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DARZALEX® (daratumumab)

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DARZALEX + DARZALEX FASPRO - Stem Cell Collection

Last Updated: 02/05/2025

SUMMARY

DARZALEX for intravenous (IV) use + DARZALEX FASPRO for subcutaneous (SC) is not approved by the regulatory agencies for use in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd), or for use in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) for the treatment of multiple myeloma (MM).
DARZALEX for IV use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of MM.
Janssen does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
CASSIOPEIA is a phase 3 study evaluating the safety and efficacy of DARZALEX (D) when administered in combination with bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).¹^,²
- Hulin et al (2021)³ reported stem cell yield and transplantation results among patients receiving induction therapy with D-VTd vs VTd in part 1 of this study. The mean number of cluster of differentiation 34 positive (CD34⁺) stem cells transplanted for D-VTd vs VTd was 3.6×10⁶/kg vs 5.0×10⁶/kg, respectively (P<0.0001).
PERSEUS is an ongoing phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of DARZALEX FASPRO when administered in combination with VRd vs VRd in transplant-eligible patients with NDMM.⁴
- Sonneveld et al (2024)⁴ reported the stem cell yield and ASCT results for transplant-eligible patients with NDMM who underwent DARZALEX FASPRO + VRd vs VRd induction prior to high-dose therapy (HDT)/ASCT in the PERSEUS trial.
GRIFFIN was a phase 2 study that evaluated the safety and efficacy of DARZALEX when administered in combination with VRd in patients with NDMM eligible for HDT and ASCT.⁵^-⁷ DARZALEX did not appear to interfere with stem cell mobilization (median CD34⁺cell yield of 8.2 vs 9.4×10⁶ cells/kg for D-VRd vs VRd, respectively).⁵^,⁷^,⁸
- Chhabra et al (2023)⁹ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes after frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. In GRIFFIN, the median CD34⁺cell yield in the D-VRd vs VRd arm was 8.3×10⁶ cells/kg vs 9.4×10⁶ cells/kg, respectively. For each regimen, a numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (D-VRd, 8.8×10⁶ cells/kg vs 7.1×10⁶ cells/kg, P=0.10; VRd, 10.5×10⁶ cells/kg vs 9.4×10⁶ cells/kg, P=0.20; respectively).
MASTER is a phase 2 study evaluating the safety and efficacy of D-KRd combination therapy in transplant-eligible patients with NDMM.¹⁰
- Chhabra et al (2023)⁹ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes after frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. In MASTER, the median CD34⁺cell yield was 6.0×10⁶ cells/kg. A numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (6.2×10⁶ cells/kg vs 5.2×10⁶ cells/kg, P=0.25).
LYRA is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with VCd in NDMM patients or in patients who have relapsed after receiving only 1 line of treatment.¹¹^-¹⁴ The median CD34⁺ stem cell yield was 6.2 (range, 2-15)×10⁶ cells/kg and median time to engraftment was 2.0 (range, 06) weeks in patients with NDMM who underwent ASCT.¹⁴ Adding DARZALEX to VCd resulted in no adverse impact on stem cell collection or engraftment.¹²
EQUULEUS is a phase 1b study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of MM. For patients in the D-KRd arm (N=22), there was no adverse impact on stem cell collection (the median number of CD34⁺ stem cells collected from eligible patients [n=20] was 10.6×10⁶ cells/kg).¹⁵
PRISM is a phase 2 study evaluating the activity and safety of the combination of D-VRd in high-risk smoldering multiple myeloma (HR-SMM). With a successful collection of stem cells in all patients, the mean stem cell yield was 5.78x10⁶ CD34⁺/kg cells.¹⁶

PRODUCT LABELING

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

CLINICAL DATA

Phase 3 Study in Transplant-Eligible Patients with NDMM

CASSIOPEIA is an ongoing, open-label, 2-arm, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VTd in patients with NDMM who are eligible for high-dose chemotherapy and ASCT.¹^,² Hulin et al (2021)³ reported stem cell yield and transplantation results among patients receiving induction therapy with D-VTd vs VTd alone in the part 1 of this study. The part 2 of this study is currently ongoing.

Study Design/Methods

Patients received induction, ASCT, and consolidation therapy in part 1. Those with a ≥partial response (PR) following consolidation were re-randomized to either DARZALEX maintenance therapy or observation in part 2.³
Primary endpoint: part 1: stringent complete response (sCR) after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days); part 2: progression-free survival (PFS) after second randomization.
Secondary endpoints: part 1: PFS, time to progression (TTP), proportion of post ASCT/consolidation minimal residual disease (MRD), proportion of post-induction sCR, progression-free survival after next line of therapy (PFS2), and overall survival (OS); part 2: TTP from second randomization, ≥complete response (CR), MRD-negativity rates (in patients with ≥CR at a threshold of 10^–5 by next-generation sequencing [NGS]), PFS2, overall response rate (ORR), and OS from second randomization.
Following induction, patients underwent stem cell mobilization with cyclophosphamide (recommended dose, 3 g/m²) and granulocyte colony-stimulating factor (G-CSF; recommended dose, 10 μg/kg/day until the last day of collection for a maximum of 10 days) after cycle 4. Plerixafor use was permitted according to institutional practice.³
Peripheral blood stem cells were harvested based on response to mobilization.³
Patients underwent conditioning with IV melphalan 200 mg/m² prior to ASCT.³
Consolidation therapy began after hematopoietic reconstitution, but not earlier than 30 days after transplant.³

Results

ASCT Parameters

A total of 1,085 patients were randomized to D-VTd (n=543) or VTd (n=542).³
- Among the treated population at clinical cutoff (D-VTd, n=536; VTd, n=538), 506 (94.4%) patients in the D-VTd arm and 492 (91.4%) patients in the VTd arm had completed mobilization, and 504 patients (94.0%) vs 490 patients (91.1%), respectively, underwent stem cell harvesting.
Stem cell mobilization and harvesting results³:
- A total of 110 patients (21.7% of 506 patients who completed mobilization) in the DVTd arm and 39 patients (7.9% of 492 patients who completed mobilization) in the VTd arm received plerixafor.
- Patients underwent a mean (range) of 1.9 (1-6) days vs 1.4 (1-4) days of apheresis for D-VTd vs VTd, respectively.
- A lower mean number of CD34⁺ stem cells were collected for patients receiving DVTd vs VTd (6.7×10⁶/kg vs 10.0×10⁶/kg, respectively; P<0.0001).
  - Nevertheless, among those who underwent apheresis, a similar percentage of patients treated with D-VTd vs VTd underwent ASCT (97.0% [n=489] vs 98.8% [n=484], respectively; P=0.0758).
Stem cell transplantation results³:
- The mean number of CD34⁺ stem cells transplanted was 3.6×10⁶/kg with D-VTd vs 5.0×10⁶/kg with VTd (P<0.0001).
- Hematopoietic reconstitution rates were similar between arms: 99.8% with D-VTd vs 99.6% with VTd (P=0.6227).
- A mean (range) of 14.4 (6-54) vs 13.7 (4-43) days was required to achieve sustained absolute neutrophil counts >500 cells/mm³for D-VTd vs VTd, respectively (P=0.0155).
- A mean (range) of 14.9 (2-56) vs 13.6 (1-47) days was required to achieve sustained platelets >20,000 cells/mm³without transfusion for D-VTd vs VTd, respectively (P=0.0004).
- The percentage of patients who achieved platelet recovery was higher with D-VTd vs VTd (84.5% vs 74.6%, respectively; P=0.0001).
- The percentage of patients who achieved neutrophil recovery was similar between DVTd vs VTd (97.1% vs 97.9%, respectively; P=0.5363).

PERSEUS is an ongoing open-label, multicenter, randomized, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO and lenalidomide (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for ASCT.⁴ Sonneveld et al (2024)⁴ reported the stem cell yield and ASCT results for transplant-eligible patients with NDMM who received D-VRd vs VRd induction prior to HDT/ASCT in the PERSEUS trial.

Study Design/Methods

Patients were randomized 1:1 to receive 4 induction cycles (28 days) and 2 post-ASCT consolidation cycles (28 days) of D-VRd or VRd. ⁴
- After induction (cycle 4), patients underwent stem cell mobilization per local standard of care.
- Per institutional practice, plerixafor was recommended in addition to the standard agents cyclophosphamide and G-CSF to help with mobilization.
- If impacted by COVID-19 related site closures, stem cells were collected after cycle 4 and transplanted immediately after cycle 6.
- Melphalan was administered as HDT prior to ASCT.
Patients received maintenance therapy (28-day cycles) consisting of D-R or R alone.⁴
Primary endpoint: PFS.
Secondary endpoints: rates of ≥CR, MRD negativity with ≥CR, and OS.

Results

Patient Disposition

At the time of data cutoff (August 1, 2023), 709 patients were randomized to receive D-VRd (n=355) or VRd (n=354).⁴
Of the 698 patients who received induction therapy (D-VRd, n=351; VRd, n=347), 652 (D-VRd, n=335; VRd, n=317) underwent mobilization.⁴
- Maintenance therapy is ongoing for 260 vs 159 patients from the D-VRd vs VRd group, respectively.
  - After ≥24 months of maintenance therapy, 207 patients who achieved ≥CR and sustained MRD negativity (≤10^–5 sensitivity threshold) for 12 months discontinued DARZALEX FASPRO but continued with lenalidomide maintenance therapy until disease progression or unacceptable toxicity.

Safety

Stem cell mobilization and harvesting details are summarized in Table: Stem Cell Mobilization and Harvesting (Safety Analysis Set).⁴
- A total of 652 patients (D-VRd, n=335; VRd, n=317) underwent stem cell mobilization and harvesting.
- The median time between administration of the last induction dose and administration of the first mobilization agent was 22 days.
- Of the 640 patients who underwent stem cell collection (D-VRd, n=326; VRd, n=314), a high percentage of patients in both groups (D-VRd, n=320 [98.2%]; VRd, n=312 [99.4%]) had sufficient stem cells collected for ASCT (≥2×10⁶/kg cells).
- Although the D-VRd vs VRd group had a numerically lower median number of CD34⁺ stem cells collected (5.52×10⁶/kg vs 7.44×10⁶/kg, respectively), the percentage of patients who underwent ASCT was similar between the D-VRd and VRd groups (89.7% vs 87.0%, respectively).
Stem cell transplantation details are summarized in Table: Stem Cell Transplantation (Safety Analysis Set).⁴
- The median number of CD34⁺ stem cells transplanted was 3.25×10⁶/kg for the D-VRd group and 3.98×10⁶/kg for the VRd group.
- The hematopoietic reconstitution rate was high in both the D-VRd (314/315 [99.7%]) and VRd (300/302 [99.3%]) groups.
  - To obtain sustained absolute neutrophil counts (≥0.5×10⁹/L), a median (range) of 13 (1-67) days vs 13 (1-38) days were needed for the D-VRd vs VRd group, respectively.
  - To obtain sustained platelet counts (≥20×10⁹/L) without transfusion, a median (range) of 14 (1-94) days vs 12 (1-137) days were needed for the D-VRd vs VRd group, respectively.
- After completion of 6 treatment cycles, 58 patients (29 in each treatment group) underwent ASCT, with 100% hematopoietic reconstitution and comparable engraftment times in both groups (D-VRd, median [range], 14 [1-67] days; VRd, 14 [12-137] days).

Stem Cell Mobilization and Harvesting (Safety Analysis Set)⁴

Characteristic	D-VRd (n=335)	VRd (n=317)
PBSC mobilizing agents used, n (%)^a
Cyclophosphamide	261 (77.9)	235 (74.1)
G-CSF^b	324 (96.7)	307 (96.8)
Plerixafor	134 (40.0)	72 (22.7)
Patients with CD34⁺stem cell collection^a (10⁶/kg) among patients with stem cell collection^c,d, n	326	314
Total CD34⁺ stem cells collected (10⁶/kg), mean (SD)	6.236 (3.3243)	8.317 (5.0732)
Total CD34⁺ stem cells collected (10⁶/kg), median (range)	5.52 (1.00-26.00)	7.44 (0.74-49.50)
Total CD34⁺ stem cells collected (≥2×10⁶/kg), n (%)	320 (98.2)	312 (99.4)
Total CD34⁺ stem cells collected (≥5×10⁶/kg), n (%)	193 (59.2)	242 (77.1)
Abbreviations: CD, cluster of differentiation; D-VRd, DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone; G-CSF, granulocyte colony-stimulating factor; PBSC, peripheral blood stem cell; SD, standard deviation; VRd, bortezomib, lenalidomide, and dexamethasone. ^aPercentages were calculated with the number of patients with available data in the related subgroup as the denominator. ^bIncluded standardized medications of filgrastim, lenograstim, and G-CSF. ^cPercentages were calculated with the number of patients in each group as the denominator. ^dThe stem cells were collected by PBSC apheresis or bone marrow harvesting.

Stem Cell Transplantation (Safety Analysis Set)⁴

Characteristic	D-VRd (n=315)	VRd (n=302)
Patients with CD34⁺ stem cells transplanted (10⁶/kg), %^a	89.7	87.0
CD34⁺ stem cells transplanted (10⁶/kg), mean (SD)	4.07 (2.628)	4.87 (3.601)
CD34⁺ stem cells transplanted (10⁶/kg), median (range)	3.25 (0.8-26.0)	3.98 (1.0-38.7)
Transplanted patients with hematopoietic reconstitution, n (%)^b	314 (99.7)	300 (99.3)
Patients with ANC ≥0.5×10⁹/L, n	314	300
Time to achieve ANC ≥0.5×10⁹/L, mean (SD), days	13.5 (5.47)	13.0 (4.88)
Time to achieve ANC ≥0.5×10⁹/L, median (range), days	13 (1-67)	13 (1-38)
Patients who achieved sustained platelets (≥20×10⁹/L) without transfusion, n^c	314	300
Time to achieve sustained platelets without transfusion, mean (SD), days	14.4 (7.79)	13.0 (9.44)
Time to achieve sustained platelets without transfusion, median (range), days	14 (1-94)	12 (1-137)
Patients with engraftment post-ASCT, n^c,d	314	300
Time to engraftment, mean (SD), days	15.7 (7.68)	14.9 (9.37)
Time to engraftment, median (range), days	14.0 (1-94)	14.0 (1-137)
Abbreviations: ANC, absolute neutrophil count; ASCT, autologous stem cell transplantation; CD, cluster of differentiation; D-VRd, DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone; SD, standard deviation; VRd, bortezomib, lenalidomide, and dexamethasone. ^aPercentages were calculated with the number of patients in each group as the denominator. ^bPercentages were calculated with the number of patients with available data in the related subgroup as the denominator. ^cNumber of days from the transplantation date, excluding patients whose counts did not reach nadir below the set threshold. ^dThe date of engraftment post-ASCT was defined as the latest date of ANC ≥0.5×10⁹/L and platelet count ≥20×10⁹/L. Patients with hematopoietic reconstitution are included.

Phase 2 Studies in Transplant-Eligible Patients with NDMM

GRIFFIN (MMY2004; ClinicalTrials.gov Identifier: NCT02874742)⁵^-⁷ was a 2-part, randomized, active-controlled, phase 2 study conducted in the United States (US) to evaluate the safety and efficacy of DARZALEX when administered in combination with VRd in patients with NDMM eligible for HDT and ASCT.

Study Design/Methods

Of note, the data presented utilized the abbreviation “RVd”, which has been replaced with “VRd” in the summary below to remain consistent throughout this scientific response.
Primary objective: determine if the addition of DARZALEX to VRd will increase the sCR rate by the end of the post-ASCT consolidation therapy.
Primary endpoint: sCR (by end of post-ASCT consolidation).
Secondary endpoints: MRD (10^-5 via NGS), CR, ORR, and ≥very good partial response (VGPR).

Results

Part 1: Safety Run-In Phase Final Analysis

Voorhees et al (2021)¹⁷ reported on the final analysis of the safety run-in cohort of the GRIFFIN study.

Results

ASCT Parameters

Median follow-up was 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.
All patients in the safety run-in phase (N=16) completed induction therapy, stem cell mobilization, ASCT, and consolidation, and entered maintenance therapy.
Stem cell collection and neutrophil and platelet engraftment are presented in the Table: Stem Cell Collection and Transplantation.

Stem Cell Collection and Transplantation¹⁷

Parameter	D-VRd (n=16)
CD34⁺ yield, median (range) (x10⁶ cells/kg)	8.05 (3.5-17.6)
CD34⁺ cells transplanted, median (range) (x10⁶ cells/kg)	4.72 (2.2-6.0)
Patients receiving plerixafor for mobilization, n (%)	9 (56.3)
Patients receiving cyclophosphamide, n (%)	0
Days to neutrophil (0.5×10⁹/L) engraftment^a median (maximum)	14
Days to platelet (20×10⁹/L) engraftment^b median (maximum)	13.5
Abbreviations: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone. ^aFor neutrophil engraftment, there were 15 evaluable patients. ^bFor platelet engraftment, there were 16 evaluable patients.

Part 2: Randomized Phase

Voorhees et al (2020)⁵^,⁷^,⁸ presented the primary analysis and updated analysis of the randomized portion of this study. Laubach et al (2021)¹⁸ presented updated efficacy and safety results after 2 years of maintenance therapy in the GRIFFIN Study.

Results

ASCT Parameters

A total of 207 patients were randomized (D-VRd, n=104; VRd, n=103).
The median follow-up was 13.5 months in the primary analysis and 22.1 months in the updated analysis.
Ninety percent of patients in the D-VRd arm underwent ASCT compared to 76% in the VRd arm (ASCT rate lower due to early discontinuations).
DARZALEX did not impact time to engraftment and hematopoietic reconstitution (Table: Stem Cell Collection and Transplantation).
- Median stem cell yield (D-VRd vs VRd): 8.2 vs 9.4×10⁶ cells, respectively.

Stem Cell Collection and Transplantation⁵

Parameter	D-VRd	VRd
Median (range) stem cell yield, ×10⁶ CD34⁺ cells/kg^a,b	8.2 (3-33)	9.4 (4-29)
Median stem cells transplanted, ×10⁶ CD34⁺ cells/kg^c	4.2	4.8
Patients receiving plerixafor for mobilization, n(%)^d	66 (70)	45 (56)
Patients receiving cyclophosphamide, n (%)^d	5 (5)	4 (5)
Median (max) days to neutrophil engraftment (0.5×10⁹/L)	12 (31)	12 (23)
Median (max) days to platelet engraftment (20×10⁹/L)	13 (31)	12 (23)
Abbreviations: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; max, maximum; VRd, bortezomib + lenalidomide + dexamethasone. ^aAmong patients who underwent peripheral blood stem cell apheresis (D-VRd, n=93; VRd, n=80). ^bOne patient in the D-VRd arm had a stem cell yield <3×10⁶ cells/kg; no patients in either arm had a stem cell yield <2×10⁶ cells/kg. ^cAmong patients receiving transplant (D-VRd, n=94; VRd, n=78). ^dAmong patients who underwent mobilization (D-VRd, n=95; VRd, n=80). Patients underwent stem cell mobilization with G-CSF with or without plerixafor, according to institutional standards; if unsuccessful, cyclophosphamide-based mobilization was permitted.

Stem Cell Collection with DARZALEX-based Regimens in the GRIFFIN Study

Chhabra et al (2023)⁹ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes following frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. Results specific to the GRIFFIN study have been summarized below.

Results

Patient Characteristics

Among the 207 patients randomized in the GRIFFIN study, 95/104 (91%) patients in the D-VRd arm and 80/103 (78%) patients in the VRd arm underwent stem cell mobilization. Among the mobilized patients, 99% (94 of 95) in the D-VRd arm and 98% (78 of 80) in the VRd arm underwent ASCT.
The baseline patient demographics and clinical characteristics are summarized in the Table: Baseline Characteristics in the GRIFFIN Study.

Baseline Characteristics in the GRIFFIN Study⁹

Characteristic	D-VRd				VRd
	All Patients	Received Upfront Plerixafor	Rescue Plerixafor Strategy (n=46)^a		All Patients	Received Upfront Plerixafor	Rescue Plerixafor Strategy (n=49)^a
	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor	Received G-CSF Only	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor	Received G-CSF Only
Patients who underwent mobilization, n	95	49	19	19	80	31	13	28
Age, years
Median (range)	59 (29-70)	60 (29-70)	55 (35-70)	58 (34-70)	59 (40-70)	59 (47-70)	62 (49-69)	61 (40-68)
<65, n (%)	69 (73)	37 (76)	12 (63)	12 (63)	60 (75)	24 (77)	7 (54)	21 (75)
≥65, n (%)	26 (27)	12 (24)	7 (37)	7 (37)	20 (25)	7 (23)	6 (46)	7 (25)
Male, n (%)	51 (54)	28 (57)	8 (42)	12 (63)	43 (54)	14 (45)	6 (46)	17 (61)
ISS disease stage, n (%)^b
I	46 (48)	22 (45)	10 (53)	10 (53)	38 (48)	16 (52)	4 (31)	13 (46)
II	36 (38)	19 (39)	6 (32)	8 (42)	29 (36)	9 (29)	7 (54)	11 (39)
II	13 (14)	8 (16)	3 (16)	1 (5)	12 (15)	5 (16)	2 (15)	4 (14)
Missing	0	0	0	0	1 (1)	1 (3)	0	0
Cytogenetic risk, n (%)^c	n=91	n=47	n=18	n=18	n=77	n=29	n=13	n=28
Standard risk	75 (82)	38 (81)	13 (72)	18 (100)	66 (86)	24 (83)	12 (92)	23 (82)
High risk	16 (18)	9 (19)	5 (28)	0	11 (14)	5 (17)	1 (8)	5 (18)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; ISS, International Staging System; VRd, bortezomib + lenalidomide + dexamethasone. ^aAmong the mobilized patients in GRIFFIN, 9 patients (D-VRd, n=5; VRd, n=4) received cyclophosphamide, and no accurate information on mobilization regimen used was available for 16 patients (D-VRd, n=8; VRd, n=8). ^bISS staging is based on the combination of serum β2-microglobulin and albumin. Higher stages indicate more advanced disease. ^cCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high cytogenetic risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data.

Summary of ASCT

A higher rate of mobilization was observed in the D-VRd vs VRd arm due to lower rates of discontinuation during induction (D-VRd, 2%; VRd, 7%) and following induction but before mobilization (D-VRd, 3%; VRd, 14%).
A total of 68 (72%) patients in the D-VRd arm and 44 (55%) in the VRd arm received plerixafor either upfront or as a rescue strategy.
A total of 5 patients in the D-VRd arm and 4 in the VRd arm received cyclophosphamide.
A total of 19 (20%) patients in the D-VRd arm and 28 (35%) in the VRd arm received G-CSF alone.
The median CD34⁺cell yield was 8.3×10⁶ cells/kg in the D-VRd arm and 9.4×10⁶ cells/kg in the VRd arm. In both arms, a numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (D-VRd, 8.8×10⁶ cells/kg vs 7.1×10⁶ cells/kg, P=0.10; VRd, 10.5×10⁶ cells/kg vs 9.4×10⁶ cells/kg, P=0.20; respectively).
Median number of days for stem cell collection was 2 in patients in the D-VRd arm and 1 in the VRd arm.
Additional data stratified by upfront plerixafor use, rescue plerixafor use, and G-CSF only use are summarized in the Table: Summary of ASCT in the GRIFFIN Study.

Summary of ASCT in the GRIFFIN Study^a,⁹

Parameter	All Patients		Received Upfront Plerixafor		Rescue Plerixafor Strategy^b
	All Patients		Received Upfront Plerixafor		Received Rescue Plerixafor		Received G-CSF Only
	D-VRd	VRd	D-VRd	VRd	D-VRd	VRd	D-VRd	VRd
Patients who underwent mobilization, n	95	80	49	31	19	13	19	28
Patients who received plerixafor, n	68	44	49	31	19	13	0	0
Mobilization attempts, n (%)
1	89 (94)	74 (93)	46 (94)	28 (90)	19 (100)	12 (92)	17 (89)	27 (96)
2	2 (2)	3 (4)	1 (2)	1 (3)	0	1 (8)	1 (5)	1 (4)
3	0	1 (1)	0	0	0	0	0	0
4	0	1 (1)	0	1 (3)	0	0	0	0
Missing	4 (4)	1 (1)	2 (4)	1 (3)	0	0	1 (5)	0
Median stem cell collection target per ASCT (range), ×10⁶ CD34⁺cells/kg	2.5 (2-4)	2.5 (2-5)	2.5 (2-4)	2.5 (2-5)	2 (2-4)	2.5 (2-4)	2 (2-3)	2 (2-4)
Median duration of stem cell collection (range), days	2 (1-4)	1 (1-4)	2 (1-4)	1 (1-4)	1 (1-3)	2 (1-4)	2 (1-4)	1 (1-4)
Median stem cell yield (range), ×10⁶ CD34⁺cells/kg	8.3 (2.6-33)	9.4 (4.1-28.7)	8.8 (2.6-33)	10.5 (5.5-22.5)	7.1 (4.2-16.7)	9.4 (4.4-17.3)	8.3 (4.4-18.6)	7.6 (4.1-23)
Patients who collected the minimum threshold for ASCT, n (%)	89 (94)	79 (99)	45 (92)	30 (97)	19 (100)	13 (100)	18 (95)	28 (100)
Patients who collected 2x the minimum threshold for ASCT, n (%)	81 (85)	74 (93)	42 (86)	29 (94)	16 (84)	11 (85)	17 (89)	26 (93)
Median number of CD34⁺ cells transplanted (range), ×10⁶ cells/kg	4.2 (2-27.6)	4.8 (1.1-15)	4.3 (2.5-27.6)	4.8 (1.1-15)	4.0 (2.0-8.3)	4.7 (1.7-12.2)	4.3 (2.8-9.3)	4.4 (2.0-13.2)
Median duration from end of induction to apheresis (range), days	27 (0-63)	24 (4-133)	23 (14-48)	25.5 (4-133)	26 (0-36)	23 (14-43)	33 (13-63)	22.5 (12-55)
Pts who completed ASCT, n (%)	94 (99)	78 (98)	49 (100)	31 (100)	18 (95)	13 (100)	19 (100)	26 (93)
Abbreviations: ASCT, autologous stem cell transplantation; CD, cluster of differentiation; D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; VRd, bortezomib + lenalidomide + dexamethasone.^aAmong the mobilized patients in GRIFFIN, 9 patients (D-VRd, n=5; VRd, n=4) received cyclophosphamide, and no accurate information on mobilization regimen used was available for 16 patients (D-VRd, n=8; VRd, n=8). ^bPatients who did not receive upfront plerixafor had the treatment plan called “rescue plerixafor strategy.” Rescue plerixafor use was defined as only using plerixafor when deemed necessary “just-in-time” based on pre-apheresis blood CD34⁺ cell count after G-CSF. Patients in the rescue plerixafor strategy group did not receive upfront plerixafor, but received either rescue plerixafor or no plerixafor at all.

Stem Cell Collection with DARZALEX-based Regimen in the MASTER Study

MASTER (Clinicaltrials.gov Identifier: NCT03224507) is an ongoing, multicenter, single-arm, phase 2 study being conducted in the US to evaluate the safety and efficacy of DARZALEX when administered in combination with KRd in patients with NDMM eligible for ASCT.¹⁰

Study Design/Methods

Patients were eligible for inclusion if they had transplant-eligible NDMM, an Eastern Cooperative Oncology Group performance status score of 0-2, and adequate organ function.
Patients received 4 cycles of induction therapy with D-KRd (16 weeks/cycle) followed by mobilization of autologous stem cells using G-CSF (10 µg/kg) with or without plerixafor (0.24 mg/kg).
The minimum required CD34⁺ stem cell dose for a single ASCT was 2×10⁶-3×10⁶ cells/kg, depending upon the site.
Primary endpoint: MRD-negativity rate (10^-5) at any time during therapy.

Chhabra et al (2023)⁹ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes after frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. Results specific to the MASTER study have been summarized below.

Results

Patient Characteristics

Among the 123 patients randomized in the MASTER study, 116 (94%) patients completed induction therapy and underwent stem cell mobilization and collection. Of these patients, 114 (98%) underwent ASCT.
The median duration of follow-up was 32 months.
The baseline patient demographics and clinical characteristics are summarized in the Table: Baseline Characteristics in the MASTER Study.

Baseline Characteristics in the MASTER Study⁹

Characteristic	D-KRd
Characteristic	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor Strategy	Received G-CSF Only^a
Patients who underwent mobilization, n	116	81	35	4
Age, years
Median (range)	61 (31-79)	61 (31-79)	60 (43-70)	67 (64-69)
≥65, n (%)	44 (38)	31 (38)	13 (37)	4 (100)
≥75, n (%)	22 (19)	21 (26)	1 (3)	0 (0)
Male, n (%)	65 (56)	47 (58)	18 (51)	1 (25)
R-ISS disease stage, n (%)
I	35 (30)	27 (33)	8 (23)	0 (0)
II	58 (50)	41 (51)	17 (49)	1 (25)
II	22 (19)	13 (16)	9 (26)	3 (75)
Cytogenetic risk, n (%)^b
Standard risk	74 (64)	52 (64)	22 (63)	2 (50)
High risk	42 (36)	29 (36)	13 (37)	2 (50)
Abbreviations: D-KRd, DARZALEX + carfilzomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; R-ISS, Revised International Staging System. ^aPatients in the D-KRd arm who received only G-CSF are a subset of those in the rescue plerixafor strategy group for this summary of patient characteristics. ^bCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high cytogenetic risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data.

Summary of ASCT

The median CD34⁺cell yield was 6.0×10⁶ cells/kg. A numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (6.2×10⁶ cells/kg vs 5.2×10⁶ cells/kg, P=0.25).
The median days of stem cell collection was 2.
Additional data stratified by upfront plerixafor use, rescue plerixafor use, and G-CSF only are summarized in the Table: Summary of ASCT in the MASTER Study.
Five patients failed to collect a minimum of 2×10⁶ cells/kg CD34⁺ stem cells in the first cycle. All 5 patients were remobilized with upfront plerixafor and 2 patients were given G-CSF.
Among the patients who underwent mobilization, 7% (8 of 116) of patients underwent 2 mobilization attempts. All 8 patients who underwent a second mobilization attempt collected sufficient stem cells and proceeded to ASCT.
- After remobilization, sufficient stem cells for 1 ASCT were collected by 100% of patients and that for 2 ASCTs were collected by 80% of patients.
After ASCT, neutrophil recovery and platelet recovery occurred at a median of 12 days (range, 9-17) and 17 days (range not reported), respectively.

Summary of ASCT in the MASTER Study⁹

Characteristic	D-KRd
	All Patients	Received Upfront Plerixafor	Rescue Plerixafor Strategy^a
	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor	Received G-CSF Only
Patients who underwent mobilization, n	116	81	31	4
Patients who received plerixafor, n	112	81	31	0
Mobilization attempts, n (%)
1	108 (93)	76 (94)	26 (90)	4 (100)
2	8 (7)	5 (6)	3 (10)	0
3	0	0	0	0
4	0	0	0	0
Missing	0	0	0	0
Median stem cell collection target per ASCT (range), ×10⁶ CD34⁺ cells/kg	3 (2-3)	3 (2-3)	3 (2-3)	2 (2-3)
Median duration of stem cell collection (range), days	2 (1-4)	2 (1-4)	2 (1-3)	1.5 (1-2)
Median stem cell yield (range), ×10⁶ CD34⁺ cells/kg	6.0 (2.2-13.9)	6.2 (2.3-13.9)	5.2 (2.2-11.5)	3.9 (2.2-5.5)
Patients who collected the minimum threshold for ASCT, n (%)	116 (100)	81 (100)	31 (100)	4 (100)
Patients who collected 2x the minimum threshold for ASCT, n (%)	93 (80)	65 (80)	26 (84)	2 (50)
Median number of CD34⁺ cells transplanted (range), ×10⁶ cells/kg	3.2 (2.0-8.3)	3.2 (2.0-8.3)	3.2 (2.1-5.7)	2.7 (2.2-2.8)
Median duration from end of induction to apheresis (range), days	24 (2-104)	26 (2-104)	22 (8-103)	12.5 (8-29)
Patients who completed ASCT, n (%)	114 (98)	81 (100)	29 (93)	4 (100)
Abbreviations: ASCT, autologous stem cell transplantation; CD, cluster of differentiation; D-KRd, DARZALEX + carfilzomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor.^aPatients who did not receive upfront plerixafor had the treatment plan called “rescue plerixafor strategy.” Rescue plerixafor use was defined as only using plerixafor when deemed necessary “just-in-time” based on pre-apheresis blood CD34⁺ cell count after G-CSF. Patients in the rescue plerixafor strategy group did not receive upfront plerixafor, but received either rescue plerixafor or no plerixafor at all.

Phase 2 Study in Patients with NDMM or Relapsed MM After 1 Line of Treatment

LYRA (ClinicalTrials.gov Identifier: NCT02951819)¹¹^-¹⁴ is a single-arm, open-label, multicenter, phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with VCd for NDMM patients or in patients who have relapsed after receiving only 1 line of treatment.

Study Design/Methods

Eligible patients underwent ASCT at the discretion of the investigator.¹¹
All patients received ≤12 DARZALEX maintenance doses monthly.¹¹
Primary endpoint: ≥VGPR after 4 induction cycles.¹¹
Key secondary endpoints: ORR, time to ≥VGPR, time to ≥PR, PFS, OS safety, and tolerability.¹¹

Results

ASCT Parameters

At the end of study, 39 patients with NDMM and 1 patient with RMM underwent ASCT.¹⁴^,¹⁹
Patients with NDMM who underwent ASCT received a median of 5.0 (range, 4-8) cycles of induction therapy. For stem cell mobilization, 9 patients underwent chemotherapy with cyclophosphamide and 19 patients received plerixafor.¹⁴
The median CD34⁺ stem cell yield was 6.2 (range, 2-15) ×10⁶ cells/kg and median time to engraftment was 2.0 (range, 0-6) weeks in patients with NDMM who underwent ASCT.¹⁴

Phase 1b Study

EQUULEUS (MMY1001) is an ongoing, phase 1b, open-label, multicenter study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of MM. Data specific to patients receiving D-KRd are summarized.¹⁵

Study Design/Methods

Eligibility criteria for the D-KRd arm: NDMM; transplant eligible and non-eligible; treatment duration: ≤13 cycles or until elective discontinuation for ASCT; no clinically significant cardiac disease
Primary endpoints: safety and tolerability
Secondary endpoints: ORR, duration of response, time to response, and infusion-related reactions
Exploratory endpoint: PFS

Results

ASCT Parameters

The median number of CD34⁺ cells collected from patients was 10.6×10⁶ cells/kg (n=20).
Patients received a median (range) of 5 (4-9) treatment cycles prior to stem cell harvest.
Among eligible patients (n=20), 15 (75%) had a best response of ≥VGPR prior to stem cell harvest.
- Among 6 patients who underwent ASCT, 3 (50.0%) had a best response of sCR and 3 (50.0%) had a best response of VGPR.
- Two patients upgraded their previous confirmed responses from VGPRs to sCRs.

Stem Cell Collection with DARZALEX-based Regimen in the PRISM Study

PRISM (ClinicalTrials.gov Identifier: NCT04775550) is a phase 2 single center, single-arm, open label study evaluating the efficacy and safety of the combination of D-VRd in patients with HR-SMM.¹⁶

Study Design/Methods

Eligibility included high risk per Mayo 2018 “20-2-20” model, presence of immunoparesis, evolving type of smoldering MM, and high risk per fluorescence in situ hybridization findings.
Eligible patients underwent stem cell collection after 6 cycles of therapy.
Primary endpoint: rate of sustained MRD negativity at 2 years.
Key secondary endpoints: PFS, response rates, and safety.

Results

At the time of data cut off there were 20 patients enrolled with a median follow up of 6 months.
Out of 16 patients that met high risk criteria 8 underwent MRD testing with negativity rates of 50% (4/8) and 25% (2/8) at thresholds of 10^-5 and 10^-6, respectively.
The response rates consisted of a 90% ORR, 40% PR, 25% VGPR, and a 25% CR.
No patients progressed while on treatment.
There was a successful collection of stem cells in all patients with a mean stem cell yield of 5.78x10⁶ CD34+/kg cells.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on
12 November 2024. For streamlining purposes, retrospective-analyses, systematic reviews, review articles, and case reports have been excluded.

In response to your specific request, summarized in this response are the relevant data from company-sponsored studies pertaining to this topic.

References

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