PERSEUS Study Summary

Key eligibility²

Transplant-eligible (TE) NDMM
Age 18-70 years
ECOG PS ≤2

Stratification factors²

ISS disease stage (I, II, or III)
Cytogenetic risk* (standard or high risk)

*High risk was defined as the presence of del(17p), t(4;14), or t(14;16).

PERSEUS study design^1-3

Open-label, multicenter, randomized phase 3 study

The trial was not designed to isolate the effect of DARZALEX FASPRO® in the maintenance phase of treatment. The efficacy of DARZALEX FASPRO® + R for maintenance has not been established.¹

*Within 12 weeks of ASCT, and when engraftment was complete.¹
^†Stratified by ISS stage and cytogenetic risk.²
^‡DARZALEX FASPRO® 1,800 mg co-formulated with rHuPH20 (2,000 U/mL).¹
^§On the days of DARZALEX FASPRO® injection, the dexamethasone dose was administered PO or IV as a pre-injection medication.¹
^‖After Week 16, patients underwent stem cell mobilization, high-dose chemotherapy, and ASCT.¹

Primary endpoint^1,2

Progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria

Major secondary endpoints^1,2

Overall response rate (ORR)
Minimal residual disease (MRD) negativity rate (next-generation sequencing [NGS]: 10^-5)

Baseline characteristics²*:

*Patients in the D-VRd group were randomly assigned to receive SC daratumumab in combination with VRd induction and consolidation therapy and R maintenance therapy. Patients in the VRd group were randomly assigned to receive VRd induction and consolidation therapy and R maintenance therapy alone. The ITT population included all patients who had undergone randomization.
^†Race was reported by the patient.
^‡ECOG PS range from 0 to 5, with higher scores indicating greater disability. In 1 patient, the ECOG PS score was 0 at randomization but had increased to 3 at baseline.
^§Other types of measurable disease include IgD, IgM, IgE, and biclonal.
^‖ISS consists of three disease stages, with higher stages indicating more severe disease: stage I, defined by a serum β₂ -microglobulin level of <3.5 mg/L (300 nmol/L) and an albumin level of 3.5 g/dL or more; stage II, defined as neither stage I nor stage III; and stage III, defined by a serum β₂ -microglobulin level of 5.5 mg/L (470 nmol/L) or more.
^¶Cytogenetic risk was assessed by means of fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), or t(14;16).

Primary endpoint: progression-free survival¹

These results are based on the full treatment regimen and include investigational maintenance of DARZALEX FASPRO® + R following post-transplant consolidation. The trial was not designed to isolate the effect of DARZALEX FASPRO® in the maintenance phase of treatment. The efficacy of DARZALEX FASPRO® + R for maintenance has not been established.

At a median follow-up of 47.5 months, the median PFS had not been reached in either arm²
The median duration of treatment for induction and consolidation was 9.9 months (range: 0.5-18.5) months in the D-VRd arm¹

progression-free-survival-ipad-mobile-img

Figure adapted from DARZALEX FASPRO® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.

In the D-VRd arm, 44.5% of patients achieved ≥CR vs 34.7% in the VRd arm

ORR through post-transplant consolidation (ITT population)

*≥CR defined as sCR + CR

MRD negativity rate (10^-5) through post-transplant consolidation*^†

MRD negativity rate (10^-5) through post-transplant consolidation in
patients who achieved CR or better*^‡

*MRD negativity rate was defined as the proportion of patients who achieved both MRD negativity and ≥CR. MRD was assessed using a next-generation sequencing assay (clonoSEQ).
^†Based on ITT population who achieved MRD negativity (10^-5) through post-transplant consolidation and ≥CR at any time during the study.
^‡Patients who achieved MRD negativity (threshold of 10^-5) and ≥CR through post-transplant consolidation.

These cytogenetic subgroup analyses are not included in the Prescribing Information for DARZALEX FASPRO® and have not been evaluated by the FDA. These analyses were conducted post hoc, and there are insufficient numbers of patients per subgroup to make conclusions of efficacy among the subgroups.

These results are based on the full treatment regimen and include investigational maintenance of DARZALEX FASPRO® + R following post-transplant consolidation. The trial was not designed to isolate the effect of DARZALEX FASPRO® in the maintenance phase. The efficacy of DARZALEX FASPRO® + R for maintenance has not been established.¹

Post hoc analysis of PERSEUS evaluating outcomes in patients based on their cytogenetic risk status after 47.5 months of follow-up⁵

Per the PERSEUS study protocol, high cytogenetic risk is defined as having at least 1 or more of the following high-risk cytogenetic abnormalities: del(17p), t(4;14), or t(14;16)
Per the revised criteria, high cytogenetic risk is defined as having at least 1 or more of the following high-risk cytogenetic abnormalities: del(17p), t(4;14), t(14;16), gain(1q21), or amp(1q21)
Revised standard risk is defined by the occurrence of none of the following: del17p, t(4;14), t(14;16), gain(1q21), amp(1q21)
- Gain(1q21) is defined as the presence of 3 copies of chromosome 1q21
- Amp(1q21) is defined as the presence of 4 or more copies of chromosome 1q21

Post hoc PFS analysis of evaluable patients from the PERSEUS study by revised cytogenetic subgroups after 47.5 months of follow-up⁵

D-VRd (n=355)	VRd (n=354)
Revised standard risk: n=174	Revised standard risk: n=167
Revised high risk: n=130	Revised high risk: n=148

D-VRd (n=355)	VRd (n=354)
Revised standard risk: n=174	Revised standard risk: n=167
Revised high risk: n=130	Revised high risk: n=148

PFS rates in patients with high cytogenetic risk⁵

PFS rates in patients based on chromosome 1q21 status⁵

The most common adverse reactions (≥20%) included¹:
- Peripheral neuropathy
- Fatigue
- Upper respiratory infection
- Constipation
- Musculoskeletal pain
- Insomnia
- Rash
- Diarrhea
- Edema
- Pyrexia
Serious adverse reactions occurred in 37% of patients who received D-VRd¹
- The most frequent serious adverse reaction in >5% of patients who received D-VRd was pneumonia (6%)¹
Fatal adverse reactions occurred in 1.7% of patients who received D-VRd¹
Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received D-VRd¹
- An adverse reaction that resulted in permanent discontinuation of D-VRd in more than 1 patients included sepsis¹

Adverse reaction	D-VRd (n=351)		VRd (n=347)
Adverse reaction	All grades (%)	Grade 3 or 4 (%)	All grades (%)	Grade 3 or 4 (%)
Nervous system disorders
Peripheral neuropathy*	52	5	54	4
Paresthesia	11	<1^†	11	<1^†
General disorders and administration site conditions
Fatigue^‡	35	3^†	37	5^†
Edema^‡	22	1	21	1^†
Pyrexia	21	2^†	22	3^†
Infections
Upper respiratory tract infection^§	32	1^†	26	2^†
Pneumonia^\|\|	14	9	10	6^¶
Gastrointestinal disorders
Constipation	31	2^†	30	2^†
Diarrhea	23	3^†	25	5^†
Nausea	16	1^†	12	1^†
Abdominal pain^‡	11	0	12	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain^‡	26	1^†	23	1^†
Muscle spasm	22	0	9	<1^†
Psychiatric disorders
Insomnia	26	2^†	16	2^†
Skin and subcutaneous tissue disorders
Rash^‡	25	3^†	31	5
Hepatobiliary disorders
Hepatotoxicity^#	16	6^†	16	5
Respiratory, thoracic, and mediastinal disorders
Cough^‡	12	<1^†	8	0
*Peripheral neuropathy includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. ^†Only Grade 3 adverse reactions occurred. ^‡Includes other related terms. ^§Upper respiratory tract infection includes fungal pharyngitis, h1n1 influenza, influenza, influenza like illness, laryngitis, nasopharyngitis, oral candidiasis, oropharyngeal candidiasis, parainfluenzae virus infection, pharyngitis, respiratory moniliasis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection, viral tonsillitis, and viral upper respiratory tract infection. ^‖Pneumonia includes bronchopulmonary aspergillosis, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, and pneumonia streptococcal. ^¶Fatal adverse reactions included Pneumonia: n=1 (0.3%) in the VRd arm. ^#Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic cytolysis, hepatic failure, hepatic function abnormal, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, and liver disorder.

Clinically relevant adverse reactions in <10% of patients who received D-VRd included¹:

Gastrointestinal disorders: vomiting, hemorrhoids

Musculoskeletal and connective tissue disorders: arthralgia

Infections: bronchitis, sepsis, urinary tract infection, herpes zoster, COVID-19, cytomegalovirus infection

Respiratory, thoracic, and mediastinal disorders: dyspnea, pulmonary edema

Metabolism and nutrition disorders: hypocalcemia, decreased appetite, hyperglycemia, dehydration

Vascular disorders: hypotension, hypertension, orthostatic hypotension

General disorders and administration site conditions: infusion reactions, injection site reaction, chills

Nervous system disorders: dizziness, headache, syncope

Cardiac disorders: thrombosis, atrial fibrillation, tachycardia

Skin and subcutaneous tissue disorders: pruritus

Laboratory abnormality	D-VRd*		VRd*
Laboratory abnormality	All grades (%)	Grade 3 or 4 (%)	All grades (%)	Grade 3 or 4 (%)
Hematology
Decreased platelets	89	34	78	25
Decreased lymphocytes	87	69	69	43
Decreased leukocytes	78	47	56	22
Decreased neutrophils	67	52	47	34
Decreased hemoglobin	39	7	43	6
Chemistry
Increased ALT	52	7	48	5
Decreased sodium	40	5	25	5
Increase alkaline phosphatase	39	0	36	1
Decreased potassium	30	6	24	3

*Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=351 for D-VRd and N=346 for VRd.

Contraindications¹:

DARZALEX FASPRO® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.

Warnings and precautions¹:

Please see the full Prescribing Information for more details.

Hypersensitivity and other administration reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®
Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®

Systemic reactions

In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%)
In all patients, (N=1639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections
The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days)
Of the 283 systemic administration-related reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO® administration
Delayed systemic administration-related reactions have occurred in 1% of the patients

Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma
Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids
Monitor patients for systemic administration-related reactions, especially following the first and second injections
For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®
Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration‑related reactions

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products
If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®

Local reactions

In this pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193), injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 1.1%
The most frequent (>1%) injection-site reaction was injection-site erythema and injection site rash
In patients with high-risk smoldering multiple myeloma (N=193), injection-site reactions occurred in 28% of patients, including Grade 2 reactions in 3%
These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO®
Monitor for local reactions and consider symptomatic management

Infections

DARZALEX FASPRO® can cause serious, life-threatening, or fatal infections
In patients who received DARZALEX FASPRO® in a pooled safety population including patients with smoldering multiple myeloma and light chain amyloidosis (N=1639), serious infections, including opportunistic infections, occurred in 24% of patients, Grade 3 or 4 infections occurred in 22%, and fatal infections occurred in 2.5%
The most common type of serious infection reported was pneumonia (8.5%)
Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO® and treat appropriately
Administer prophylactic antimicrobials according to guidelines

Neutropenia

Daratumumab may increase neutropenia induced by background therapy
Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies
Monitor patients with neutropenia for signs of infection
Consider withholding DARZALEX FASPRO® until recovery of neutrophils
In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed

Thrombocytopenia

Daratumumab may increase thrombocytopenia induced by background therapy
Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies
Consider withholding DARZALEX FASPRO® until recovery of platelets

Embryo-fetal toxicity

Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman
DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density
Advise pregnant women of the potential risk to a fetus
Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose
The combination of DARZALEX FASPRO® with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child
Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy

Interference with serological testing

Daratumumab binds to CD38 on RBCs and results in a positive Indirect Antiglobulin Test (Indirect Coombs test)
Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration
Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum
The determination of a patient’s ABO and Rh blood type are not impacted
Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®
Type and screen patients prior to starting DARZALEX FASPRO®

Interference with determination of complete response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M‑protein
This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO®-treated patients with IgG kappa myeloma protein

Adverse reactions

In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection
The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, sleep disorder, headache, rash, renal impairment, motor dysfunction, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, musculoskeletal pain, decreased appetite, urinary tract infection, abdominal pain, upper respiratory tract infection, peripheral neuropathy, peripheral sensory neuropathy, constipation, pneumonia, edema, dizziness, bruising, and COVID-19
The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin

DARZALEX FASPRO® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313.
Supplement to: Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313.
Data on file. Janssen Biotech, Inc.
Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): Analysis of PERSEUS based on cytogenetic risk. Oral presentation at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.

ALT	Alanine aminotransferase	IV	Intravenous
ASCT	Autologous stem cell transplant	MM	Multiple myeloma
CI	Confidence interval	MRD	Minimal residual disease
COVID-19	Coronavirus disease 2019	NDMM	Newly diagnosed multiple myeloma
CR	Complete response	NGS	Next generation sequencing
DARA	Daratumumab	ORR	Overall response rate
DR	Daratumumab + lenalidomide	PFS	Progression-free survival
D-VRd	Daratumumab + bortezomib + lenalidomide + dexamethasone	PO	Oral
ECOG PS	Eastern Cooperative Oncology Group performance status	PR	Partial response
FDA	U.S. Food and Drug Administration	R	Lenalidomide
HRCA	High-risk cytogenetic abnormality	RBC	Red blood cell
HR	Hazard ratio	SC	Subcutaneous
Ig	Immunoglobulin	sCR	Stringent complete response
IMWG	International Myeloma Working Group	TE	Transplant eligible
ISS	International Staging System	VGPR	Very good partial response
ITT	Intention-to-treat	VRd	Bortezomib + lenalidomide + dexamethasone