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(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO - MMY2040 (PLEIADES) Study

Last Updated: 07/31/2024

SUMMARY

PLEIADES (MMY2040) is an ongoing, non-randomized, open-label, multicenter, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care treatment regimens in patients with MM. Specifically with¹^-⁶:
- Transplant-eligible newly diagnosed multiple myeloma (NDMM):
- DARZALEX FASPRO in combination with VRd (D-VRd) for patients with transplant-eligible NDMM (n=67).
- Transplant-ineligible NDMM:
  - DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP) for patients with transplant-ineligible NDMM (n=67).
- Relapsed refractory multiple myeloma (RRMM):
  - DARZALEX FASPRO in combination with lenalidomide and dexamethasone (D-Rd) for patients with RRMM with ≥1 prior line of therapy (n=65).
  - DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd) in patients with RRMM with 1 prior line of therapy (n=66).
Moreau et al (2020)¹ presented (at the 62nd American Society of Hematology [ASH] Annual Meeting & Exposition) the safety and efficacy results of the PLEIADES study with a median follow-up of 9.2 months for D-Kd (primary analysis), 25.7 months for D-Rd, and 25.2 months for D-VMP (updated analysis). The overall response rate (ORR) was 84.8% for D-Kd, 93.8% for D-Rd, and 89.6% for D-VMP. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 71%, 94%, and 78% in the D-Kd, D-Rd, and D-VMP cohorts, respectively.
Chari et al (2021)² presented the safety and efficacy results of the PLEIADES study at a median follow-up of 3.9 months for D-VRd (primary analysis), 14.3 months for D-VMP, and 14.7 months for D-Rd (updated analysis). The ORR was 97.0% for D-VRd, 89.6% for D-VMP, and 93.8% for D-Rd. The rate of very good partial response or better (≥VGPR) was 71.6% for D-VRd, 77.6% for D-VMP, and 78.5% for D-Rd. Grade 3/4 TEAEs occurred in 58.2%, 74.6%, and 89.2% of patients in the D-VRd, D-VMP, and DRd cohorts, respectively.
Moreau et al (2023)⁶ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies at a median follow-up of 12.4 and 23.7 months, respectively. In the PLEIADES study, in the overall population and the lenalidomide-refractory population, the ORR was 84.8% and 84.1%, and the rate of ≥VGPR was 77.3% and 72.7%, respectively. Grade 3/4 TEAEs occurred in 74.2% of patients in the PLEIADES study.

CLINICAL DATA

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, nonrandomized, open-label, multicenter, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM.¹^-⁵ Moreau et al (2020)¹ presented updated safety and efficacy results of the D-Kd, D-Rd, and D-VMP arms in the PLEIADES study. Chari et al (2021)² presented updated safety and efficacy results of the D-VRd, D-VMP, and D-Rd arms in the PLEIADES study.³^-⁵ Moreau et al (2023)⁶ reported the final results from the D-Kd arm of the PLEIADES study.

Study Design

The study design has been presented in the Figure: PLEIADES Study Design.

PLEIADES Study Design¹^-⁵

Abbreviations: CR, complete response; C_max, maximum observed serum concentration; C_min, minimum observed serum concentration; CD38, cluster of differentiation 38; d, dexamethasone; D, daratumumab and hyaluronidase; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; IMWG, International Myeloma Working Group; IRR, infusion-related reaction; IV, intravenously; K, carfilzomib; M, melphalan; MM, multiple myeloma; M-protein, monoclonal paraprotein; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; P, prednisone; PD, progressive disease; PO, orally; QW, weekly; R, lenalidomide; RRMM, relapsed or refractory multiple myeloma; SC, subcutaneously; V, bortezomib; VGPR, very good partial response.
^aDefined by serum M-protein level ≥1.0 g/dL; or urine M-protein level ≥200 mg/24 hours; or light chain MM for patients without measurable disease in the serum or urine: serum Ig FLC ≥10 mg/dL; and abnormal FLC ratio.

Moreau et al (2020)¹ presented updated safety and efficacy results of the D-Kd, D-Rd, and D-VMP arms in the PLEIADES study.

Results: D-Kd, D-Rd, and D-VMP

Patient and Treatment Characteristics

The baseline patient demographics and disease characteristics are presented in the Table: Baseline Demographics and Patient Characteristics.
Patient disposition data is presented in the Table: Patient Disposition and drug exposure data is presented in the Table: Patient Drug Exposure.

Baseline Demographics and Patient Characteristics^a,¹

Characteristics	D-Kd (n=66)	D-Rd (n=65)	D-VMP (n=67)
Characteristics	RRMM with 1 prior line of therapy	RRMM with ≥1 prior line of therapy	Transplant-ineligible NDMM
Age, years
Median (range)	61 (42-84)	69 (33-82)	75 (66-86)
18 to <65, n (%)	39 (59)	22 (34)	0 (0)
65 to <75, n (%)	23 (35)	29 (45)	33 (49)
≥75, n (%)	4 (6)	14 (22)	34 (51)
Male, n (%)	34 (52)	45 (69)	31 (46)
Body weight, median (range), kg	74 (48-114)	81 (54-143)	66 (45-100)
Race, n (%)
White	48 (73)	45 (69)	46 (69)
ECOG PS score, n (%)
0	40 (61)	36 (55)	25 (37)
1	23 (35)	29 (45)	38 (57)
2	3 (5)	0 (0)	4 (6)
ISS disease stage, n (%)
n	66	64	67
I	45 (68)	27 (42)	22 (33)
II	12 (18)	19 (30)	30 (45)
III	9 (14)	18 (28)	15 (22)
Time since initial diagnosis, median (range), months	32.3 (6.9-132.2)	35.0 (3.6-384.5)	1.2 (0.5-5.3)
Prior ASCT, n (%)	52 (79)	34 (52)	-
Prior lines of therapy, median (range)	1 (1-1)	1 (1-5)	-
Refractory to, n (%)
Last prior line of therapy	41 (62)	20 (31)	-
PI and IMiD	9 (14)	1 (2)	-
Lenalidomide	41 (62)	-	-
Bone marrow % plasma cells, n (%)
n	65	65	67
<10	21 (32)	15 (23)	3 (5)
10-30	23 (35)	28 (43)	31 (46)
>30	21 (32)	22 (34)	33 (49)
Cytogenetic profile^c
n	44	31	41
Standard risk, n (%)	28 (64)	20 (65)	33 (81)
High risk, n (%)	16 (36)	11 (36)	8 (20)
t(4;14)	9 (20)	6 (19)	2 (5)
t(14;16)	9 (20)	3 (10)	2 (5)
del17p	2 (5)	4 (13)	4 (10)
Abbreviations: ASCT, autologous stem cell transplant; D-Kd, DARZALEX FASPRO + carfilzomib + dexamethasone; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; IMiD, immunomodulatory drug; ISS, International Staging System; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; RRMM, relapsed or refractory multiple myeloma. ^aAll-treated population, defined as patients who received ≥1 dose of study treatment. ^bBased on the combination of serum β2-microglobulin and albumin. ^cBased on fluorescence in situ hybridization/karyotype testing.

Patient Disposition^a,¹

n (%)	D-Kd (n=66)	D-Rd (n=65)	D-VMP (n=67)
n (%)	RRMM with 1 prior line of therapy	RRMM with ≥1 prior line of therapy	Transplant-ineligible NDMM
Patients who are still on treatment	41 (62)	41 (63)	42 (63)
Patients who discontinued treatment	25 (38)	24 (37)	25 (37)
Reason for discontinuation
Progressive disease	19 (29)	13 (20)	16 (24)
Patient withdrawal	2 (3)	2 (3)	2 (3)
Death	2 (3)	1 (2)	2 (3)
Adverse event	1 (2)	7 (11)	4 (6)
Other	1 (2)	0 (0)	0 (0)
Protocol deviation	0 (0)	1 (2)	0 (0)
Physician decision	0 (0)	0 (0)	1 (1)
Abbreviations: D-Kd, DARZALEX FASPRO + carfilzomib + dexamethasone; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma. ^aAll-treated population, defined as patients who received ≥1 dose of study treatment.

Patient Drug Exposure^a,¹

Parameter	D-Kd (n=66)	D-Rd (n=65)	D-VMP (n=67)
Parameter	RRMM with 1 prior line of therapy	RRMM with ≥1 prior line of therapy	Transplant-ineligible NDMM
Median (range) number of treatment cycles	9.0 (1-19)	27.0 (1-31)	23.0 (1-26)
Median (range) duration of treatment, months	8.3 (0-17)	25.6 (0-28)	24.9 (0-28)
Relative dose intensity, median %
Daratumumab	100.0	100.0	100.0
Carfilzomib	95.2	-	-
Dexamethasone^b	89.5	59.7	-
Lenalidomide	-	77.8	-
Bortezomib	-	-	95.2
Melphalan	-	-	97.5
Prednisone	-	-	98.0
Abbreviations: COVID-19, coronavirus disease 2019; D-Kd, DARZALEX FASPRO + carfilzomib + dexamethasone; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma;. ^aAll-treated population, defined as patients who received ≥1 dose of study treatment. ^bDexamethasone dose intensity was affected by dose modifications due to the COVID-19 pandemic.

Efficacy

Median duration of follow-up was 9.2 months (primary analysis), 25.7 months, and 25.2 months for D-Kd, D-Rd, and D-VMP cohorts, respectively.
Response rates were similar to DARZALEX studies in CANDOR⁷^,⁸, POLLUX⁹, and ALCYONE¹⁰.
- In the D-Kd cohort (n=66):
  - ORR was 84.8% vs 84% in the CANDOR study⁷^,⁸
  - Stringent complete response (sCR) was 16.7% vs 0%
  - Complete response (CR) was 21.2% vs 28.5%
  - VGPR was 39.4% vs 40.7%
  - Partial response (PR) was 7.6% vs 15.1%
- In the D-Rd cohort (n=65):
  - ORR was 93.8% vs 92.9% in the POLLUX study⁹
  - sCR was 23.1% vs 29.5%
  - CR was 26.2% vs 28.1%
  - VGPR was 30.8% versus 23.5%
  - PR was 13.8% vs 11.7%
- In the D-VMP cohort (n=67):
  - ORR was 89.6% vs 90.9% in the ALCYONE study¹⁰
  - sCR was 31.3% vs 23.1%
  - CR was 23.9% vs 22.6%
  - VGPR was 22.4% vs 27.1%
  - PR was 11.9% vs 18.0%
Minimal residual disease (MRD)-negativity rates were evaluated via next-generation sequencing (NGS) at a sensitivity threshold of 10^-5.
- MRD-negativity rates were 24.2% in the D-Kd cohort, 20.0% in the D-Rd cohort, and 25.4% in the D-VMP cohort.
- MRD-negative ≥CR rates were 21.2% in the D-Kd cohort, 20.0% in the D-Rd cohort, and 25.4% in the D-VMP cohort.

Safety

A summary of TEAEs reported in each cohort is presented in the Table: Summary of TEAEs.
Cardiac toxicities were infrequent (<5%) in all cohorts.
Most patients with infusion-related reactions (IRRs) experienced them on the first administration (D-Kd, 100%; DRd, 100%; D-VMP, 83%).
IRRs were mild (grade 1/2); 2 patients in the D-Kd cohort had a grade 3 IRR, and no patients reported grade 4 IRR.
Median (range) time to onset of IRRs was 65 (4-75) minutes, 330 (254-330) minutes, and 411 (121-534) minutes in the D-Kd, D-Rd, and D-VMP cohorts, respectively.
Across all 3 cohorts, local injection-site reactions (ISRs) occurred in 6% (11/198) of patients (all grade 1/2).

Summary of TEAEs^a,¹

n (%)	D-Kd (n=66)	D-Rd (n=65)	D-VMP (n=67)
n (%)	RRMM with 1 prior line of therapy	RRMM with ≥1 prior line of therapy	Transplant-ineligible NDMM
Any-grade TEAE	66 (100)	65 (100)	67 (100)
Grade 3/4 TEAE	47 (71)	61 (94)	52 (78)
Most common (≥5% in any cohort)
Hypertension	14 (21)	8 (12)	6 (9)
Thrombocytopenia	13 (20)	9 (14)	30 (45)
Lymphopenia	8 (12)	7 (11)	15 (22)
Anemia	7 (11)	6 (9)	13 (19)
Neutropenia	7 (11)	36 (55)	25 (37)
Insomnia	4 (6)	3 (5)	2 (3)
Pneumonia	2 (3)	10 (15)	5 (7)
Leukopenia	2 (3)	6 (9)	4 (6)
Hyperglycemia	1 (2)	6 (9)	1 (1)
Hypokalemia	0	4 (6)	2 (3)
Diarrhea	0	4 (6)	2 (3)
Lower respiratory tract infection	0	4 (6)	0
Grade 5 TEAEs	2 (3)	2 (3)	3 (4)
Serious TEAEs	18 (27)	36 (55)	30 (45)
TEAEs leading to treatment discontinuation^b	1 (2)	6 (9)	4 (6)
Any grade IRR	3 (5)	3 (5)	6 (9)
Abbreviations: D-Kd, DARZALEX FASPRO + carfilzomib + dexamethasone; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; IRR, infusion-related reaction; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma; TEAE, treatment-emergent adverse event. ^aAll-treated population, defined as patients who received ≥1 dose of study treatment. ^bD-Kd cohort: fatigue (n=1); D-Rd cohort: pneumonia (n=2), diverticulitis (n=1), Enterobacter infection (n=1), myocardial infarction (n=1), and face edema (n=1); D-VMP cohort: neutropenic sepsis (n=1), hepatic neoplasm (n=1), cognitive disorder (n=1), and pneumonitis (n=1).

Chari et al (2021)² presented updated safety and efficacy results of the D-VRd, D-VMP, and D-Rd arms in the PLEIADES study.³^-⁵

Results: D-VRd, D-VMP, and D-Rd

Patient and Treatment Characteristics

The baseline patient demographics and disease characteristics are summarized in the Table: Baseline Demographics and Patient Characteristics.
Patient disposition and exposure data are summarized in the Table: Patient Disposition and Exposure.

Baseline Demographics and Patient Characteristics²

Characteristic	Transplant-eligible NDMM	Transplant-ineligible NDMM	RRMM with ≥ 1 prior line of therapy
Characteristic	D-VRd (n=67)	D-VMP (n=67)	D-Rd (n=65)
Age, years
Median (range)	59 (33-76)	75 (66-86)	69 (33-82)
18 to <65, n (%)	54 (80.6)	0 (0)	22 (33.8)
65 to <75, n (%)	12 (17.9)	33 (49.3)	29 (44.6)
≥75, n (%)	1 (1.5)	34 (50.7)	14 (21.5)
Male, n (%)	48 (71.6)	31 (46.3)	45 (69.2)
Median (range) body weight, kg	77 (43-148)	66 (45-100)	80.6 (54-143)
Race, n (%)
White	38 (56.7)	46 (68.7)	45 (69.2)
Black or African American	5 (7.5)	1 (1.5)	2 (3.1)
Asian	0 (0)	5 (7.5)	0 (0)
ECOG PS score, n (%)
0	40 (59.7)	25 (37.3)	36 (55.4)
1	26 (38.8)	38 (56.7)	29 (44.6)
2	1 (1.5)	4 (6)	0
Median (range) number of prior lines of therapy, n	N/A	N/A	1 (1-5)
ISS staging^b,n (%)
I	30 (44.8)	22 (32.8)	27 (41.5)
II	23 (34.3)	30 (44.8)	19 (29.2)
III	14 (20.9)	15 (22.4)	18 (27.7)
Cytogenetic risk^c,d
n	53	41	31
Standard risk, n (%)	40 (75.5)	33 (80.5)	20 (64.5)
High risk, n (%)	13 (24.5)	8 (19.5)	11 (35.5)
t(4;14)	9 (17.0)	2 (4.9)	6 (19.4)
t(14;16)	1 (1.9)	2 (4.9)	3 (9.7)
del17p	5 (9.4)	4 (9.8)	4 (12.9)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; D-VRd, DARZALEX FASPRO + lenalidomide + bortezomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, international staging system; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma. ^aAll-treated population, defined as patients who received ≥1 dose of study treatment.^bBased on the combination of serum β2-microglobulin and albumin at screening.^cBased on fluorescence in situ hybridization or karyotyping testing conducted locally. ^dHigh cytogenetic risk was defined as having ≥1 of t(4;14), t(14;16) or del17p abnormalities.

Patient Disposition and Exposure^a,²

Parameter	Transplant-eligible NDMM	Transplant-ineligible NDMM	RRMM with ≥ 1 prior line of therapy
Parameter	D-VRd (n=67)	D-VMP (n=67)	D-Rd (n=65)
Median (range) # of treatment cycles	4 (1-4)	12 (1-14)	16 (1-19)
Median (range) duration of treatment, months	2.6 (0-4)	14.3 (0-17)	14.9 (0-17)
Relative dose intensity, median %
DARZALEX FASPRO	100	100	100
Bortezomib	97.9	95.2	-
Melphalan	-	97.5	-
Prednisone	-	98.4	-
Lenalidomide	100	-	81.9
Dexamethasone	100	-	65.6
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; D-VRd, DARZALEX FASPRO + lenalidomide + bortezomib + dexamethasone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma. ^aThe all-treatedpopulation included all patients who received ≥1 dose of study treatment.

Efficacy

The pre-specified primary analysis with a median follow-up was 3.9 months, 6.9 months, and 7.1 months for D-VRd, D-VMP, and D-Rd cohorts, respectively.
At a subsequent clinical cut-off, the median duration of follow-up was 14.3 months, and 14.7 months for D-VMP, and D-Rd cohorts respectively.
Primary endpoints were met for all 3 cohorts with available data and response rates were similar to DARZALEX studies in GRIFFIN¹¹, ALCYONE¹², and POLLUX¹³.
- In the D-VRd cohort (n=67):
  - ORR was 97% vs 98%
  - ≥VGPR was 71.6% vs 71.7% in the GRIFFIN study¹¹
  - PR was 25.4% vs 26.3%
  - CR was 7.5% vs 12.1%
  - sCR was 9% vs 7.1%
- In the D-VMP cohort (n=67):
  - ORR was 89.6% vs 90.9% in the ALCYONE study¹²
  - VGPR was 29.9% vs 28.6%
  - PR was 11.9% vs 19.7%
  - CR was 28.4% vs 18%
  - sCR was 19.4% vs 24.6%
- In the D-Rd cohort (n=65):
  - ORR was 93.8% vs 92.9% in the POLLUX study¹³
  - VGPR was 40% vs 32.7%
  - PR was 15.4% vs 17.1%
  - CR was 20% vs 24.9%
  - sCR was 18.5% vs 18.1%
MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10^-5.
- MRD-negativity rates were 16.4% (90% confidence interval [CI], 9.4-25.7) in the DVMP cohort and 15.4% (90% CI, 8.6-24.7) in the D-Rd cohort.

Pharmacokinetics

Overall, the trough serum concentrations (C_trough) and immunogenicity values were consistent with historical DARZALEX data.
Maximum serum concentration (C_max) after the 1^st dose was:
- D-VRd: 100 ± 48.5 µg/mL
- D-VMP: 98.6 ±51.6 µg/mL
- D-Rd: 108 ± 49.9 µg/mL
Eleven patients developed antibodies against recombinant human hyaluronidase (rHuPh20; all were non-neutralizing).
No patients developed anti-daratumumab antibodies.

Safety

Treatment discontinuation due to TEAEs were 2% in the D-VRd arm, 5% in the D-VMP arm and 8% in the D-Rd arm.
A summary of TEAEs reported in each cohort is presented in the Table: Safety Summary.

Safety Summary²

Event, n (%)	Transplant-eligible NDMM	Transplant-ineligible NDMM	RRMM with ≥ 1 prior line of therapy
Event, n (%)	D-VRd (n=67)	D-VMP (n=67)	D-Rd (n=65)
Any TEAE	67 (100)	67 (100)	65 (100)
Serious	19 (28.4)	28 (41.8)	34 (52.3)
Grade 3/4	39 (58.2)	50 (74.6)	58 (89.2)
Grade 5	1 (1.5)	2 (3.0)	2 (3.1)
TEAEs leading to treatment discontinuation	1 (1.5)	3 (4.5)	5 (7.7)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; D-VRd, DARZALEX FASPRO + lenalidomide + bortezomib + dexamethasone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed or refractory multiple myeloma; TEAE, treatment-emergent adverse event.

Across all 3 cohorts with available data any grade IRRs occurred in 7.5% (15/199) of patients.
- IRRs were mild (grade 1/2), one patient had grade 3 IRR and no patients reported grade 4 IRR.
Median time to onset of IRRs was 4.4 hours, 6.9 hours, and 5.5 hours in the D-VRd, DVMP, and D-Rd cohorts, respectively.
Across all 3 cohorts with available data local ISRs occurred in 7.5% (15/199) of patient (all grade 1/2).
A summary of most common TEAEs is in the Table: Most Common Grade 3/4 TEAEs (≥ 5% in any cohorts).

Most common Grade 3/4 TEAEs (≥5% in any cohorts)^a,²

Event, n (%)	Transplant-eligible NDMM	Transplant-ineligible NDMM	RRMM with ≥ 1 prior line of therapy
Event, n (%)	D-VRd (n=67)	D-VMP (n=67)	D-Rd (n=65)
Hematologic
Neutropenia	19 (28.4)	25 (37.3)	32 (49.2)
Lymphopenia	11 (16.4)	15 (22.4)	7 (10.8)
Thrombocytopenia	10 (14.9)	29 (43.3)	9 (13.8)
Leukopenia	5 (7.5)	4 (6)	6 (9.2)
Anemia	3 (4.5)	12 (17.9)	6 (9.2)
Non-hematologic
Pneumonia	2 (3)	5 (7.5)	8 (12.3)
Hypertension	1 (1.5)	6 (9)	1 (1.5)
Hyperglycemia	1 (1.5)	1 (1.5)	6 (9.2)
Hypokalemia	0 (0)	2 (3)	4 (6.2)
Any-Grade IRR	6 (9.0)	6 (9.0)	3 (4.6)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide +dexamethasone; IRR, infusion-related reaction; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/refractory multiple myeloma; TEAE, treatment-emergent adverse event. ^aThe all-treatedpopulation included all patients who received ≥1 dose of study treatment.

Moreau et al (2023)⁶ reported the final results from the D-Kd arm of the PLEIADES and EQUULEUS studies. Results specific to the D-Kd arm of the PLEIADES study have been summarized below.

Results: D-Kd

Patient and Treatment Characteristics

Overall, 66 patients received D-Kd in the PLEIADES study.
The median duration of follow-up was 12.4 months (range, 0.2-20.6).
The baseline patient demographics and disease characteristics of the D-Kd arm has been previously reported by Moreau et al (2020) and are summarized in the Table: Baseline Demographics and Patient Characteristics.
The median duration of treatment was 12 months (range, 0-21) and the median number of D-Kd cycles received was 13.0 (range, 1-23).¹⁴
In total, 31 (47%) patients discontinued treatment due to progressive disease (24 [36.4%]), death (3 [4.5%], including 1 due to coronavirus disease 2019 [COVID19]), patient withdrawal (2 [3.0%]), adverse events (AEs; 1 [1.5%]), and other reasons (1 [1.5%]).¹⁴

Efficacy

Response outcomes in patients receiving D-Kd are summarized below:
- All patients in the D-Kd arm (n=66):
  - ORR was 84.8%
  - ≥VGPR rate was 77.3%
  - ≥CR rate was 42.4%
  - ≥sCR rate was 19.7%
  - CR rate was 22.7%
  - VGPR rate was 34.8%
  - PR rate was 7.6%
- Lenalidomide-refractory patients (n=44):
  - ORR was 84.1%
  - ≥VGPR rate was 72.7%
  - ≥CR rate was 36.4%
  - sCR rate was 18.2%
  - CR rate was 18.2%
  - VGPR rate was 36.4%
  - PR rate was 11.4%
- Patients with high cytogenetic risk (n=16):
  - ORR was 75.0%
- Patients with standard cytogenetic risk (n=28):
  - ORR was 82.1%
The median duration of response was not reached.
The 9-month response rate was 85.4%.
Progression-free survival (PFS) and overall survival (OS) were not analyzed.

Safety

The most common TEAEs are summarized in the Table: Most Common Any-Grade (≥25%) and Grade 3/4 (≥5%) TEAEs.
Grade 3/4 infections were reported in 9 (13.6%) patients, the most common being pneumonia (4.5%).
Grade 3/4 cardiac TEAEs were reported in 2 (3.0%) patients (grade 3 cardiac failure and grade 4 left ventricular dysfunction; 1 patient each).
Serious TEAEs were reported in 22 (33.3%) patients, the most common being pneumonia (4.5%).
Treatment was discontinued in 1 patient due to a TEAE.
Grade 5 TEAEs were reported in 3 patients (COVID-19 pneumonia, sepsis, and respiratory failure; 1 patient each).
IRRs were reported in 3 (4.5%) patients, of whom 2 patients experienced grade 3 IRR.
All IRRs occurred during the first administration and the median time to onset was 65 minutes (range, 4-75).
Local ISRs (all of grade 1/2) were reported in 7 (10.6%) patients.
No patient tested positive for anti-daratumumab antibodies in the immunogenicity evaluable population. Treatment-emergent anti-rHuPH20 antibodies were reported in 3 (4.7%) patients; none were neutralizing.

Most Common Any-Grade (≥25%) and Grade 3/4 (≥5%) TEAEs⁶

TEAE	D-Kd (n=66)
TEAE	Any-Grade	Grade 3/4
TEAEs, n (%)	66 (100)	49 (74.2)
Hematologic
Thrombocytopenia	34 (51.5)	13 (19.7)
Anemia	25 (37.9)	8 (12.1)
Neutropenia	15 (22.7)	7 (10.6)
Lymphopenia	12 (18.2)	8 (12.1)
Nonhematologic
Hypertension	23 (34.8)	14 (21.2)
Insomnia	23 (34.8)	4 (6.1)
Diarrhea	20 (30.3)	0
Nausea	17 (25.8)	0
Nasopharyngitis	17 (25.8)	0
Headache	15 (22.7)	0
Pyrexia	14 (21.2)	1 (1.5)
Asthenia	14 (21.2)	0
Cough	13 (19.7)	0
Dyspnea	12 (18.2)	1 (1.5)
Upper respiratory tract infection	12 (18.2)	0
Vomiting	11 (16.7)	0
Abbreviation: TEAE, treatment-emergent adverse event.

Pharmacokinetics

The maximum serum concentration of daratumumab was observed at cycle 1, day 4 after the first dose, or at cycle 3, day 4 of the ninth dose. See Table: Daratumumab Serum Concentrations in the PLEIADES Study.

Daratumumab Serum Concentrations in the PLEIADES Study^a,¹⁴

Timepoint	Serum Concentrations, µg/mL
Cycle 1 day 4 post-dose, n	57
Mean (SD)	137 (56.7)
Cycle 3 day 1 pre-dose, n	60
Mean (SD)	744 (289)
Cycle 3 day 4 post-dose, n	46
Mean (SD)	853 (292)
Cycle 6 day 1 pre-dose, n	49
Mean (SD)	728 (275)
Cycle 9 day 1 pre-dose, n	41
Mean (SD)	577 (238)
Cycle 12 day 1 pre-dose, n	38
Mean (SD)	459 (194)
End of treatment, n	13
Mean (SD)	247 (228)
Abbreviation: SD, standard deviation. ^aAll cycle 1 day 1 pre-dose daratumumab concentrations were below the lower limit of quantitation.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File

databases (and/or other resources, including internal/external databases) was conducted on 08 April 2024.

References

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