
High-risk cytogenetic abnormalityc
53 (16.9)
14 (15.9)
6
(13.0)
8
(19.0)
45 (14.9)
4
(17.4)
2
(22.2)
2
(14.3)
del(17p)
29 (9.2)
8 (9.1)
4 (8.7)
4 (9.5)
27 (8.9)
3 (13.0)
1 (11.1)
2 (14.3)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.
All data are n (%) unless otherwise indicated.
aISS staging is derived based on the combination of serum β2-microglobulin and albumin.
bCytogenetic risk status was determined by fluorescence in situ hybridization or karyotype testing.
cHigh risk is defined as having a positive test for any of the del17p, t(14;16), or t(4;14) molecular abnormalities.
Efficacy
  • In the ITT population and among patients with ≥CR, patients receiving the DVMP regimen achieved higher rates of MRD negativity and durability compared with VMP. Please see Table: Rates of Sustained MRD-negativity Status in Transplant-ineligible NDMM.
  • In the ITT population, MRD-negative patients had improved PFS compared with MRD-positive patients.
  • Durable MRD negativity lasting ≥6 months or ≥12 months improved PFS compared with MRD-negative patients who did not maintain MRD negativity for ≥6 months or ≥12 months.
  • Estimated 36-month rates of time to subsequent anticancer therapy were mostly higher for patients who achieved MRD negativity at any time versus MRD-positive patients, and for patients with sustained MRD negativity lasting ≥6 months or ≥12 months compared with those who did not have durable MRD negativity. Please see Table: PFS on Next Subsequent Line of Treatment Based on MRD Status
  • Estimated 36-month PFS on next line of therapy (PFS2) rate (ITT; DVMP, n=350; VMP, n=356)14:
    • MRD negative (10-5) at ≥1 time point: DVMP: 87.0% (n=94); VMP: 92.0% (n=25)
    • MRD positive: DVMP: 67.9% (n=256); VMP: 51.9% (n=331)

Rates of Sustained MRD-negativity Status in Transplant-ineligible NDMM4
MRD negativity (10-5)
(N=706)
DVMP
VMP
P valuea
ITT
n=350
n=356
MRD-negative status, n (%)
94 (26.9)
25 (7.0)
<0.0001
≥6 months sustained
55 (15.7)
16 (4.5)
<0.0001
≥12 months sustained
49 (14.0)
10 (2.8)
<0.0001
≥CR
n=160
n=90
MRD-negative status, n (%)
94 (58.8)
25 (27.8)
<0.0001
≥6 months sustained
55 (34.4)
16 (17.8)
0.0055
≥12 months sustained
49 (30.6)
10 (11.1)
0.0006
Abbreviations: CR, complete response; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; VMP, bortezomib + melphalan + prednisone.aP value was calculated using Fisher’s exact test.

PFS on Next Subsequent Line of Treatment Based on MRD Status14
PFS2a
DVMP
N=350 (ITT)
VMP
N=356 (ITT)
MRD negative (10‒5) at ≥1 time point, n (%)b
94 (26.9)
25 (7.0)
Number of events (%); number censored (%)c
15 (16.0); 79 (84.0)
4 (16.0%); 21 (84.0)
Median (95% CI), months
NR (NE-NE)
NR (40.7-NE)
HR (95% CI), P value
1.02 (0.34-3.09); P = 0.9668d
36-month PFS2 rate, % (95% CI)
87.0 (78.2-92.4)
92.0 (71.6-97.9)
MRD positive, n (%)b
256 (73.1)
331 (93.0)
Number of events (%); number censored (%)c
87 (34.0); 169 (66.0)
148 (44.7); 183 (55.3)
Median (95% CI), months
NR (NE-NE)
38.0 (34.1-NE)
HR (95% CI), P value
0.64 (0.49-0.83); P = 0.0008d
36-month PFS2 rate, % (95% CI)
67.9 (61.6-73.5)
51.9 (45.9-57.6)
Abbreviations: CI, confidence interval; DVMP, DARZALEX + bortezomib + melphalan + prednisone; HR, hazard ratio; ITT, intention-to-treat; MRD, minimal residual disease; NE, not evaluable; NR, not reached; PFS2, progression-free survival on next subsequent line of therapy; VMP, bortezomib + melphalan + prednisone.aPFS2 was defined as the time from randomization to progression on the next line of treatment or death, whichever came first. Disease progression was based on investigator judgement. For those patients who where still alive and not yet progressed on the next line of treatment, they were censored on the last date of follow-up.bPercentages calculated using the ITT population as the denominator. cPercentages calculated using the # of patients in each column from the row immediately above the number of events (%); number censored (%). dHR and 95% CI from a Cox proportional hazards model with treatment group as the sole explanatory variable. A HR<1 indicates an advantage for DVMP. P value is based on the log-rank test.

Pooled Analysis of Transplant-Ineligible, High-Risk NDMM Patients from MAIA and ALCYONE Studies

Jakubowiak et al (2022)5 reported the results of a pooled analysis of patient-level data from the MAIA and ALCYONE studies analyzing PFS and best response in transplant-ineligible NDMM patients with high-risk cytogenetic abnormalities. Results regarding the ALCYONE study have been summarized below.

Study Design/Methods

  • Patients with baseline high-risk cytogenetics [del(17p), t(4;14), or t(14;16)] were included.
  • Primary endpoint: PFS
  • Secondary endpoint: ORR, best response, ≥VGPR, MRD-negative CR

Results

Patient Characteristics
  • Overall, 101 patients (DARZALEX + lenalidomide + dexamethasone [D-Rd; MAIA], n=48; DVMP [ALCYONE], n=53) were included in the pooled DARZALEX cohort and 89 patients (Rd [MAIA], n=44; VMP [ALCYONE], n=45) were included in the pooled control cohort.
  • The combined median follow-up duration of both the trials was 43.7 months (MAIA, 47.9 months; ALCYONE, 40.1 months).
  • In the pooled DARZALEX and control cohorts, the median duration of treatment was 19.9 and 12.0 months, respectively.
  • Baseline characteristics of patients in the ALCYONE study are summarized in Table: Summary of Baseline Characteristics in ALCYONE.

Summary of Baseline Characteristics in ALCYONE5
Characteristic, n (%)
DVMP (n=53)
VMP (n=45)
Standardized Differencea
Median age, years
71.0
70.0
-
    <75
34 (64.2) 
34 (75.6) 
25.0%
    ≥75
19 (35.8) 
11 (24.4) 
25.0%
Male
25 (47.2)
20 (44.4) 
5.5%
ECOG PS score
    0
10 (18.9) 
13 (28.9) 
23.7%
    1
24 (45.3) 
23 (51.1) 
11.7%
    ≥2b
19 (35.8) 
9 (20.0) 
35.9%
Type of MM by immunofixation or serum FLC
    IgG
27 (50.9) 
25 (55.6) 
9.3%
    Non-IgG
26 (49.1) 
20 (44.4) 
9.3%
ISS Stagec
    I
6 (11.3) 
4 (8.9) 
8.1%
    II
23 (43.4) 
18 (40.0) 
6.9%
    III
24 (45.3) 
23 (51.1) 
11.7%
Cytogenetic riskd
    del(17p)
29 (54.7) 
27 (60.0) 
10.7%
    t(4;14)
25 (47.2) 
17 (37.8) 
19.1%
    t(14;16)
6 (11.3) 
6 (13.3) 
6.1%
Renal Impairmente
22 (41.5) 
17 (37.8) 
7.6%
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; FLC, free light chain; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; VMP, bortezomib + melphalan + prednisone.
aStandardized difference is a measure of effect size independent of sample size, where characteristics with a standardized difference <10% were considered balanced.bALCYONE had maximum baseline ECOG score of 2.cISS staging was derived based on the combination of serum β2-microglobulin and albumin.dCytogenetic risk was based on FISH or karyotype testing.eRenal impairment was defined as having baseline creatinine clearance <60 mL/minute.
Efficacy
  • The median PFS was 21.2 months in the pooled DARZALEX cohort vs 19.3 months in the pooled control cohort (adjusted HR, 0.59; 95% CI, 0.41-0.85; P=0.0046), representing a 41% reduction in risk of disease progression or death.
    • After adjusting for age differences, the pooled HR for PFS was 0.59 (95% CI, 0.410.85; P=0.0044).
    • In the subgroup of patients with del(17p) at baseline (pooled DARZALEX, n=54; pooled control, n=56) the adjusted HR for PFS was 0.63 (95% CI, 0.39-1.03; P=0.0659).
    • In the individual studies, the adjusted HRs for PFS were 0.73 (95% CI, 0.46-1.14) in the ALCYONE study and 0.57 (95% CI, 0.33-1.00) in the MAIA study. See Table: HRs for PFS in Individual Studies.
  • The 36-month PFS rate was 41.3% in the pooled DARZALEX cohort vs 19.9% in the pooled control cohort.

HRs for PFS in Individual Studies5
Study Name
Progression Events
Adjusted HR (95% CI)
DARZALEX + Control
n/N
Control
n/N
ALCYONE
41/53
36/45
0.73 (0.46-1.14)
MAIA
23/48
28/44
0.57 (0.33-1.00)
Pooleda
64/101
64/89
0.59 (0.41-0.85)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; CI, confidence interval; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; PFS, progression-free survival.
aFor the pooled analysis, a multivariate stratified Cox regression analysis was used to calculate adjusted HR, with the study identifier as the stratification factor. HR was adjusted for cytogenetic abnormalities [ie, del(17p), t(4, 14), 4(14, 16)], baseline ECOG performance status, ISS stage, type of multiple myeloma (ie, IgG vs. non-IgG), and renal impairment (defined as creatinine clearance <60 mL/min).
  • The median time to ≥CR was 9.3 months (range, 3.5-34.5) in the pooled DARZALEX cohort vs 7.1 months (range, 2.3-43.8) in the pooled control cohort. See Table: Response Rates.
  • In the pooled DARZALEX vs control cohorts, the median PFS was NR vs 31 months in patients achieving ≥CR and 16.4 months vs 15.6 months in patients not achieving CR.

Response Rates5
Parameter
DARZALEX + Control (n=101)
Control (n=89)
Relative Response Ratioa (95% CI)
Adjusted ORb
(95% CI)
P Value
Sensitivity Analysis Adjusting For Age
Adjusted ORc (95% CI)
P Value
Best response
≥CR (sCR + CR)
42 (41.6%)
20 (22.5%)
1.85
(1.18-2.90)
2.63
(1.34-5.16)
0.0051
2.57
(1.30-5.06)
0.0064
sCR
27 (26.7%)
5 (5.6%)
-
-
-
-
-
CR
15 (14.9%)
15 (16.9%)
-
-
-
-
-
MRD-negative CR
25 (24.8%)
5 (5.6%)
4.35
(1.75-10.82)
5.50
(1.97-15.34)
0.0011
5.31
(1.89-14.88)
0.0015
VGPR
34 (33.7%)
21 (23.6%)
-
-
-
-
-
PR
17 (16.8%)
25 (28.1%)
-
-
-
-
-
SD
3 (3.0%)
19 (21.3%)
-
-
-
-
-
PD
0 (0.0%)
0 (0.0%)
-
-
-
-
-
NE
5 (5.0%)
4 (4.5%)
-
-
-
-
-
≥VGPR (sCR + CR + VGPR)
76 (75.2%)
41 (46.1%)
1.64
(1.27-2.10)
4.03
(2.09-7.78)
<0.0001
4.08
(2.10-7.91)
<0.0001
Overall response (sCR + CR + VGPR + PR)
93 (92.1%)
66 (74.2%)
1.24
(1.08-1.42)
4.88
(1.94-12.27)
0.0008
4.71
(1.87-11.88)
0.0010
Abbreviations: ASCT, autologous stem cell transplant; CI, confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
aRelative response ratio was calculated using the Mantel-Haenszel method, with the study identifier as the stratification factor.
bAdjusted OR was calculated using stratified logistic regression analysis, with the study identifier as the stratification factor. OR was adjusted for cytogenetic abnormalities [ie, del(17p), t(4;14), 4(14;16)], baseline ECOG performance status, ISS stage, type of MM (ie, IgG vs non-IgG), and renal impairment (defined as creatinine clearance <60 mL/minute).
cOR was additionally adjusted for age (<75 vs ≥75 years).

Pooled Analysis of Patients from the POLLUX, CASTOR, ALCYONE, and MAIA Studies

Cavo et al (2022)6 conducted a pooled analysis of patient-level data from the POLLUX, CASTOR, ALCYONE, and MAIA studies. The data were used to assess the predictive value of MRD-negativity with best response and its prognostic value for DARZALEX-based treatment regimens. Results regarding the ALCYONE study have been summarized below.

Study Design/Methods

  • Patient-level data were pooled from all 4 studies and for patients who received ≤2 prior lines of therapy (≤2PL).
  • For patients who achieved ≥CR, additional MRD (next-generation sequencing [NGS]
    10-5 threshold) testing occurred at 3- and 6- months following CR/ stringent complete response (sCR), and thereafter, every 12 months post-CR/sCR.
  • MRD-negativity rate was defined as the proportion of patients with ≥CR and ≥1 MRD negative result at any time point during DARZALEX-based treatment and prior to subsequent therapy for multiple myeloma.
  • PFS was evaluated by response and MRD status.

Results

  • Of the 2,510 patients included in the analysis, 706 had been treated in the ALCYONE study (DVMP, n=350; VMP, n=356).
  • The median duration of follow-up was 40.1 (range, 0-52.1) months in the ALCYONE study.
  • In the ITT population and among patients with ≥CR, MRD-negativity rate was higher in the DVMP vs VMP arm. See Table: Rates of MRD-negativity Status in NDMM.
  • In patients with high cytogenetic risk, rate of ≥CR and MRD-negativity was 26.4% (n=14/53) vs 8.9% (n=4/45) in the DVMP vs VMP arm, respectively.15

Rates of MRD-negativity Status in NDMM6
MRD-negativity (10-5) rates in TIE NDMM, n (%)
DVMP
VMP
P valuea
ITT
Number of evaluable patients
n=350
n=356
Rate
99 (28.3)
25 (7.0)
<0.0001
≥CR
Number of evaluable patients
n=160
n=90
Rate
94 (58.8)
25 (27.8)
<0.0001
Abbreviations: CR, complete response; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; VMP, bortezomib + melphalan + prednisone.
aP value was calculated using Fisherʼs exact test.

Impact of Frailty on Safety and Efficacy in the ALCYONE Study

Mateos et al (2021)7 conducted a subgroup analysis of frailty status in patients enrolled in the ALCYONE study.

Study Design/Methods

  • Based on the retrospective frailty assessment conducted, patients were classified as fit (0), intermediate (1), or frail (≥2) based on age, Charlson Comordibity Index and baseline ECOG PS score. Non-frail subgroup was defined as patients who had a frailty score of fit or intermediate.

Results

Patient Characteristics
  • Median duration of follow-up was 40.1 months.
  • All patients (DVMP, n=350; VMP, n=356) were stratified based on frailty status:
    • Frail patients (n=315; 44.6%): 163 (46.6%) in the DVMP arm vs 152 (42.7%) in the VMP arm.
    • Non-frail patients (n=391; 55.4%): 187 (53.4%) in the DVMP arm vs 204 (57.3%) in the VMP arm.
  • The baseline characteristics based on frailty scores for DVMP vs VMP is presented in the Table: Key Demographics and Baseline Characteristics by Frailty Status (ALCYONE).

Key Demographics and Baseline Characteristics by Frailty Status (ALCYONE)7
Non-fraila
Frail
Fit (n=122)
Intermediate (n=269)
Total non-fraila (n=391)
Frail (n=315)
DVMP (n=48)
VMP (n=74)
DVMP (n=139)
VMP (n=130)
DVMP (n=187)
VMP (n=204)
DVMP (n=163)
VMP (n=152)
Age, years, n (%)
  Median (range)
70.0
(65-75)
71.0
(56-75)
71.0
(52-80)
70.0
(52-80)
70.0
(52-80)
70.0
(52-80)
74.0
(40-93)
74.0
(50-91)
    <65
0
3 (4.1)
13 (9.4)
10 (7.7)
13 (7.0)
13 (6.4)
23 (14.1)
11 (7.2)
    65-<75
45 (93.8)
60 (81.1)
105 (75.5)
98 (75.4)
150 (80.2)
158 (77.5)
60 (36.8)
67 (44.1)
    ≥75
3 (6.3)
11 (14.9)
21 (15.1)
22 (16.9)
24 (12.8)
33 (16.2)
80 (49.1)
74 (48.7)
    ≥80
0
0
1 (0.7)
3 (2.3)
1 (0.5)
3 (1.5)
32 (19.6)
29 (19.1)
ECOG PS score, n (%)
    0
48 (100)
74 (100)
18 (12.9)
17 (13.1)
66 (35.3)
91 (44.6)
12 (7.4)
8 (5.3)
    1
0
0
121 (87.1)
113 (86.9)
121 (64.7)
113 (55.4)
61 (37.9)
60 (39.5)
    2
0
0
0
0
0
0
90 (55.2)
84 (55.3)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; VMP, bortezomib + melphalan + prednisone.
aTotal non frail consists of fit and intermediate patients.
Efficacy
  • The median relative dose intensity of daratumumab was comparable across the frailty subgroups (non-frail, 99.3%; frail, 98.5%).
  • PFS benefit was observed in all subgroups:
    • For total non-frail patients, median PFS was 45.7 months in the DVMP arm vs 19.1 months in the VMP arm (HR, 0.36; 95% CI, 0.28-0.47; P<0.0001).
      • For fit patients, median PFS was not reached in the DVMP arm vs 22.2 months in the VMP arm (HR, 0.34; 95% CI, 0.20-0.57; P<0.0001).
      • For intermediate patients, median PFS was 40.1 months in the DVMP arm vs 18.3 months in the VMP arm (HR, 0.37; 95% CI, 0.27-0.50; P<0.0001).
    • For frail patients, median PFS was 32.9 months in the DVMP arm vs 19.5 months in the VMP arm (HR, 0.51; 95% CI, 0.39-0.68; P<0.0001).
  • OS benefit was maintained in all subgroups:
    • For total non-frail patients, median OS was not reached in both arms (HR, 0.52; 95% CI, 0.34-0.79; P=0.0017).
      • For fit patients, median OS was not reached in the DVMP arm vs 46.2 months in the VMP arm (HR, 0.18; 95% CI, 0.05-0.62; P=0.0021).
      • For intermediate patients, median OS was not reached in both arms (HR, 0.62; 95% CI, 0.39-0.98; P=0.0407).
    • For frail patients, median OS was not reached in both arms (HR, 0.66; 95% CI, 0.46-0.96; P=0.0292).
  • The ORR was higher in the DVMP arm vs VMP arm across frailty subgroups (ITT population):
    • For total non-frail patients, ORR was achieved by 93.0% (n=174) in the DVMP arm vs 75.0% (n=153) in the VMP arm (P<0.0001).
    • For frail patients, ORR was achieved by 88.3% (n=144) in the DVMP arm vs 72.4% (n=110) patients in the VMP arm (P=0.0003).
  • Improved MRD-negativity (10-5) rate was observed in the DVMP arm vs VMP arm across frailty subgroups (ITT Population):
    • For total non-frail patients, MRD-negativity (10-5) rate was 27.8% (n=52) in the DVMP arm vs 6.4% (n=13) in the VMP arm (P<0.0001).
    • For frail patients, MRD-negativity (10-5) rate was 28.8% (n=47) in the DVMP arm vs 7.9% (n=12) in the VMP arm (P<0.0001).
Safety

Most Common Grade 3/4 (≥10%) TEAEs in the Safety Population (ALCYONE)7
Event, n (%)
Total non-fraila (n=389)
Frail (n=311)
DVMP (n=186)
VMP (n=203)
DVMP (n=160)
VMP (n=151)
Total number of patients with grade 3/4 TEAE
150 (80.6)
151 (74.4)
127 (79.4)
123 (81.5)
Hematologic
   Neutropenia
73 (39.2)
86 (42.4)
66 (41.3)
52 (34.4)
   Thrombocytopenia
61 (32.8)
75 (36.9)
59 (36.9)
59 (39.1)
   Anemia
26 (14.0)
38 (18.7)
34 (21.3)
32 (21.2)
   Leukopenia
15 (8.1)
12 (5.9)
13 (8.1)
18 (11.9)
   Lymphopenia
13 (7.0)
9 (4.4)
14 (8.8)
13 (8.6)
Non-hematologic
   Infections
44 (23.7)
26 (12.8)
48 (30.0)
27 (17.9)
      Pneumonia
22 (11.8)
7 (3.4)
23 (14.4)
8 (5.3)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse events; VMP, bortezomib + melphalan + prednisone.
aTotal non-frail subgroup consists of fit and intermediate patients.

Most Common TEAEs Leading to Treatment Discontinuation (>1 Patient) and an Outcome of Death in the Safety Population (ALCYONE)7,16
Event, n (%)
Total non-fraila (n=389)
Frail (n=311)
DVMP (n=186)
VMP (n=203)
DVMP (n=160)
VMP (n=151)
Total number of patients with a TEAE leading to treatment discontinuation
10 (5.4)
14 (6.9)
14 (8.8)
19 (12.6)
Non-hematologic
   Fatigue
0
0
1 (0.6)
2 (1.3)
   Peripheral sensory neuropathy
0
2 (1.0)
0
4 (2.6)
   Infections
4 (2.2)
3 (1.5)
2 (1.3)
3 (2.0)
      Pneumonia
2 (1.1)
0
1 (0.6)
1 (0.7)
Total number of patients with a TEAE with an outcome of death
7 (3.8)
7 (3.4)
17 (10.6)
13 (8.6)
   Cardiac arrest
1 (0.5)
0
0
2 (1.3)
   Death
0
0
2 (1.3)
2 (1.3)
   Pneumonia
0
0
2 (1.3)
0
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone.
aTotal non-frail subgroup consists of fit and intermediate patients.

Patient Reported Outcomes Results from ALCYONE

Knop et al (2021)8 evaluated the treatment effect of DVMP on PROs in the ALCYONE study. HRQoL scores were assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L).

Results

  • The ITT population was the primary analysis population (DVMP, n=350; VMP, n=356).
  • The PRO data set was the ITT population of patients with a baseline and >1 postbaseline PRO assessment.
  • At baseline, completion rates for EORTC QLQ-C30 and EQ-5D-5L, respectively:
    • DVMP: 90.6% and 90.3%
    • VMP: 91.9% and 91.3%
  • Compliance remained high (>76%) throughout the study.
  • At month 3, least squares (LS) mean change in Global Health Status (GHS) score from baseline was 7.3 vs 3.9 for DVMP vs VMP (difference, 3.4; P=0.0240). For results throughout the first 36 months of treatment, see Table: Least Squares Mean Change in EORTC QLQ-C30 GHS Score from Baseline.
    • LS mean changes from baseline for EORTC QLQ-C30 functional scales and symptom scales were not significantly different between groups.
    • Point estimates favored DVMP at all time points for physical functioning and at most time points for role functioning, cognitive functioning, and social functioning.  
    • Point estimates generally favored DVMP for LS mean change in symptom scores for pain, fatigue, or nausea and vomiting.
    • The proportion of patients with a clinically meaningful change (≥10 points) in EORTC QLQ-C30 scores at month 36 were numerically greater in the DVMP group for all scales.

Least Squares Mean Change in EORTC QLQ-C30 GHS Score from Baseline8
Time Point (Month)
Least Squares Mean Change
DVMP
VMP
3
7.3
3.9
6
8.4
8.7
9
10.4
10.1
12
11.1
10.5
18
12.7
11.6
24
9.3
11.3
30
10.8
11.3
36
12.3
7.9
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; GHS, Global Health Status; VMP, bortezomib + melphalan + prednisone.
  • At month 3, LS mean difference in EQ-5D-5L visual analog scale (VAS) score from baseline was 7 vs 3.8 for DVMP vs VMP (difference 3.1, P=0.0160). For results throughout the first 36 months of treatment, see Table: Least Squares Mean Change in EQ-5D-5L VAS Score from Baseline.
    • At month 3, the proportion of patients with a clinically meaningful improvement (≥7 points) in VAS score was 54.8% vs 41.3% for DVMP vs VMP, respectively (OR, 1.72; P=0.0025)

Least Squares Mean Change in EQ-5D-5L VAS Score from Baseline8
Time Point (Month)
Least Squares Mean Change
Patients Reporting Clinically Meaningful Improvement (%)
DVMP
VMP
DVMP
VMP
3
7.0
3.8
54.8
41.3
6
7.9
6.6
57.1
48.1
9
9.5
8.8
59.9
56.6
12
8.3
9.8
56.9
60.5
18
11.7
11.0
65.8
56.0
24
9.4
10.7
62.0
56.1
30
9.6
9.9
66.7
62.5
36
11.2
9.5
64.6
54.8
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; EQ-5D-5L, EuroQol 5-dimensional descriptive system; VAS, visual analog scale; VMP, bortezomib + melphalan + prednisone.

Long-Term Efficacy Outcomes and HRQoL by Response Status in ALCYONE

Rodriguez-Otero et al (2020)9 examined long-term efficacy outcomes and HRQoL based on response status in patients treated in the ALCYONE study.

Results

Patient Characteristics
  • At the cutoff for the analysis, all patients who received study treatment had either completed or discontinued the first 9 treatment cycles and 146 (42%) of 350 patients in the DVMP group continued to receive DARZALEX therapy.
Efficacy
  • Median duration of follow-up was 40.1 months.
  • More patients achieved deeper responses with DVMP, which led to better outcomes of PFS, time to next therapy (subsequent antimyeloma therapy), and OS; for these patients, clinically meaningful improvements in global health status, physical functioning, fatigue, and pain were observed. See Table: Efficacy by Response Status and Table: Clinically Meaningful Improvements in EORTC QLQ-C30 Scales at Month 12 by Response Status.
  • In the pooled study population (DVMP and VMP patients), EORTC QLQ-C30 global health status improved with deepening responses from months 3 to 12.

Efficacy by Response Status9
Response category
DVMP
(n=350)
VMP
(n=356)
HR
(95% CI)
P value
PR, n (%)
63 (18.0)
86 (24.2)
Median PFS, months
17.1
16.1
0.58 (0.40-0.85)
0.0043
Median time to next therapy (subsequent antimyeloma therapy), months
23.6
20.7
0.74 (0.50-1.11)
0.1429
OS
Median, months
NR
NR
0.69 (0.39-1.21)
0.1879
36-month survival rate, %
71.4
63.5
-
-
VGPR, n (%)
95 (27.1)
87 (24.4)
Median PFS, months
25.6
19.5
0.57 (0.40-0.81)
0.0014
Median time to next therapy (subsequent antimyeloma therapy), months
43.8
27.5
0.54 (0.36-0.81)
0.0027
OS
Median, months
NR
46.2
0.68 (0.40-1.15)
0.1463
36-month survival rate, %
75.4
68.8
-
-
CR or better, n (%)
160 (45.7)
90 (25.3)
Median PFS, months
NR
34.6
0.41 (0.28-0.61)
<0.0001
Median time to next therapy (subsequent antimyeloma therapy), months
NR
44.4
0.38 (0.23-0.63)
<0.0001
OS
Median, months
NR
NR
0.86 (0.44-1.69)
0.6673
36-month survival rate, %
89.3
88.5
-
-
CR or better + MRD negative, n (%)
94 (26.9)
25 (7.0)
Median PFS, months
NR
41.8
0.57 (0.27-1.20)
0.1314
Median time to next therapy (subsequent antimyeloma therapy), months
NR
44.4
0.38 (0.16-0.88)
0.0197
OS
Median, months
NR
NR
1.07 (0.30-3.78)
0.9202
36-month survival rate, %
89.3
96.0
-
-
Abbreviations: CI, confidence interval; CR, complete response; DVMP, DARZALEX + bortezomib + melphalan + prednisone; HR, hazard ratio; MRD, minimal residual disease; NR, not reached; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; VMP, bortezomib + melphalan + prednisone.

Clinically Meaningful Improvementsa in EORTC QLQ-C30 Scales at Month 12 by Response Status9
Response Category, n (%)
DVMP
(n=350)
VMP
(n=356)
Odds Ratio
(95% CI)b
PR
63 (18.0)
86 (24.2)
EORTC QLQ-C30 scalesc
Global health status
16 (41.0)
28 (58.3)
0.50 (0.21-1.17)
Physical functioning
17 (43.6)
24 (50.0)
0.77 (0.33-1.81)
Fatigue
22 (56.4)
27 (56.3)
1.01 (0.43-2.36)
Pain
19 (48.7)
26 (54.2)
0.80 (0.34-1.87)
VGPR
95 (27.1)
87 (24.4)
EORTC QLQ-C30 scales
Global health status
35 (57.4)
28 (51.9)
1.25 (0.60-2.61)
Physical functioning
34 (55.7)
29 (53.7)
1.09 (0.52-2.27)
Fatigue
33 (54.1)
33 (61.1)
0.75 (0.36-1.58)
Pain
34 (55.7)
35 (64.8)
0.68 (0.32-1.45)
CR or better
160 (45.7)
90 (25.3)
EORTC QLQ-C30 scales
Global health status
63 (52.9)
35 (54.7)
0.93 (0.51-1.72)
Physical functioning
69 (58.0)
29 (45.3)
1.67 (0.90-3.07)
Fatigue
71 (59.7)
36 (56.3)
1.15 (0.6-2.13)
Pain
82 (68.9)
34 (53.1)
1.96 (1.05-3.66)
CR or better + MRD negative
94 (26.9)
25 (7.0)
EORTC QLQ-C30 scales
Global health status
42 (57.5)
8 (53.3)
1.19 (0.39-3.62)
Physical functioning
43 (58.9)
7 (46.7)
1.64 (0.54-5.00)
Fatigue
46 (63.0)
9 (60.0)
1.14 (0.36-3.54)
Pain
52 (71.2)
11 (73.3)
0.90 (0.26-3.15)
Abbreviations: CI, confidence interval; CR, complete response; DVMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; MRD, minimal residual disease; PR, partial response; VGPR, very good partial response; VMP, bortezomib + melphalan + prednisone.
aShown are the number of patients with clinically meaningful improvements in EORTC QLQ-C30 scales. Clinically meaningful improvements were defined as a ≥10-point increase in the EORTC QLQ-C30 function scales and a decrease for symptom scales.
bMantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DVMP.
cPercentages for EORTC QLQ-C30 subscales calculated with the number of 10-point improvement patients divided by the number of patients in each visit and each subscale.

Elderly (≥75 Years) and Non-Elderly (<75 Years) Patients

Cavo et al (2018)10 analyzed safety and efficacy data of elderly patients aged <75 and ≥75 treated in the ALCYONE study.

Results

  • The median duration of follow-up was 16.5 months.
  • Among patients aged ≥75 years (DVMP, n=104; VMP, n=107):
    • Median duration of study treatment: 14.5 months DVMP vs 12.0 months VMP
  • Among patients aged <75 years (DVMP, n=246; VMP, n=249):
    • Median duration of study treatment: 15.0 months DVMP vs 12.0 months VMP
  • Among patients aged <75 years:
    • Median duration of study treatment: 15.0 months DVMP vs 12.0 months VMP
Efficacy
  • Response rates and characteristics are presented in Table: Response Rates and Characteristics in ALCYONE.
  • Median PFS:
    • ITT population: not reached DVMP vs 18.1 months VMP (HR, 0.50; 95% CI, 0.38-0.65; P<0.001)
    • ≥75 years: not reached DVMP vs 20.4 months VMP (HR, 0.53; 95% CI, 0.32-0.85)
    • <75 years: not reached DVMP vs 17.9 months VMP (HR, 0.49; 95% CI, 0.36-0.68)
  • MRD negativity rates (10-5 sensitivity threshold):
    • Overall population: 22% DVMP (n=350) vs 6% VMP (n=356) (P<0.0001)
    • ≥75 years: 24% DVMP (n=104) vs 8% VMP (n=107) (P=0.0011)
    • <75 years: 22% DVMP (n=246) vs 6% VMP (n=249) (P<0.0001)

Response Rates and Characteristics in ALCYONE10
Response characteristic: ALCYONE
ITT
<75 years
≥75 years
DVMP
(n=350)
VMP
(n=356)
DVMP
(n=246)
VMP
(n=249)
DVMP
(n=104)
VMP
(n=107)
ORR, %
90.9
73.9
92.3
75.5
87.5
70.1
sCR, %
18.0
7.0
17.5
7.2
19.2
6.5
≥CR, %
42.6
24.4
43.1
24.5
41.3
24.3
≥VGPR, %
71.1
49.7
72.4
50.2
68.3
48.6
Median (range) time to first responsea, months
0.79
(0.4-15.5)
0.82
(0.7-12.6)
0.79
(0.4-15.3)
0.85
(0.7-12.6)
0.82
(0.7-15.5)
0.82
(0.7-6.3)
Median (range) time to ≥CR a, months
8.31
(1.9-21.0)
7.46
(0.7-20.5)
8.41
(1.9-18.3)
7.10
(1.4-20.5)
6.93
(2.6-21.0)
9.00
(0.7-14.0)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib +melphalan + prednisone; CR, complete response; ITT, intent-to-treat; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response.
aResponse of partial response or better in response-evaluable population (ie, patients who have a confirmed diagnosis of multiple myeloma and measurable disease at baseline and must have received ≥1 component of study treatment and have adequate post-baseline disease assessments).
Safety

Most Common All-grade TEAEs and TEAEs of Interest Among Elderly Patients in ALCYONE10
All-grade TEAEs: ALCYONE
Overall Populationa
<75 years
≥75 years
DVMP
(n=346)
VMP
(n=354)
DVMP
(n=244)
VMP
(n=248)
DVMP
(n=102)
VMP
(n=106)
Most common (≥25%) TEAEs, %
Neutropenia
50
53
45
52
62
55
Thrombocytopenia
49
54
42
51
65
59
Anemia
28
38
25
36
36
42
URTI
26
14
26
13
28
15
Diarrhea
24
25
21
21
30
33
Pyrexia
23
21
20
21
31
20
Nausea
21
22
19
18
26
30
TEAEs of interest, %
Peripheral sensory neuropathy
28
34
30
32
24
40
Infectionsb
67
48
64
46
73
52
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.
aIncludes all patients who received ≥1 dose of study treatment.
bMedDRA system organ class.

Most Common Grade 3/4 TEAEs and Grade 3/4 TEAEs of Interest Among Elderly Patients in ALCYONE10
Grade 3/4 TEAEs: ALCYONE
Overall Populationa
<75 years
≥75 years
DVMP
(n=346)
VMP
(n=354)
DVMP
(n=244)
VMP
(n=248)
DVMP
(n=102)
VMP
(n=106)
Patients with grade 3/4 TEAEs, %
78
77
73
74
89
85
Most common (≥10%) grade 3/4 TEAEs, %
Neutropenia
40
39
35
38
52
42
Thrombocytopenia
34
38
28
35
51
43
Anemia
16
20
13
19
24
23
Leukopenia
8
9
6
9
13
9
Lymphopenia
8
6
7
4
10
10
Pneumonia
11
4
9
2
18
9
Grade 3/4 TEAEs of interest, %
Peripheral sensory neuropathy
1
4
2
3
0
6
Infectionsb
23
15
21
13
28
20
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.
aIncludes all patients who received ≥1 dose of study treatment.
bMedDRA system organ class.

Impact of Baseline Renal Function

Cavo et al (2018)11 presented data on the impact of baseline renal function on efficacy and safety of DVMP from the ALCYONE study.

Study Design/Methods


Baseline Characteristics11
Characteristic
Baseline CrCl ≤60 mL/min
Baseline CrCl >60 mL/min
DVMP
(n=150)
VMP
(n=145)
DVMP
(n=200)
VMP
(n=211)
Age
Median (range), years
74 (52-93)
74 (59-91)
70 (40-85)
70 (50-82)
 Male, %
39
37
51
54
 ECOG status,a %
0
24
20
21
33
1
45
55
58
45
2
31
26
22
22
ISS stage,b %
I
9
8
28
27
II
33
39
45
49
III
57
54
28
24
Cytogenetic profilec
N
127
124
187
178
Standard risk, %
83
86
83
84
High risk, %
17
14
17
16
Abbreviations: CrCl, creatinine clearance; DVMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; VMP, bortezomib +melphalan + prednisone.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bBased on the combination of serum β2-microglobulin and albumin.
cBased on fluorescence in situ hybridization/karyotype testing performed at local sites; t(4;14), t(14;16), and del17p were classified as high risk.

Results

  • Median duration of follow-up was 16.5 months.
  • Median duration of study treatment:
    • Creatinine clearance (CrCl) ≤60 mL/min: 15.3 months with DVMP vs 12.0 months with VMP
    • CrCl >60 mL/min: 14.5 months with DVMP vs 12.0 months with VMP
  • Median cumulative dose of bortezomib:
    • CrCl ≤60 mL/min: 45.7 mg/m2 with DVMP vs 41.2 mg/m2 with VMP
    • CrCl >60 mL/min: 48.1 mg/m2 with DVMP vs 42.7 mg/m2 with VMP
  • Overall treatment discontinuations by the end of cycle 9:
    • CrCl ≤60 mL/min: 18% with DVMP vs 41% with VMP
    • CrCl >60 mL/min: 21% with DVMP vs 28% with VMP
    • Treatment discontinuations due to progressive disease:
      • CrCl ≤60 mL/min: 4% with DVMP vs 15% with VMP
      • CrCl >60 mL/min: 9% with DVMP vs 12% with VMP
    • Treatment discontinuations due to AEs:
      • CrCl ≤60 mL/min: 6% with DVMP vs 12% with VMP
      • CrCl >60 mL/min: 4% with DVMP vs 8% with VMP
Efficacy
  • Response rates and characteristics are presented in Table: Response Rates and Characteristics With DVMP Versus VMP by Renal Function Subgroup.
  • In the ITT population, DVMP reduced the risk of disease progression or death by 50% (median PFS: DVMP, not reached vs VMP, 18.1 months; HR, 0.50; 95% CI, 0.38-0.65; P<0.0001).
  • Median PFS:
    • CrCl ≤60 mL/min: not reached with DVMP vs 16.9 months with VMP (HR, 0.36; 95% CI, 0.24-0.56)
    • CrCl >60 mL/min: not reached with DVMP vs 18.3 months with VMP (HR, 0.63; 95% CI, 0.45-0.88)
  • 18-month PFS (Kaplan-Meier estimate):
    • CrCl ≤60 mL/min: 78% with DVMP vs 48% with VMP
    • CrCl >60 mL/min: 66% with DVMP vs 52% with VMP
  • The MRD-negativity rate (10-5 sensitivity threshold) was increased with DVMP vs VMP in patients with baseline CrCl ≤60 mL/min (25% vs 8%; P<0.0001) and >60 mL/min (20% vs 5%; P<0.0001), consistent with the ITT population (22% vs 6%; P<0.0001).

Response Rates and Characteristics With DVMP Versus VMP by Renal Function Subgroup11
Response characteristic
ITT
Baseline CrCl ≤60 mL/min
Baseline CrCl >60 mL/min
DVMP
(n=350)
VMP
(n=356)
DVMP
(n=150)
VMP
(n=145)
DVMP
(n=200)
VMP
(n=211)
ORR, %
90.9
73.9
89.3
73.1
92.0
74.4
≥CR, %
42.6
24.4
42.7
24.1
42.5
24.6
sCR, %
18.0
7.0
19.3
9.0
17.0
5.7
≥VGPR, %
71.1
49.7
74.7
49.0
68.5
50.2
Median (range) time to first response a, months
0.79(0.4-15.5)
0.82(0.7-12.6)
0.79(0.5-15.3)
0.84(0.7-12.6)
0.80(0.4-15.5)
0.82(0.7-10.0)
Median (range) time to ≥CRa, months
8.31(1.9-21.0)
7.46(0.7-20.5)
6.93(1.9-21.0)
7.46(2.8-14.4)
9.00(2.3-18.3)
7.67(0.7-20.5)
Abbreviations: DVMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone; CR, complete response; CrCl, creatinine clearance; ITT, intent-to-treat; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response.aResponse of partial response or better in the response-evaluable population (ie, subjects who have a confirmed diagnosis of multiple myeloma and measurable disease at baseline and must have received ≥1 component of study treatment and have adequate post-baseline disease assessments).
Safety

Most Common (≥25%) All-grade TEAEs and Incidences of Peripheral Sensory Neuropathy and Infections11
All-grade TEAEs
Overall populationa
Baseline CrCl ≤60 mL/mina
Baseline CrCl >60 mL/mina
DVMP(n=346)
VMP(n=354)
DVMP(n=146)
VMP(n=144)
DVMP(n=200)
VMP(n=210)
Most common (≥25%) TEAEs, %
Neutropenia
50
53
58
55
44
51
Thrombocytopenia
49
54
54
58
45
51
Anemia
28
38
32
47
26
31
URTI
26
14
25
17
27
12
Diarrhea
24
25
27
31
21
21
Pyrexia
23
21
27
18
20
23
Peripheral sensory neuropathy, %
28
34
28
35
29
33
Infections,b %
67
48
71
49
64
47
Abbreviations: CrCl, creatinine clearance; DVMP, DARZALEX +bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection; VMP, bortezomib + melphalan + prednisone.aIncludes all patients who received ≥1 dose of study treatment. bMedDRA system organ class.

Most Common (≥10%) Grade 3/4 TEAEs and Incidences of Peripheral Sensory Neuropathy and Infections11
Grade 3/4 TEAEs
Overall populationa
Baseline CrCl ≤60 mL/mina
Baseline CrCl >60 mL/mina
DVMP(n=346)
VMP(n=354)
DVMP(n=102)
VMP(n=106)
DVMP(n=244)
VMP(n=248)
Patients with grade 3/4 TEAEs, %
78
77
81
82
75
74
Most common (≥10%) TEAEs, %
Neutropenia
40
39
47
38
35
39
Thrombocytopenia
34
38
43
42
28
34
Anemia
16
20
21
29
12
13
Pneumonia
11
4
15
6
9
2
Peripheral sensory neuropathy, %
1
4
2
4
1
4
Infections,b %
23
15
26
17
21
13
Abbreviations: CrCl, creatinine clearance; DVMP, DARZALEX + bortezomib + melphalan + prednisone; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; VMP, bortezomib +melphalan +prednisone.
aIncludes all patients who received ≥1 dose of study treatment.
bMedDRA system organ class.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on
20 November 2024.

 

References

Show
1 Mateos M, Dimopoulos M, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528.  
2 MV Mateos, J San-Miguel, M Cavo, et al. Daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 ALCYONE study. 2022;(Poster).  
3 Fu W, Bang SM, Huang H, et al. Subgroup analyses of progression-free survival from the phase 3 OCTANS and ALCYONE studies in transplant-ineligible patients with newly diagnosed multiple myeloma treated with bortezomib, melphalan, and prednisone with or without daratumumab. Poster presented at: 65th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA.  
4 San-Miguel J, Avet-Loiseau H, Paiva B, et al. Sustained minimal residual disease negativity with daratumumab in newly diagnosed multiple myeloma: MAIA and ALCYONE. Blood. 2022;139:492-501.  
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6 Cavo M, San-Miguel J, Usmani SZ, et al. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2021;139(6):835-844.  
7 Mateos M, Dimopoulos M, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of ALCYONE. Clin Lymphoma Myeloma Leuk. 2021;21:785-798.  
8 Knop S, Mateos MV, Dimopoulos MA, et al. Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial. Bmc Cancer. 2021;21(1):659.  
9 Burton T, Larholt K, Apgar E, et al. Long-term outcomes and health-related quality of life (HRQoL) by response status for bortezomib, melphalan, and prednisone (VMP) ¬± daratumumab (DARA) in ALCYONE. Poster presented at: Virtual 62ndAmerican Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020.  
10 Cavo M, Iida S, Blade J, et al. Daratumumab plus bortezomib-melphalan-prednisone (VMP) in elderly ( ≥75 y) patients (pts)  with newly diagnosed multiple myeloma (NDMM) ineligible for transplantation (ALCYONE). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1-5, 2018; Chicago, IL.  
11 Cavo M, Dimopoulos M, San-Miguel J, et al. Impact of baseline renal function on efficacy and safety of daratumumab plus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients ineligible for transplantation (ALCYONE). Poster presented at: The 23rd European Hematology Association (EHA) Annual Congress; June 14-17, 2018; Stockholm, Sweden.  
12 Neal B, Perkovic V, Mahaffey KW, et al. Protocol for: Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.  
13 Mateos M, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395:132-141.  
14 San-Miguel J, Avet-Loiseau H, Paiva B, et al. Supplement to: Sustained minimal residual disease negativity with daratumumab in newly diagnosed multiple myeloma: MAIA and ALCYONE. Blood. 2022;139:492-501.  
15 Cavo M, San-Miguel J, USmani S, et al. Supplement to: Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, MAIA. Blood. 2022;139:835-844.  
16 Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE. Clin Lymphoma Myeloma Leukemia. 2021;21(11):785-798.