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DARZALEX® (daratumumab)

Medical Information

DARZALEX - MMY3007 (ALCYONE) Study

Last Updated: 06/10/2025

SUMMARY

ALCYONE is a phase 3 study evaluating the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (D-VMP) 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, D-VMP 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 (2025)² reported the final efficacy and safety analysis results of the ALCYONE study at a median follow-up of 86.7 months (interquartile range [IQR], 28.5-85.2). The median PFS on the next line of therapy in the D-VMP vs VMP group was 66.7 months (95% CI, 58.6-80.1) vs 42.4 months (95% CI, 7.3-7.1), respectively (HR, 0.56; 95% CI, 0.46-0.68; P<0.0001). The minimal residual disease (MRD)-negativity rate at the 10^-5 sensitivity level in the D-VMP vs VMP group was 28% vs 7%, respectively (odds ratio [OR], 5.23; 95% CI, 3.27-8.36; P<0.0001). The most common grade 3 or 4 treatment-emergent adverse events (TEAEs) in the D-VMP vs VMP group were neutropenia (40% vs 39%, respectively), thrombocytopenia (35% vs 38%, respectively), and anemia (18% vs 20%, respectively). Pneumonia was the most common grade 3 or 4 infection, reported by 16% of patients in the D-VMP group and 5% of patients in the VMP group.
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 D-VMP 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 (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
D-VMP 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
D-VMP arm vs VMP arm across frailty subgroups. For frail patients, ORR was achieved by 88.3% (n=144) patients in the D-VMP 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 D-VMP on patient-reported soutcomes (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 D-VMP from the ALCYONE study.

PRODUCT LABELING

DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf

CLINICAL DATA

ALCYONE (MMY3007; NCT02195479) is an open-label, active controlled, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VMP 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 at a median follow-up of 16.5 months. 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. Mateos et al (2025)² reported the final efficacy and safety analysis results at a median follow-up of 86.7 months.

Study Design/Methods

Patients were randomly assigned 1:1 to receive either VMP alone or D-VMP 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
- D-VMP:
  - 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 overall survival (OS)
Other endpoints: safety, side-effect profile, time to response (TTR), and duration of response (DOR)

Results

Patient Characteristics

A total of 706 patients (D-VMP, n=350; VMP, n=356) were randomly assigned to treatment, of whom 700 patients received study treatment (D-VMP, n=346; VMP, n=354).
At the planned interim analysis:
- 276 (79.8%) patients in the D-VMP 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 D-VMP arm vs 33.1% of patients in the VMP arm discontinued treatment.
  - A higher proportion of patients in the VMP arm than in the D-VMP 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 D-VMP arm 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 D-VMP 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 D-VMP arm vs 143 (40.2%) patients in the VMP arm.
D-VMP 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 D-VMP 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 D-VMP 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 D-VMP over VMP alone was generally consistent across the subgroups analyzed. Results are summarized in Table: Prespecified Subgroup Analyses of PFS (Planned Interim Analysis).¹
Secondary endpoints are summarized in Table: Secondary Endpoints (ITT Population; Planned Interim Analysis).

Prespecified Subgroup Analyses of PFS (Planned Interim Analysis)¹

Subgroup	D-VMP	VMP	HR (95% CI)
Subgroup	Number of PFS Events, n/N		HR (95% CI)
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 >60 mL/min	32/150	63/145	0.36 (0.24-0.56)
≤60 mL/min >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 myeloma^a
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 risk^b	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; D-VMP, 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	D-VMP	VMP	P-value
OR^a, n (%) [95% CI]	318 (90.9) [87.3-93.7]	263 (73.9) [69.0-78.4]	<0.001
≥VGPR^a, n (%)	249 (71.1)	177 (49.7)	<0.001
≥CR^a n (%)	149 (42.6)	87 (24.4)	<0.001
MRD negativity^a,b, n (%)	78 (22.3)	22 (6.2)	<0.001
Median overall survival^c	not reached	not reached	—
Abbreviations: CI, confidence interval; CR, complete response; D-VMP, 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 D-VMP arm than in the VMP arm.
Among other endpoints, in the D-VMP 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).¹
Grade 3/4 infections were more frequent in the D-VMP 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 D-VMP 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 D-VMP arm and 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 D-VMP 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 D-VMP arm and in 16 (4.5%) patients 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 (%)	D-VMP (n=346)		VMP (n=354)
Event, n (%)	Any Grade^a	Grade 3/4^b	Any Grade^a	Grade 3/4^b
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: D-VMP, 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.

Final Analysis of the ALCYONE Study

Mateos et al (2025)² reported the final efficacy and safety analysis results of the ALCYONE study at a median follow-up of 86.7 months.

Results

Patient Characteristics and Disposition

Baseline characteristics were balanced between the D-VMP and VMP treatment groups and are summarized in Table: Baseline Demographics and Patient Characteristics in the ITT Population.¹⁴

Baseline Demographics and Patient Characteristics in the ITT Population^a,¹⁴

Characteristic	D-VMP (n=350)	VMP (n=356)	Total (N=706)
Age
Median (range), years	71 (40-93)	71 (50-91)	71 (40-93)
Distribution, n (%)
<65 years	36 (10)	24 (7)	60 (8)
65-74 years	210 (60)	225 (63)	435 (62)
≥75 years	104 (30)	107 (30)	211 (30)
Sex^b, n (%)
Male	160 (46)	167 (47)	327 (46)
Female	190 (54)	189 (53)	379 (54)
Race^b, n (%)
White	297 (85)	304 (85)	601 (85)
Asian	47 (13)	45 (13)	92 (13)
Black or African American	3 (1)	3 (1)	6 (1)
Other^c	1 (<1)	3 (1)	4 (1)
Unknown/not reported	2 (1)	1 (<1)	3 (<1)
Ethnicity, n (%)
Hispanic or Latino	24 (7)	16 (4)	40 (6)
Not Hispanic or Latino	320 (91)	332 (93)	652 (92)
Unknown/not reported	6 (2)	8 (2)	14 (2)
ECOG performance status^d, n (%)
0	78 (22)	99 (28)	177 (25)
1	182 (52)	173 (49)	355 (50)
2	90 (26)	84 (24)	174 (25)
ISS disease stage^e, n (%)
I	69 (20)	67 (19)	136 (19)
II	139 (40)	160 (45)	299 (42)
III	142 (41)	129 (36)	271 (38)
Cytogenetic risk profile^f n/n (%)
Standard risk	261/314 (83)	257/302 (85)	518/616 (84)
High-risk	53/314 (17)	45/302 (15)	98/616 (16)
Median time since diagnosis of multiple myeloma (range), months	0.76 (0.1-11.4)	0.82 (0.1-25.3)	0.79 (0.1-25.3)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; ITT, intention-to-treat; VMP, bortezomib + melphalan + prednisone. ^aThe ITT population was defined as all patients who were randomized. ^bSex and race were self-reported by patients. ^cPatients reporting multiple races. ^dThe ECOG performance status is scored on a scale from 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability. ^eThe ISS disease stage is based on the combination of serum β₂-microglobulin and albumin levels. Higher stages indicate more advanced disease. ^fCytogenetic risk was assessed by fluorescence in situ hybridisation or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del(17p).

At the final analysis clinical cutoff date of May 31, 2023, the median duration of treatment in the D-VMP vs VMP group was 33.0 months (IQR, 14.5-77.3) vs 12.0 months (IQR, 7.2-12.0), respectively.²
Patient disposition in the ITT population is summarized in Table: Summary of Patient Disposition.²^,¹⁴

Summary of Patient Disposition²^,¹⁴

Parameter	D-VMP (n=350)	VMP (n=356)
Patients treated, n (%)	346 (99)	354 (99)
Patients still on treatment, n (%)	76 (22)	0 (0)
Patients who discontinued treatment, n (%)	270 (78)	118 (33)
Reason for discontinuation
Progressive disease, n (%)	167 (48)	47 (13)
Adverse event, n	32	34
Death, n	28	8
Noncompliance with study drug, n	16	15
Patient withdrawal, n	15	6
Physician decision, n	4	7
Lost to follow-up, n	2	0
Other, n	6	1
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone.

Efficacy

At a median follow-up of 86.7 months (IQR, 28.5-85.2), the median OS in the D-VMP vs VMP group was 83.0 months (95% CI, 72.5-not estimable) vs 53.6 months (95% CI, 46.3-60.9), respectively (HR, 0.65; 95% CI, 0.53-0.80; P<0.0001).²
- Details regarding patients censored for OS are summarized in Table: Summary of Reasons for Censoring of OS in the ITT Population.¹⁴
- A prespecified subgroup analysis of OS indicated a nonsignificant trend favoring
  D-VMP vs VMP group in patients ≥75 years of age and other subgroups with poor prognosis, such as those with renal impairment or ISS stage III disease. Results of prespecified subgroup analyses for OS in the D-VMP and VMP groups are presented in Table: OS in Prespecified Subgroups in the ITT Population.²

Summary of Reasons for Censoring of OS in the ITT Population¹⁴

Parameter, n (%)	D-VMP (n=350)	VMP (n=356)
Patients censored	178 (51)	139 (39)
Reason for censoring
Other	134 (38)	90 (25)
End of data collection	130 (37)	87 (24)
Withdrawal by patient	29 (8)	30 (8)
Lost to follow-up	15 (4)	18 (5)
Physician decision	0	1 (<1)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; OS, overall survival; VMP, bortezomib + melphalan + prednisone.

OS in Prespecified Subgroups in the ITT Population²

Subgroup	D-VMP		VMP		HR (95% CI)
Subgroup	Events/ Patients n/N	Median (95% CI), Months	Events/ Patients n/N	Median (95% CI), Months	HR (95% CI)
All patients	172/350	83.0 (72.5-NE)	217/356	53.6 (46.3-60.9)	0.65 (0.53-0.80)
Sex
Male	84/160	72.7 (60.3-89.1)	99/167	50.7 (42.3-68.5)	0.71 (0.53-0.95)
Female	88/190	89.2 (74.1-NE)	118/189	55.1 (46.9-64.8)	0.60 (0.46-0.79)
Age
<75 years	112/246	89.2 (78.7-NE)	144/249	56.6 (47.7-69.4)	0.62 (0.48-0.79)
≥75 years	60/104	59.1 (50.7-82.7)	73/107	49.7 (39.2-57.5)	0.74 (0.53-1.04)
Race
White	154/297	80.1 (63.6-89.1)	191/304	52.9 (45.7-58.8)	0.67 (0.54-0.83)
Other	18/53	NE (72.7-NE)	26/52	78·1 (39·6–NE)	0·54 (0·29–0·98)
Region
Europe	149/289	81.0 (63.8-89.1)	187/295	53.6 (45.7-58.9)	0.67 (0.54-0.83)
Other	23/61	NE (69·7–NE)	30/61	57·9 (39·6–NE)	‘0·57 (0·33–0·99)
Baseline renal function (CrCl)
>60 mL/min	99/200	85.9 (64.5-NE)	119/211	57.9 (47.9-72.6)	0.72 (0.55-0.94)
≤60 mL/min	73/150	80.1 (63.6-NE)	98/145	48.1 (38.0-56.0)	0.56 (0.41-0.76)
Baseline hepatic function^a
Normal	151/304	82.7 (69.7-NE)	181/304	55.7 (48.1-66.4)	0.68 (0.55-0.85)
Impaired	21/46	85.9 (44.6-NE)	36/52	40.7 (26.5-56.0)	0.49 (0.28-0.84)
ISS disease stage^b
I	19/69	94.4 (94.4-NE)	27/67	NE (67.0-NE)	0.53 (0.29-0.95)
II	68/139	83.0 (59.5-NE)	96/160	61.3 (50.7-78.1)	0.70 (0.51-0.96)
III	85/142	63.6 (52.9-79.2)	94/129	42.3 (36.0-46.9)	0.60 (0.45-0.81)
Type of MM
IgG	105/207	81.0 (62.9-NE)	133/218	58.2 (46.9-69.4)	0.70 (0.54-0.90)
Non-IgG	48/82	72.5 (54.4-85.9)	52/83	46.2 (42.7-56.6)	0.73 (0.49-1.08)
Cytogenetic risk at study entry^c
High-risk	35/53	46.2 (26.7-72.5)	31/45	39.5 (31.6-54.1)	0.91 (0.56-1.47)
Standard risk	122/261	85.9 (78.7-NE)	156/257	55.1 (48.1-66.4)	0.59 (0.47-0.75)
ECOG performance status
0	26/78	NE (83.0-NE)	58/99	53.7 (43.9-75.7)	0.40 (0.25-0.63)
1-2	146/272	72.5 (59.2-85.9)	159/257	52.9 (45.2-58.9)	0.72 (0.58-0.90)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; NE, not estimable; OS, overall survival; ULN, upper limit of normal; VMP, bortezomib + melphalan + prednisone. ^aImpaired baseline hepatic function includes mild (total bilirubin ≤ULN and aspartate aminotransferase >ULN or total bilirubin >ULN but ≤1.5× ULN), moderate (total bilirubin >1.5× ULN but ≤3× ULN), and severe (total bilirubin >3× ULN). ^bThe ISS disease stage is derived based on the combination of serum β₂-microglobulin and albumin concentrations. ^cHigh-risk cytogenetics are defined either by fluorescence in situ hybridization testing: t(4;14), t(14;16), or del(17p); or by karyotype testing: t(4;14) or del(17p).

The MRD-negativity rate (at the 10^-5 and 10^-6 sensitivity levels) was higher in the D-VMP group than in the VMP group. Compared with the VMP group, the D-VMP group had a higher durable MRD-negativity rate (10^-5 sensitivity level) for ≥6 and ≥12 months. The MRD status of the D-VMP and VMP groups is summarized in Table: Summary of MRD-Negativity Rates and Durable MRD-Negativity Rates in the ITT Population.²
In the D-VMP and VMP groups, a longer OS was observed in patients who were MRD-negative (HR, 0.60; 95% CI, 0.31-1.14) than that in patients who were not MRD-negative (HR, 0.77; 95% CI, 0.62-0.95).²

Summary of MRD-Negativity Rates and Durable MRD-Negativity Rates in the ITT Population²

Parameter	D-VMP (n=350)	VMP (n=356)	OR (95% CI)^a,b	P Value^c
MRD-negativity, n (%)
10^-5	99 (28)	25 (7)	5.23 (3.27-8.36)	<0.0001
10^-6	33 (9)	3 (1)	12.96 (3.85-43.57)	<0.0001
Durable MRD-negativity (10^-5)^d, n (%)
≥6 months	56 (16)	16 (4)	4.05 (2.27-7.21)	<0.0001
≥12 months	49 (14)	10 (3)	5.63 (2.80-11.31)	<0.0001
Abbreviations: CI, confidence interval; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; VMP, bortezomib + melphalan + prednisone. ^aMantel-Haenszel estimate of the common OR for stratified tables was used for the MRD status. The stratification factors were as follows: ISS disease stage (I, II, or III), region (Europe vs other), and age (<75 years vs ≥75 years) as randomized. An OR of greater than 1 indicates an advantage for D-VMP. ^bA Mantel-Haenszel estimate of the common OR without stratification was used for the durable MRD status. An OR greater than 1 indicates an advantage for D-VMP. ^cP values were derived from a Fisher’s exact test. ^dDurable MRD-negativity was defined as the absence of MRD confirmed at least 6 or 12 months apart without any instances of MRD-positivity in between the assessments.

In the ITT population, 46% vs 72% of patients in the D-VMP vs VMP group, respectively, were initiated on subsequent antimyeloma therapy or died from progressive disease without subsequent treatment.²
- The median time-to-subsequent antimyeloma therapy in the D-VMP vs VMP group was 66.8 months (95% CI, 47.9-not estimable) vs 25.9 months (95% CI, 23.4-28.6), respectively (HR, 0.37; 95% CI, 0.30-0.46; P<0.0001).²
- Overall, 12 (3%) of 346 patients in the D-VMP group and 93 (26%) of 354 patients in the VMP group received DARZALEX as a subsequent antimyeloma therapy.²
- Details pertaining to subsequent antimyeloma therapies in the safety population are summarized in Table: Summary of the Most Common Subsequent Antimyeloma Therapies in the Safety Population.¹⁴

Summary of the Most Common^a Subsequent Antimyeloma Therapies in the Safety Population²^,¹⁴

Parameter, n (%)	D-VMP (n=346)	VMP (n=354)	Total (N=700)
Patients receiving ≥1 subsequent antimyeloma therapy	150 (43)	243 (69)	393 (56)
Most common first subsequent therapy regimens
Lenalidomide/dexamethasone	47 (14)	77 (22)	124 (18)
Carfilzomib/lenalidomide/dexamethasone	18 (5)	15 (4)	33 (5)
Lenalidomide/dexamethasone/ixazomib	16 (5)	8 (2)	24 (3)
Bortezomib/dexamethasone	7 (2)	3 (1)	10 (1)
Thalidomide/cyclophosphamide/dexamethasone	6 (2)	17 (5)	23 (3)
Bortezomib/cyclophosphamide/dexamethasone	5 (1)	9 (3)	14 (2)
Lenalidomide/dexamethasone/elotuzumab	2 (1)	8 (2)	10 (1)
DARZALEX/lenalidomide/dexamethasone	1 (<1)	25 (7)	26 (4)
DARZALEX/bortezomib/dexamethasone	0	11 (3)	11 (2)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone. ^aMost common defined as ≥2% of patients in either treatment group.

- PFS events on the subsequent line of therapy were reported in 53% vs 67% of patients in the D-VMP vs VMP group, respectively.²
- The median PFS on the next line of therapy in the D-VMP vs VMP group was 66.7 months (95% CI, 58.6-80.1) vs 42.4 months (95% CI, 37.3-47.1), respectively (HR, 0.56; 95% CI, 0.46-0.68; P<0.0001).²

Safety

No new safety concerns were identified with a longer follow-up.
TEAEs were experienced by 98% of patients in the D-VMP group and 97% of patients in the VMP group. The most common TEAEs are summarized in Table: Summary of the Most Common TEAEs.²
- Grade 3 or 4 TEAEs occurred in 83% of patients receiving D-VMP and 77% of patients receiving VMP.²
- The most common grade 3 or 4 infection in both treatment groups was pneumonia (D-VMP, 16%; VMP, 5%).²
- Infusion-related reactions (IRRs) of any grade were reported in 29% of patients in the D-VMP group, including a grade 3 reaction in 4% and a grade 4 reaction in 1% of patients.²
  - In the D-VMP group, IRRs of any grade, grade 3 and serious TEAE were reported in <1% of patients.¹⁴
  - No IRR of any grade was reported in the VMP group.¹⁴
- The D-VMP group experienced a higher rate of serious TEAEs compared to the VMP group (21% vs 16%). The most common serious TEAE observed in D-VMP vs VMP group was pneumonia (5% vs 2%).²
The rate of treatment discontinuation due to TEAEs was 9% in both the D-VMP and VMP groups. TEAEs in both groups are detailed in Table: Summary of Treatment Discontinuation Due to TEAEs.²^,¹⁴

Summary of the Most Common TEAEs²

Event, n (%)	D-VMP (n=346)					VMP (n=354)
Event, n (%)	Any Grade^a	Grade 1-2	Grade 3	Grade 4	Grade 5	Any Grade^a	Grade 1-2	Grade 3	Grade 4	Grade 5
Any TEAEs	338 (98)	47 (14)	184 (53)	77 (22)	30 (9)	342 (97)	65 (18)	180 (51)	77 (22)	20 (6)
Hematologic AE
Neutropenia	175 (51)	35 (10)	107 (31)	33 (10)	0	186 (53)	48 (14)	103 (29)	35 (10)	0
Thrombocytopenia	173 (50)	53 (15)	83 (24)	37 (11)	0	190 (54)	56 (16)	83 (23)	51 (14)	0
Anemia	112 (32)	49 (14)	61 (18)	2 (1)	0	131 (37)	61 (17)	68 (19)	2 (1)	0
Nonhematological AE
Peripheral sensory neuropathy	100 (29)	95 (27)	4 (1)	1 (<1)	0	122 (34)	108 (31)	14 (4)	0	0
Diarrhea	101 (29)	92 (27)	9 (3)	0	0	87 (25)	76 (21)	11 (3)	0	0
Pyrexia	89 (26)	87 (25)	2 (1)	0	0	74 (21)	72 (20)	2 (1)	0	0
Nausea	76 (22)	73 (21)	3 (1)	0	0	76 (21)	72 (20)	4 (1)	0	0
Back pain	73 (21)	65 (19)	8 (2)	0	0	42 (12)	38 (11)	4 (1)	0	0
Cough	71 (21)	70 (20)	1 (<1)	0	0	27 (8)	26 (7)	1 (<1)	0	0
Upper respiratory tract infection	107 (31)	99 (29)	7 (2)	0	1 (<1)	50 (14)	44 (12)	6 (2)	0	0
Bronchitis	77 (22)	66 (19)	11 (3)	0	0	27 (8)	24 (7)	3 (1)	0	0
Pneumonia	78 (23)	19 (5)	53 (15)	4 (1)	2 (1)	19 (5)	3 (1)	15 (4)	1 (<1)	0
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone; AE, adverse event. ^aPreferred terms for any grade of TEAEs with an occurrence of ≥20% are reported.

Summary of Treatment Discontinuation Due to TEAEs²^,¹⁴

TEAEs	D-VMP n=346	VMP n=354
Patients with TEAEs leading to treatment discontinuation, n (%)	31 (9)	33 (9)
TEAEs leading to treatment discontinuation^a, n (%)
Pneumonia	4 (1)	1 (<1)
Upper respiratory tract infection	2 (1)	0
Acute respiratory failure	2 (1)	0
Fatigue	1 (<1)	2 (1)
Peripheral sensory neuropathy	0	6 (2)
Neuralgia	0	2 (1)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intent to treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone; TEAE, treatment-related adverse event. ^aTEAEs leading to treatment discontinuation in at least 2 patients in either treatment group are reported.

The incidence of second primary malignancies in the D-VMP vs VMP group was 8% vs 6%, respectively.²
- The most frequently reported second primary malignancies in the D-VMP vs VMP group were basal cell carcinoma (1.2% vs 0.6%, respectively) and myelodysplastic syndrome (1.2% vs 0.6%, respectively).²^,¹⁴
Deaths due to an adverse event considered related to at least 1 of 4 study treatment components occurred in 5 (1%) of 346 D-VMP patients (due to pneumonia, acute myocardial infarction, neuroendocrine tumor, tumor lysis syndrome, and acute respiratory failure [1 each]) and in 3 (1%) of 354 VMP patients (due to acute myeloid leukemia, pulmonary embolism, and bacterial pneumonia [1 each]).²

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-Item Assessment (EORTC QLQ-C30)

In the D-VMP vs VMP group, respectively, the mean (standard deviation) EORTC QLQ-C30 score in the ITT population was as follows:²
- Global health status (GHS): 50.7 (21.0) vs 52.4 (22.6).
- Pain: 46.3 (33.1) vs 43.1 (31.4).
- Physical functioning: 59.9 (27.0) vs 63.6 (25.6).
The least-squares (LS) mean change in EORTC QLQ-C30 scores from baseline at 3 months in the ITT population is presented in Table: LS Mean Change in EORTC QLQ-C30 Scores From Baseline at 3 Months in the ITT Population.²
Mean (standard deviation) EORTC QLQ-C30 scores in the ITT population with bone lesions at baseline in the D-VMP vs VMP group were as follows: ²
- GHS: 49.9 (21.2) vs 51.2 (22.6).
- Pain: 50.8 (31.3) vs 46.8 (31.7).
- Physical functioning: 58.1 (26.9) vs 61.4 (26.2).
- Both the D-VMP and VMP groups showed a decrease in the pain score in addition to bone lesion and improvement in physical functioning score. LS mean changes in EORTC QLQ-C30 scores from baseline at 3 months in the ITT population with bone lesion and pain symptom score in addition to bone lesion are presented in Table: LS Mean Change in EORTC QLQ-C30 Scores From Baseline at 3 Months in the ITT Population With Bone Lesion and Pain Symptom Score in Addition to Bone Lesion.²^,¹⁴
Completion rates of the EORTC QLQ-30 questionnaires at baseline and at each time point are provided in Table: Compliance With EORTC QLQ-C30 Assessments Over Time in the ITT Population.¹⁴

LS Mean Change in EORTC QLQ-C30 Scores From Baseline at 3 Months in the ITT Population²^,¹⁴

Parameter	LS^a Mean Change (95% CI)
Parameter	D-VMP (n=350)	VMP (n=356)	P Value
Global health status score	7.5 (5.2-9.7)	4.0 (1.7-6.3)	0.0233
Pain score	-13.7 (-16.5 to -10.9)	-10.4 (-13.3 to -7.5)	≥0.05
Physical functioning score	5.4 (3.1-7.7)	4.3 (2.0-6.7).	≥0.05
Abbreviations: CI, confidence interval; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; ISS, International Staging System; ITT, intention-to-treat; LS, least-squares; VMP, bortezomib + melphalan + prednisone. ^aLS means are derived based on the mixed-effects model with repeated measures in which the dependent variable is change from baseline in score and independent variables are baseline, visit, treatment, visit by treatment interaction, and randomization stratification factors (ISS disease stage [I, II, III], region [Europe vs other], and age [<75 years vs ≥75 years]) as fixed effects and individual patient as random effect.

LS Mean Change in EORTC QLQ-C30 ScoresFrom Baseline at 3 Months in the ITT Population With Bone Lesion and Pain Symptom Score in Addition to Bone Lesion²^,¹⁴

Parameter	LS^a Mean Change (95% CI)
Parameter	D-VMP	VMP	PValue
Patients with bone lesion, n	279	273	-
Global health status score	10.4 (8.1-12.7)	7.0 (4.6-9.4)	0.0443
Patients with pain symptom score in addition to bone lesion, n	251	253	-
Pain score	-19.4 (-22.3 to -16.6)	-15.0 (-18.0 to -12.0).	0.0376
Physical functioning score	9.9 (7.5-12.2)	8.1 (5.6-10.5)	≥0.05
Abbreviations: CI, confidence interval; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; ISS, International Staging System; ITT, intention-to-treat; LS, least-squares; VMP, bortezomib + melphalan + prednisone. ^aLS means are derived based on the mixed-effects model with repeated measures in which the dependent variable is change from baseline in score and independent variables are baseline, visit, treatment, visit by treatment interaction, and randomization stratification factors (ISS disease stage [I, II, III], region [Europe vs other], and age [<75 years vs ≥75 years]) as fixed effects and individual patient as random effect.

Compliance With EORTC QLQ-C30 Assessments Over Time in the ITT Population¹⁴

Time Points	D-VMP (n=350)		VMP (n=356)
Time Points	Expected^a	Received, n (%)	Expected^a	Received, n (%)
Baseline	350	317 (90.6)	356	327 (91.9)
Month 3	326	281 (86.2)	324	260 (80.2)
Month 6	317	251 (79.2)	286	221 (77.3)
Month 9	300	241 (80.3)	258	192 (74.4)
Month 12	288	231 (80.2)	243	186 (76.5)
Month 18	253	206 (81.4)	178	127 (71.3)
Month 24	210	160 (76.2)	122	76 (62.3)
Month 30	190	165 (86.8)	84	64 (76.2)
Month 36	168	146 (86.9)	64	44 (68.8)
Month 42	150	126 (84.0)	41	28 (68.3)
Month 48	132	104 (78.8)	34	20 (58.8)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; ITT, intention-to-treat; VMP, bortezomib + melphalan + prednisone. ^aFor the D-VMP group, EORTC QLQ-C30 assessments were expected from all patients who were still on study treatment by the month indicated. For the VMP group, EORTC QLQ-C30 assessments were expected through Month 12 from all patients who were still on study treatment by the month indicated and for Month 18 and beyond from all patients who were on study and had not progressed or received subsequent antimyeloma therapy by the month indicated. Data are shown through Month 48 due to the low number of expected assessments in the VMP group after this time.

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 profile^b
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 Value^a	D-VMP (n=350)	VMP (n=356)	P Value^a
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: D-VMP, 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)
Subgroups	n/N	Median PFS, Months	n/N	Median PFS, Months	HR (95% CI)
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

The baseline characteristics of the ITT and MRD-negative populations are presented in the Table: Demographics and Baseline Characteristics by MRD Durability.
Follow-up median duration was 36.4 months (range: 0.0-49.9).

Demographics and Baseline Characteristics by MRD Durability¹⁵

Characteristic	D-VMP				VMP
	ITT (n=350)	MRD-Negative Patients			ITT (n=356)	MRD-Negative Patients
	ITT (n=350)	At Any Time (n=94)	≥12 Months (n=49)	Not ≥12 Months (n=45)	ITT (n=356)	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 stage^a, 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 profile^b, 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 abnormality^c	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: D-VMP, 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 D-VMP 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; D-VMP, n=350; VMP, n=356)¹⁵:
- MRD negative (10^-5) at ≥1 time point: D-VMP: 87.0% (n=94); VMP: 92.0% (n=25)
- MRD positive: D-VMP: 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)
MRD Negativity (10^-5)	D-VMP	VMP	P Value^a
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; D-VMP, 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 Status¹⁵

PFS2^a	D-VMP 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 = 0.9668^d
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 = 0.0008^d
36-month PFS2 rate, % (95% CI)	67.9 (61.6-73.5)	51.9 (45.9-57.6)
Abbreviations: CI, confidence interval; D-VMP, 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 D-VMP. 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; D-VMP [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 (%)	D-VMP (n=53)	VMP (n=45)	Standardized Difference^a
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%
≥2^b	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 stage^c
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 risk^d
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 impairment^e	22 (41.5)	17 (37.8)	7.6%
Abbreviations: D-VMP, 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)
Study Name	DARZALEX + Control n/N	Control n/N	Adjusted HR (95% CI)
ALCYONE	41/53	36/45	0.73 (0.46-1.14)
MAIA	23/48	28/44	0.57 (0.33-1.00)
Pooled^a	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 Ratio^a (95% CI)	Adjusted OR^b (95% CI)	P Value	Sensitivity Analysis Adjusting For Age
Parameter	DARZALEX + Control (n=101)	Control (n=89)	Relative Response Ratio^a (95% CI)	Adjusted OR^b (95% CI)	P Value	Adjusted OR^c(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 (D-VMP, 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 D-VMP 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 D-VMP vs VMP arm, respectively.¹⁶

Rates of MRD-negativity Status in NDMM⁶

MRD-Negativity (10^-5) Rates in TIE NDMM, n (%)	D-VMP	VMP	P Value^a
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; D-VMP, 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 (D-VMP, n=350; VMP, n=356) were stratified based on frailty status:
- Frail patients (n=315; 44.6%): 163 (46.6%) in the D-VMP arm vs 152 (42.7%) in the VMP arm.
- Non-frail patients (n=391; 55.4%): 187 (53.4%) in the D-VMP arm vs 204 (57.3%) in the VMP arm.
The baseline characteristics based on frailty scores for D-VMP 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-Frail^a						Frail
	Fit (n=122)		Intermediate (n=269)		Total Non-Frail^a (n=391)		Frail (n=315)
	D-VMP (n=48)	VMP (n=74)	D-VMP (n=139)	VMP (n=130)	D-VMP (n=187)	VMP (n=204)	D-VMP (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: D-VMP, 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 D-VMP 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 D-VMP 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 D-VMP 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 D-VMP 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 D-VMP 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 D-VMP arm vs VMP arm across frailty subgroups (ITT population):
- For total non-frail patients, ORR was achieved by 93.0% (n=174) in the D-VMP arm vs 75.0% (n=153) in the VMP arm (P<0.0001).
- For frail patients, ORR was achieved by 88.3% (n=144) patients in the D-VMP arm vs 72.4% (n=110) patients in the VMP arm (P=0.0003).
Improved MRD-negativity (10^-5) rate was observed in the D-VMP 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 D-VMP 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 D-VMP arm vs 7.9% (n=12) in the VMP arm (P<0.0001).

Safety

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).
Treatment discontinuations due to any grade TEAEs across all frailty subgroups are presented in the Table: Most Common TEAEs Leading to Treatment Discontinuation (>1 Patient) and an Outcome of Death in the Safety Population (ALCYONE).

Most Common Grade 3/4 (≥10%) TEAEs in the Safety Population (ALCYONE)⁷

Event, n (%)	Total Non-Frail^a (n=389)		Frail (n=311)
Event, n (%)	D-VMP (n=186)	VMP (n=203)	D-VMP (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: D-VMP, 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^,¹⁷

Event, n (%)	Total Non-Frail^a (n=389)		Frail (n=311)
Event, n (%)	D-VMP (n=186)	VMP (n=203)	D-VMP (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: D-VMP, 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 D-VMP on PROs in the ALCYONE study. HRQoL scores were assessed by the EORTC QLQ-C30 and the EuroQol 5-dimensional descriptive system (EQ-5D-5L).

Results

The ITT population was the primary analysis population (D-VMP, 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:
- D-VMP: 90.6% and 90.3%
- VMP: 91.9% and 91.3%
Compliance remained high (>76%) throughout the study.
At month 3, LS mean change in GHS score from baseline was 7.3 vs 3.9 for D-VMP 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 D-VMP at all time points for physical functioning and at most time points for role functioning, cognitive functioning, and social functioning.
- Point estimates generally favored D-VMP 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 D-VMP group for all scales.

Least Squares Mean Change in EORTC QLQ-C30 GHS Score from Baseline⁸

Time Point (Month)	Least Squares Mean Change
Time Point (Month)	D-VMP	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: D-VMP, 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 D-VMP 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 D-VMP 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 (%)
Time Point (Month)	D-VMP	VMP	D-VMP	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: D-VMP, 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 D-VMP group continued to receive DARZALEX therapy.

Efficacy

Median duration of follow-up was 40.1 months.
More patients achieved deeper responses with D-VMP, which led to better outcomes of PFS, time to next therapy (subsequent antimyeloma therapy), and OS; for these patients, clinically meaningful improvements in GHS, 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 (D-VMP and VMP patients), EORTC QLQ-C30 GHS improved with deepening responses from months 3 to 12.

Efficacy by Response Status⁹

Response Category	D-VMP (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; D-VMP, 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 Improvements^a in EORTC QLQ-C30 Scales at Month 12 by Response Status⁹

Response Category, n (%)	D-VMP (n=350)	VMP (n=356)	Odds Ratio (95% CI)^b
PR	63 (18.0)	86 (24.2)
EORTC QLQ-C30 scales^c
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; D-VMP, 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 D-VMP. ^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 (D-VMP, n=104; VMP, n=107):
- Median duration of study treatment: 14.5 months D-VMP vs 12.0 months VMP
Among patients aged <75 years (D-VMP, n=246; VMP, n=249):
- Median duration of study treatment: 15.0 months D-VMP vs 12.0 months VMP
Among patients aged <75 years:
- Median duration of study treatment: 15.0 months D-VMP 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 D-VMP vs 18.1 months VMP (HR, 0.50; 95% CI, 0.38-0.65; P<0.001)
- ≥75 years: not reached D-VMP vs 20.4 months VMP (HR, 0.53; 95% CI, 0.32-0.85)
- <75 years: not reached D-VMP vs 17.9 months VMP (HR, 0.49; 95% CI, 0.36-0.68)
MRD negativity rates (10^-5 sensitivity threshold):
- Overall population: 22% D-VMP (n=350) vs 6% VMP (n=356) (P<0.0001)
- ≥75 years: 24% D-VMP (n=104) vs 8% VMP (n=107) (P=0.0011)
- <75 years: 22% D-VMP (n=246) vs 6% VMP (n=249) (P<0.0001)

Response Rates and Characteristics in ALCYONE¹⁰

Response characteristic: ALCYONE	ITT		<75 Years		≥75 Years
Response characteristic: ALCYONE	D-VMP (n=350)	VMP (n=356)	D-VMP (n=246)	VMP (n=249)	D-VMP (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 response^a, 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: D-VMP, 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

The most common all-grade TEAEs and TEAEs of interest are presented in Table: Most Common All-grade TEAEs and TEAEs of Interest Among Elderly Patients in ALCYONE.
The most common grade 3/4 TEAEs and grade 3/4 TEAEs of interest are presented in Table: Most Common Grade 3/4 TEAEs and Grade 3/4 TEAEs of Interest Among Elderly Patients in ALCYONE.
In the D-VMP arm, IRRs were reported by 36% (9% grade 3/4) of patients aged ≥75 years and 24% (3% grade 3/4) of patients aged <75 years; most occurred during the first infusion.
Among patients aged ≥75 years, second primary malignancies were reported in 6 D-VMP patients and 2 VMP patients.
Among patients aged <75 years, second primary malignancies were reported in 2 D-VMP patients and 7 VMP patients.

Most Common All-grade TEAEs and TEAEs of Interest Among Elderly Patients in ALCYONE¹⁰

All-grade TEAEs: ALCYONE	Overall Population^a		<75 Years		≥75 Years
All-grade TEAEs: ALCYONE	D-VMP (n=346)	VMP (n=354)	D-VMP (n=244)	VMP (n=248)	D-VMP (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
Infections^b	67	48	64	46	73	52
Abbreviations: D-VMP, 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 Population^a		<75 Years		≥75 Years
Grade 3/4 TEAEs: ALCYONE	D-VMP (n=346)	VMP (n=354)	D-VMP (n=244)	VMP (n=248)	D-VMP (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
Infections^b	23	15	21	13	28	20
Abbreviations: D-VMP, 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 D-VMP from the ALCYONE study.

Study Design/Methods

Baseline Characteristics¹¹

Characteristic	Baseline CrCl ≤60 mL/min		Baseline CrCl >60 mL/min
Characteristic	D-VMP (n=150)	VMP (n=145)	D-VMP (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 profile^c
N	127	124	187	178
Standard risk, %	83	86	83	84
High risk, %	17	14	17	16
Abbreviations: CrCl, creatinine clearance; D-VMP, 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 D-VMP vs 12.0 months with VMP
- CrCl >60 mL/min: 14.5 months with D-VMP vs 12.0 months with VMP
Median cumulative dose of bortezomib:
- CrCl ≤60 mL/min: 45.7 mg/m² with D-VMP vs 41.2 mg/m² with VMP
- CrCl >60 mL/min: 48.1 mg/m² with D-VMP vs 42.7 mg/m² with VMP
Overall treatment discontinuations by the end of cycle 9:
- CrCl ≤60 mL/min: 18% with D-VMP vs 41% with VMP
- CrCl >60 mL/min: 21% with D-VMP vs 28% with VMP
- Treatment discontinuations due to progressive disease:
  - CrCl ≤60 mL/min: 4% with D-VMP vs 15% with VMP
  - CrCl >60 mL/min: 9% with D-VMP vs 12% with VMP
- Treatment discontinuations due to AEs:
  - CrCl ≤60 mL/min: 6% with D-VMP vs 12% with VMP
  - CrCl >60 mL/min: 4% with D-VMP vs 8% with VMP

Efficacy

Response rates and characteristics are presented in Table: Response Rates and Characteristics With D-VMP Versus VMP by Renal Function Subgroup.
In the ITT population, D-VMP reduced the risk of disease progression or death by 50% (median PFS: D-VMP, 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 D-VMP vs 16.9 months with VMP (HR, 0.36; 95% CI, 0.24-0.56)
- CrCl >60 mL/min: not reached with D-VMP 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 D-VMP vs 48% with VMP
- CrCl >60 mL/min: 66% with D-VMP vs 52% with VMP
The MRD-negativity rate (10^-5 sensitivity threshold) was increased with D-VMP 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 D-VMP Versus VMP by Renal Function Subgroup¹¹

Response characteristic	ITT		Baseline CrCl ≤60 mL/min		Baseline CrCl >60 mL/min
Response characteristic	D-VMP (n=350)	VMP (n=356)	D-VMP (n=150)	VMP (n=145)	D-VMP (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 ≥CR^a, 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: D-VMP, 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

Incidences of the most common (≥25%) all-grade TEAEs, along with TEAEs of interest (peripheral sensory neuropathy and infections) are presented in Table: Most Common (≥25%) All-grade TEAEs and Incidences of Peripheral Sensory Neuropathy and Infections.
Incidences of the most common (≥10%) grade 3/4 TEAEs, along with TEAEs of interest (peripheral sensory neuropathy and infections) are presented in Table: Most Common (≥10%) Grade 3/4 TEAEs and Incidences of Peripheral Sensory Neuropathy and Infections.
In the D-VMP arm, IRRs were observed in 27% (5% grade 3/4) of patients with baseline CrCl ≤60 mL/min and 29% (5% grade 3/4) of patients with CrCl >60 mL/min. Most IRRs occurred during the first infusion.
In the CrCl ≤60 mL/min subgroup, second primary malignancies occurred in 4 patients in the D-VMP arm and in 4 patients in the VMP arm. In the CrCl >60 mL/min subgroup, secondary primary malignancies occurred in 4 patients in the D-VMP arm and in 5 patients in the VMP arm.

Most Common (≥25%) All-grade TEAEs and Incidences of Peripheral Sensory Neuropathy and Infections¹¹

All-grade TEAEs	Overall population^a		Baseline CrCl ≤60 mL/min^a		Baseline CrCl >60 mL/min^a
All-grade TEAEs	D-VMP (n=346)	VMP (n=354)	D-VMP (n=146)	VMP (n=144)	D-VMP (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; D-VMP, 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 population^a		Baseline CrCl ≤60 mL/min^a		Baseline CrCl >60 mL/min^a
Grade 3/4 TEAEs	D-VMP (n=346)	VMP (n=354)	D-VMP (n=102)	VMP (n=106)	D-VMP (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; D-VMP, 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
04 June 2025.

References

Show

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