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DARZALEX® (daratumumab)

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DARZALEX - MMY3008 (MAIA) Study

Last Updated: 07/05/2024

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Click on the following links to related sections within the document: MAIA (MMY3008) Study Overview, Prespecified Interim Results, and Updated Results (64.5 Month Follow-up).
Abbreviations: AE, adverse event; CI, confidence interval; CR, complete response; CrCl, creatinine clearance; Dara, daratumumab; D-Rd, daratumumab + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IRR, infusion-related reaction; IV, intravenous; MRD, minimal residual disease; NA, not applicable; NDMM, newly diagnosed multiple myeloma; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PFS2, PFS on the next line of therapy; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SPM, second primary malignancy; TEAE, treatment-emergent adverse event; VGPR, very good partial response.
^aFacon (2019)¹. ^bFacon (2018)². ^cIn either treatment arm. ^dFacon (2024)⁴. ^eAll events were related to the general health condition of the patient.

SUMMARY

MAIA is a phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared to lenalidomide and dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients.¹^,²
- Facon et al (2019)¹ reported the pre-specified interim results of this ongoing study which indicated a 44% reduction in the risk of progression or death with D-Rd (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43-0.73; P<0.001). Refer to Table: Most Common Adverse Events and Second Primary Cancers in the Safety Population for reported adverse event (AE) information.
- Facon et al (2024)⁴ presented (at the European Hematology Association [EHA] Hybrid Congress) the results of the updated efficacy and safety analysis of the MAIA study. At a median follow-up of 89.3 months (range, 0-102.2), a 33% reduction in the risk of death was observed with the D-Rd vs Rd arms. Median OS was reached for the D-Rd arm and was prolonged for patients in the D-Rd vs Rd arms (90.3 vs 64.1 months [HR, 0.67; 95% CI, 0.55-0.82; nominal P<0.0001]). The median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and not reached (NR) in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression.
- Kumar et al (2022)³ presented (at the 64th American Society of Hematology [ASH] Annual Meeting and Exposition) the results of the updated efficacy and safety analysis of the MAIA study. At a median follow-up of 64.5 months, progression-free survival (PFS) improved with D-Rd vs Rd treatment. The overall response rate (ORR) and minimal residual disease (MRD)-negativity rate were also higher in the D-Rd vs Rd treatment. At a median follow-up of 73.6 months, a 35% reduction in the risk of death was observed with D-Rd vs Rd treatment. The most common grade 3/4 treatment-emergent adverse events (TEAEs; ≥20%) in any arm were neutropenia (DRd, 54.1%; Rd, 37.0%) and anemia (D-Rd, 17.0%; Rd, 21.6%).
Moreau et al (2022)⁵ presented (at the 64th ASH Annual Meeting and Exposition) the efficacy and safety results in clinically important subgroups of patients from the MAIA study. The PFS duration was longer in the D-Rd vs Rd arm in the majority of subgroups. Treatment with D-Rd generally resulted in a greater improvement in ORR, MRDnegativity (10^-5) rate, and sustained MRD-negativity (10^-5) rate for ≥12 months across subgroups, compared with Rd. Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95.0% patients in the D-Rd vs Rd arm. The most common (≥20%) grade 3/4 TEAEs were neutropenia (D-Rd, 62.4%; Rd, 41.5%), lymphopenia (DRd, 21.0%; Rd, 12.6%), anemia (D-Rd, 20.4%; Rd, 25.2%), and pneumonia (DRd, 20.4%; Rd, 14.5%).
Facon et al (2022)⁶ reported a post hoc subgroup analysis of frailty status in patients with NDMM ineligible for transplant in the MAIA study. Median PFS benefit was observed in the D-Rd vs Rd arm across all frailty subgroups. The most common serious TEAE was pneumonia and the most common reasons for treatment discontinuation across all frailty subgroups were progressive disease (PD) and AEs.
Facon et al (2022)⁷ presented (at the 64th ASH Annual Meeting and Exposition) the efficacy results of the MAIA study according to age group (<70 years, ≥70 to <75 years, and <75 years) at a median follow-up of 64.5 months. All evaluated survival and response endpoints (including PFS, overall survival [OS], ORR, complete response [CR] or better, stringent complete response [sCR], very good partial response [VGPR] or better, and MRDnegativity [10^-5]) were more favorable in the D-Rd arm than the Rd arm in patients aged <75 years, with the most pronounced PFS and OS benefit observed in patients aged <70 years.
Jakubowiak et al (2022)⁸ conducted a pooled analysis of patient-level data from the MAIA and ALCYONE studies, analyzing PFS and best response in transplant-ineligible patients with NDMM and high-risk cytogenetic abnormalities (HRCAs). 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. ≥CR was achieved in 41.6% (n=42) of patients in the pooled DARZALEX cohort vs 22.5% (n=20) of patients in the pooled control cohort (adjusted odds ratio [OR], 2.63; 95% CI, 1.34-5.16; P=0.0051).
Perrot et al (2022)⁹ presented (at the 64th ASH Annual Meeting and Exposition) a post hoc analysis of patient-reported outcomes (PROs) in a subgroup of frail patients from the MAIA study (median follow-up, 64.5 months). In the D-Rd arm, larger (≥20 point) reductions in least square (LS) mean pain scores, moderate reductions in fatigue scores, and similar improvements in global health status (GHS) scores were reported compared with the Rd arm. Overall, the median time to worsening of the health-related quality of life (HRQoL) scores were longer in the D-Rd vs Rd arm.
Facon et al (2022)¹⁰ presented (at the 58th American Society of Clinical Oncology [ASCO] Annual Meeting) the results of a subgroup analysis of the phase 3 MAIA study that evaluated the efficacy and PROs of D-Rd vs Rd in subgroups of patients with NDMM who had renal impairment and/or high-risk cytogenetics.
San-Miguel et al (2022)¹¹ presented an analysis of the predictive and prognostic role of MRD negativity and durability in patients treated in the MAIA study. Patients receiving the D-Rd regimen achieved higher rates of MRD-negativity and durability compared with those receiving Rd.
Moreau et al (2022)¹² presented (at the 19th International Myeloma Society [IMS] Annual Meeting) the results of a post hoc analysis of the phase 3 MAIA study to evaluate the impact of treatment duration on long-term clinical outcomes. The median OS in the D-Rd arm was NR vs 20.5 months in patients who received treatment for ≥18 months vs <18 months, respectively. In patients who received treatment for ≥18 months, PFS benefit (HR, 0.57; 95% CI, 0.43-0.76; P<0.0001) and OS benefit (HR, 0.68; 95% CI, 0.47-0.98; P=0.0379) was observed in D-Rd vs Rd arms. Grade 3/4 TEAEs were reported in 96.5% vs 91.2% patients who received treatment for ≥18 months in the D-Rd vs Rd arm, respectively. The most common (≥15% in either treatment arm) grade 3/4 TEAEs were neutropenia (D-Rd, 56.9%; Rd, 41.2%), anemia (D-Rd, 17%; Rd, 18.1%), lymphopenia (D-Rd, 17%; Rd, 12.3%), pneumonia (D-Rd, 19.8%; Rd, 10.8%), and cataract (D-Rd, 13.8%; Rd, 18.6%).
Perrot et al (2021)¹³ presented (at the 63rd ASH Annual Meeting & Exposition) updated PRO analyses from the MAIA study at a median follow-up of 56.2 months.
Perrot et al (2021)¹⁴ presented (at the 63rd ASH Annual Meeting & Exposition) results of post hoc analyses of the MAIA study, which assessed the association between key clinical efficacy endpoints and PROs.
Usmani et al (2021)¹⁵ presented (at the 63rd ASH Annual Meeting & Exposition) on the impact of impaired renal function and lenalidomide starting dose in patients treated in the MAIA study.
Moreau et al (2020)¹⁶ presented (at the 8th Annual Meeting of the Society of Hematologic Oncology [SOHO]) safety and efficacy results of patients on DARZALEX for intravenous (IV) use that discontinued lenalidomide with or without dexamethasone (R±d) in the MAIA study. This analysis is listed in the References section below.
Other relevant literature has been identified in addition to the data summarized above.¹⁷^-¹⁹

PRODUCT LABELING

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

CLINICAL DATA

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an ongoing, international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT; N=737).¹^,² Facon et al (2019)¹ reported the prespecified interim results of this ongoing study, which is summarized below. Bahlis et al (2019)²⁰ presented updated safety and efficacy results from an additional 9-month follow-up in the MAIA study. Kumar et al (2020)²¹ presented updated safety and efficacy results after approximately 4 years of follow-up in the MAIA study. Facon et al (2021)²² reported the updated safety and efficacy results of the MAIA study at the pre-specified interim OS analysis with a median follow-up of 56.2 months. Kumar et al (2022)³ presented the results of an updated efficacy and safety analysis at a median follow-up of 64.5 months. Facon et a (2024)⁴ presented updated efficacy and safety results at a median follow-up of 89.3 months.

Study Design/Methods

Phase 3, multicenter, randomized, open-label, active-controlled (Rd arm), international study.
Key eligibility criteria: documented NDMM, ineligible for high-dose chemotherapy with ASCT due to age (≥65 years) or due to the presence of comorbidities impacting ASCT tolerability, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, creatinine clearance (CrCl) ≥30 mL/min.
Patients were randomized 1:1 to D-Rd (n=368) or Rd (n=369) and received 28-day cycles of:
- Patients in the Rd arm were administered until PD or unacceptable safety event:
  - Lenalidomide 25 mg orally (PO) daily on days 1-21 until PD (10 mg daily if CrCl between 30-50 mL/min).
  - Dexamethasone: 40 mg PO or IV weekly on days 1, 8, 15, and 22, until PD
    (20 mg weekly in patients >75 years of age or with a body mass index [BMI] <18.5 kg/m²).
- Patients in the D-Rd arm were administered until PD or unacceptable safety event the same as above along with:
  - DARZALEX 16 mg/kg IV weekly during cycles 1-2, every 2 weeks during cycles 36, then every 4 weeks during cycle 7+. Following a protocol amendment (2020), patients in the D-Rd arm were given the option to switch from DARZALEX IV to DARZALEX FASPRO for subcutaneous (SC) use. DARZALEX FASPRO was to be administered at a fixed dose of 1800 mg SC over 3-5 minutes in the abdominal SC tissue once every 4 weeks.
Dose modifications:
- Delays in DARZALEX treatment were permissible if patients experienced any of the following AEs that could not be attributed to lenalidomide: grade 4 hematologic events, grade 3 thrombocytopenia with bleeding, febrile neutropenia, neutropenia with infection (any grade), and grade ≥3 nonhematologic AEs (excluding: grade 3 nausea, vomiting, diarrhea that responded to either antiemetics or antidiarrheal treatment within a week and grade 3 fatigue/asthenia that was existing at baseline or that lasted for <7 days after the last DARZALEX administration).²²
Patients in the D-Rd arm were administered the following pre-infusion medications:²²
- Acetaminophen 650-1000 mg IV/PO
- Diphenhydramine 25-50 mg (or equivalent) IV/PO
- Dexamethasone 40 mg IV/PO approximately 1 hours prior to DARZALEX infusion
  (20 mg once weekly for patients >75 years of age or with a BMI <18.5 kg/m²)
For patients with a higher risk of respiratory complications such as mild asthma or chronic obstructive pulmonary disease who have forced expiratory volume in
1 second <80% (FEV1); could receive the following post-infusion mediations: diphenhydramine (or equivalent), short-acting ß2 adrenergic receptor agonists, control medications for lung disease.²²
Serum and urine samples were collected at screening, on day 1 of every cycle for
2 years and every 8 weeks thereafter until PD.
Safety was monitored throughout the study until 30 days after the last dose of the study treatment.²²
Cytogenetic risk was evaluated locally by fluorescence in situ hybridization (FISH) or karyotype testing. High-risk cytogenetics was determined by a deletion (del)17p and/or translocations t(14;16), or t(4;14).
Primary endpoint: PFS
Secondary endpoints: ≥CR rate, duration of response, ≥VGPR rate; MRD-negativity rate, ORR, OS, time from randomization to disease progression on the next line of therapy or death (PFS2), safety, sCR, time to next (2nd-line) treatment, time to response, and time to progression

Results

Efficacy

Median follow-up: 28.0 months (range, 0.0-41.4)
Patients (52% male) ranged in age from 45-90 years (median, 73 years; 70-<75 years, 35%; ≥75 years, 44%), with key baseline characteristics being well-balanced between the arms.
HR for the primary endpoint of PFS: 0.56 (95% CI, 0.43-0.73; P<0.001) indicating a 44% reduction in the risk of progression or death with D-Rd.
Median time to first response was 1.05 months in both arms.
Median PFS: 31.9 months for Rd (95% CI, 28.9-NR); NR for D-Rd
- PFS was maintained among patients ≥75 years (HR, 0.63; 95% CI, 0.44-0.92).
ORR: 92.9% (95% CI, 89.8-95.3) for D-Rd vs 81.3% (95% CI, 76.9-85.1) for Rd (P<0.001)
≥CR was achieved in 175 (47.6%) patients in the D-Rd arm vs 92 (24.9%) patients in the Rd arm (P<0.001).
Median time to ≥CR was 10.4 months for D-Rd and 11.2 months for Rd.
≥VGPR of 79.3% was reported for D-Rd vs 53.1% for Rd (P<0.001).
MRD-negativity was >3 times higher with D-Rd than with Rd (89 [24.2%] vs 27 [7.3%]; P<0.001).
HR for OS: 0.78 (95% CI, 0.56-1.1); data immature after a median follow-up of
28.0 months

Safety

Serious AEs: 62.9% for D-Rd; 62.7% for Rd
AEs leading to discontinuation: 7.1% for D-Rd; 15.9% for Rd
TEAEs with outcome of death: 6.9% for D-Rd; 6.3% for Rd
- Pneumonia was the most common AE that resulted in death (D-Rd, 0.5%; Rd, 0.8%).

Most Common Adverse Events and Second Primary Cancers in the Safety Population^a,¹

Event, n (%)	D-Rd (n=364)		Rd (n=365)
Event, n (%)	Any Grade	Grade 3/4	Any Grade	Grade 3/4
Hematologic
Neutropenia	207 (56.9)	182 (50.0)	154 (42.2)	129 (35.3)
Anemia	126 (34.6)	43 (11.8)	138 (37.8)	72 (19.7)
Leukopenia	68 (18.7)	40 (11.0)	34 (9.3)	18 (4.9)
Lymphopenia	66 (18.1)	55 (15.1)	45 (12.3)	39 (10.7)
Nonhematologic
Infections	314 (86.3)	117 (32.1)	268 (73.4)	85 (23.3)
Pneumonia	82 (22.5)	50 (13.7)	46 (12.6)	29 (7.9)
Diarrhea	207 (56.9)	24 (6.6)	168 (46.0)	15 (4.1)
Constipation	149 (40.9)	6 (1.6)	130 (35.6)	1 (0.3)
Fatigue	147 (40.4)	29 (8.0)	104 (28.5)	14 (3.8)
Peripheral edema	140 (38.5)	7 (1.9)	107 (29.3)	2 (0.5)
Back Pain	123 (33.8)	11 (3.0)	96 (26.3)	11 (3.0)
Asthenia	117 (32.1)	16 (4.4)	90 (24.7)	13 (3.6)
Nausea	115 (31.6)	5 (1.4)	84 (23.0)	2 (0.5)
Second primary cancer^b	32 (8.8)	NA	26 (7.1)	NA
Invasive second primary cancer	12 (3.3)	NA	13 (3.6)	NA
Any infusion-related reaction	149 (40.9)	10 (2.7)	NA	NA
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; NA, not applicable; Rd, lenalidomide + dexamethasone. ^aThe safety population included all patients who received at least one dose of the trial treatment. Adverse events of any grade that were reported in >30% of patients in either treatment arm and grade 3/4 adverse events that were reported in >10% of patients in either treatment arm are listed. ^bThe presence of a second primary cancer was prespecified in the statistical analysis plan as an adverse event of clinical interest.

Final Survival Analysis of the MAIA Study

Facon et al (2024)⁴ presented the updated OS results for the D-Rd vs Rd arm at a long-term median follow-up of around 7.5 years.

Results

Patient Characteristics

A total of 737 (D-Rd, n=368; Rd, n=369) patients were randomized in this study.
The median duration of follow-up was around 7.5 years.
Baseline characteristics of the intent-to-treat (ITT) population are summarized in Table: Demographic and Baseline Disease Characteristics of the ITT Population.

Demographic and Baseline Disease Characteristics of the ITT Population^a^,⁴

Characteristic	D-Rd (n=368)	Rd (n=369)
Age
Median age (range), years	73 (50-90)	74 (45-89)
≥75 years, n (%)	160 (43.5)	161 (43.6)
Male, n (%)	189 (51.4)	195 (52.8)
ECOG PS, n (%)
0	127 (34.5)	123 (33.3)
1	178 (48.4)	187 (50.7)
≥2	63 (17.1)	59 (16.0)
ISS disease stage, n (%)
I	98 (26.6)	103 (27.9)
II	163 (44.3)	156 (42.3)
III	107 (29.1)	110 (29.8)
Type of measurable disease, n (%)
IgG	225 (61.1)	231 (62.6)
IgA	65 (17.7)	66 (17.9)
Other^b	9 (2.4)	10 (2.7)
Detected in urine only	40 (10.9)	34 (9.2)
Detected as serum FLC only	29 (7.9)	28 (7.6)
Cytogenetic risk^c, n (%)
n	319	323
Standard risk	271 (85.0)	279 (86.4)
High risk	48 (15.0)	44 (13.6)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; ITT, intent-to-treat; Rd, lenalidomide/dexamethasone. ^aThe ITT population included all randomized patients. ^bInclusive of IgD, IgE, IgM, and biclonal disease. ^cCytogenetic risk was based on fluorescence in situ hybridization or karyotype analysis; patients who had a high-risk cytogenetic profile had ≥1 of the following high-risk abnormalities: del(17p), t(14;16), or t(4;14).

Efficacy

At a median follow-up of 89.3 months (range, 0-102.2), the 7-year OS rate was 53.1% for the D-Rd arm and 39.3% for the Rd arm.
Median OS was reached for the D-Rd group and was prolonged for patients in the D-Rd vs Rd arm (90.3 vs 64.1 months [HR, 0.67; 95% CI, 0.55-0.82; nominal P<0.0001]). See Table: Analysis of OS in Pre-Specified Patient Subgroups.
Median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and NR in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). See Table: Summary of First Subsequent Antimyeloma Therapy in the Safety Population.
- In the D-Rd vs Rd arm, 10.7% (15/140) vs 24.4% (49/201) of patients received DARZALEX-containing regimens as their first subsequent therapy.
- Among treated patients, 38.5% (140/364) vs 55.1% (201/365) of patients in the D-Rd vs Rd arm received ≥1 subsequent antimyeloma therapy.
- Across subsequent therapy lines, the most common antineoplastic agents in the D-Rd vs Rd arms were bortezomib (27.7% vs 41.9%), DARZALEX (6.3% vs 28.8%), and carfilzomib (7.7% vs 12.3%).
- In patients evaluable for best response to first subsequent antimyeloma therapy, ≥CR was achieved by 4.6% (6/130) vs 4.1% (8/193) in the D-Rd vs Rd arm, and ≥VGPR was achieved by 13.8% (18/130) vs 23.8% (46/193) of patients in the D-Rd vs Rd arm.
- No patient in either group reported the use of B-cell maturation antigen (BCMA)- or G protein–coupled receptor class C group 5 member D (GPRC5D)-targeted therapy.
- Investigational drug was given to 2 patients in the D-Rd group and 2 patients in the Rd group in subsequent therapy lines.

Analysis of OS in Pre-Specified Patient Subgroups^a,⁴

Subgroup	D-Rd		Rd		HR (95% CI)^b
Subgroup	n/N	Median OS, Months	n/N	Median OS, Months	HR (95% CI)^b
Sex
Male	95/189	82.5	120/195	60.6	0.72 (0.55-0.94)
Female	80/179	NE	98/174	67.8	0.66 (0.49-0.89)
Age
<75 years	84/208	NE	107/208	79.6	0.69 (0.52-0.92)
≥75 years	91/160	72.3	111/161	54.8	0.67 (0.51-0.88)
Race
White	161/336	92.7	197/339	65.5	0.71 (0.57-0.87)
Other	14/32	90.3	21/30	49.1	0.50 (0.25-0.99)
Region
North America	46/101	92.7	64/102	54.8	0.57 (0.39-0.83)
Other	129/267	90.3	154/267	66.8	0.74 (0.58-0.93)
Baseline renal function (CrCl)
>60 mL/min	99/206	92.7	123/227	69.9	0.78 (0.60-1.01)
≤60 mL/min	76/162	90.3	95/142	54.4	0.57 (0.42-0.77)
Baseline hepatic function
Normal	156/335	NE	203/340	63.8	0.65 (0.53-0.80)
Impaired	19/31	63.5	15/29	87.4	1.31 (0.66-2.58)
ISS disease stage
I	34/98	NE	42/103	NE	0.79 (0.50-1.24)
II	77/163	92.7	95/156	61.7	0.63 (0.46-0.85)
III	64/107	65.2	81/110	47.3	0.68 (0.49-0.95)
Type of MM
IgG	111/225	87.2	132/231	69.3	0.78 (0.60-1.00)
Non-IgG	35/74	86.4	49/76	53.7	0.58 (0.37-0.89)
Cytogenetic risk at study entry^c
High risk	31/48	55.6	36/44	42.5	0.65 (0.40-1.06)
Standard risk	122/271	NE	160/279	65.5	0.66 (0.52-0.84)
ECOG PS
0	48/127	NE	56/123	NE	0.76 (0.52-1.12)
1	86/178	92.7	118/187	58.3	0.64 (0.48-0.84)
≥2	41/63	62.8	44/59	39.0	0.68 (0.44-1.04)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; 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; Rd, lenalidomide + dexamethasone; t, translocation. ^aIn the ITT population, which included all randomized patients. ^bHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd. ^cCytogenetic risk was based on fluorescence in situ hybridization or karyotype analysis; patients who had a high-risk cytogenetic profile had ≥1 of the following high-risk abnormalities: del(17p), t(14;16), or t(4;14).

Summary of First Subsequent Antimyeloma Therapy in the Safety Population^a,⁴

n (%)	D-Rd (n=140)	Rd (n=201)
First subsequent therapy class^b,c
PI only	69 (49.3)	101 (50.2)
IMiD only	22 (15.7)	25 (12.4)
PI + IMiD	25 (17.9)	16 (8.0)
DARZALEX monotherapy or combination	15 (10.7)	49 (24.4)
Other	9 (6.4)	10 (5.0)
Most common first subsequent therapy regimens^b,d
Bortezomib/cyclophosphamide/dexamethasone	19 (13.6)	29 (14.4)
Bortezomib/dexamethasone	20 (14.3)	28 (13.9)
Bortezomib/melphalan/prednisone	14 (10.0)	28 (13.9)
DARZALEX/bortezomib/dexamethasone	4 (2.9)	27 (13.4)
Lenalidomide/dexamethasone	13 (9.3)	16 (8.0)
Bortezomib/pomalidomide/dexamethasone	9 (6.4)	3 (1.5)
Bortezomib/lenalidomide/dexamethasone	8 (5.7)	3 (1.5)
DARZALEX/lenalidomide/dexamethasone	4 (2.9)	6 (3.0)
Pomalidomide/dexamethasone	2 (1.4)	6 (3.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; IMiD, immunomodulatory drugs; PI, proteasome inhibitor; Rd, lenalidomide + dexamethasone. ^aThe safety population included all randomized patients who received ≥1 dose of study treatment. ^bPercentages were calculated with the number of patients who received subsequent therapy in each treatment group as the denominator. ^cTherapy classes are mutually exclusive. Patients in any therapy class subgroup may have received additional agents (other than PI, IMiD, or DARZALEX), such as dexamethasone. ^dRegimens received by ≥3% of patients in either treatment group.

Safety and Tolerability

Among the safety population, 78.3% (n=285) of patients in the D-Rd arm and 94.5% (n=345) in the Rd arm discontinued study treatment.
- Progressive disease was the primary reason for discontinuation in both the D-Rd (32.7%) and Rd arms (38.6%).
- A lower proportion of patients in the D-Rd (16.5%) and Rd arms (25.8%) discontinued study treatment due to AEs.
In the D-Rd vs Rd arm, 33% reduction in the risk of death was reported.
- Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression. See Table: Summary of Death and Causes of Death in the Safety Population.

Summary of Death and Causes of Death in the Safety Population^a,⁴

n (%)	D-Rd (n=364)	Rd (n=365)
Total number of patients who died during the study	173 (47.5)	218 (59.7)
Primary cause of death
Disease progression	76 (20.9)	88 (24.1)
Adverse events	44 (12.1)	40 (11.0)
Related to study treatment^b	14 (3.8)	10 (2.7)
Unrelated to study treatment	28 (7.7)	29 (7.9)
Others^c	53 (14.6)	90 (24.7)
Infections/infestations	9 (2.5)	30 (8.2)
General disorders/administration site conditions^d	11 (3.0)	5 (1.4)
Neoplasms (benign, malignant, or unspecified)	11 (3.0)	4 (1.1)
Cardiac disorders	1 (0.3)	8 (2.2)
Nervous system disorders	3 (0.8)	5 (1.4)
Unknown	13 (3.6)	27 (7.4)
Deaths within 30 days of last study treatment dose	31 (8.5)	35 (9.6)
Primary cause of death
Disease progression	1 (0.3)	1 (0.3)
Adverse events	29 (8.0)	32 (8.8)
Related to study treatment^b	11 (3.0)	10 (2.7)
Unrelated to study treatment	18 (4.9)	22 (6.0)
Other^e	1 (0.3)	2 (0.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide/dexamethasone.^aThe safety population included all randomized patients who received ≥1 dose of study treatment.^bAdverse events were related to ≥1 of the 3 components of study treatment: DARZALEX, lenalidomide, and dexamethasone. ^cOther reasons were reported in ≥1% of patients in either treatment group. ^dAll events were related to the general health condition of the patient. ^eIncludes a nervous system disorder in 1 patient in the D-Rd group and a blood and lymphatic system disorder and general disorder/administration site condition in 1 patient each in the Rd group.

Kumar et al (2022)³ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months), of the MAIA study in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT.

Results

Patient Characteristics

A total of 737 patients were randomized (D-Rd, n=368; Rd, n=369).
The median duration of follow-up was 64.5 months overall, and 73.6 months for OS.
Patient disposition in the ITT population is summarized in the Table: Summary of Patient Disposition in the ITT Population (MAIA).

Summary of Patient Disposition in the ITT Population (MAIA)³

Parameter	D-Rd (n=368)^a	Rd (n=369)^a
Patients treated, n (%)^b	364 (98.9)	365 (98.9)
Patients who discontinued treatment, n (%)^c	233 (64.0)	311 (85.2)
Reason for discontinuation, n (%)
Progressive disease	107 (29.4)	131 (35.9)
Adverse event	57 (15.7)	89 (24.4)
Death	24 (6.6)	25 (6.8)
Noncompliance with study drug	21 (5.8)	30 (8.2)
Patient withdrawal	2 (0.5)	8 (2.2)
Physician decision	16 (4.4)	24 (6.6)
Loss to follow-up	1 (0.3)	2 (0.5)
Other	5 (1.4)	2 (0.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; Rd, lenalidomide + dexamethasone. ^aData are based on a median follow-up of 64.5 months. ^bPercentages are based on the number of patients randomized. ^cPercentages are based on the number of patients treated.

Efficacy

At a median follow-up of 64.5 months, the median PFS in the D-Rd vs Rd arm was 61.9 vs 34.4 months (HR, 0.55; 95% CI, 0.45-0.67; P<0.0001).
- The 60-month PFS rate in the D-Rd vs Rd arm was 52.1% vs 29.6%.
At a median follow-up of 73.6 months, the median OS in the D-Rd vs Rd arm was NR vs 64.1 months (HR, 0.65; 95% CI, 0.52-0.80; P<0.0001).
- The 60-month OS rate in the D-Rd vs Rd arm was 66.7% vs 53.7%.
- OS benefit with D-Rd vs Rd treatment was generally consistent across the prespecified patient subgroups, see Table: OS in Prespecified Subgroups (MAIA).

OS in Prespecified Subgroups (MAIA)³

Subgroup	D-Rd^a		Rd^a		HR (95% CI)^{a, b}
Subgroup	n/N	Median OS, Months	n/N	Median OS, Months	HR (95% CI)^{a, b}
Sex
Male	86/189	NE	114/195	60.6	0.70 (0.53-0.93)
Female	64/179	NE	88/174	67.8	0.62 (0.45-0.85)
Age
<75 years	71/208	NE	101/208	77.6	0.64 (0.47-0.86)
≥75 years	79/160	73.5	101/161	54.8	0.67 (0.50-0.90)
Race
White	138/336	NE	181/339	65.4	0.69 (0.55-0.86)
Other	12/32	NE	21/30	49.1	0.43 (0.21-0.88)
Region
North America	40/101	NE	61/102	54.8	0.54 (0.36-0.80)
Other	110/267	NE	141/267	66.4	0.71 (0.55-0.91)
Baseline renal function (CrCl)
>60 mL/min	83/206	NE	113/227	69.7	0.72 (0.55-0.96)
≤60 mL/min	67/162	NE	89/142	54.8	0.56 (0.41-0.77)
Baseline hepatic function
Normal	132/335	NE	188/340	63.8	0.62 (0.49-0.77)
Impaired	18/31	63.5	14/29	73.8	1.29 (0.64-2.60)
ISS disease stage
I	28/98	NE	36/103	NE	0.78 (0.48-1.28)
II	64/163	NE	88/156	61.7	0.59 (0.43-0.81)
III	58/107	65.2	78/110	47.3	0.66 (0.47-0.93)
Type of MM
IgG	93/225	NE	120/231	68.6	0.74 (0.56-0.97)
Non-IgG	29/74	NE	46/76	53.7	0.54 (0.34-0.85)
Cytogenetic risk at study entry
High risk^c	28/48	55.6	36/44	42.5	0.65 (0.39-1.06)
Standard risk	105/271	NE	147/279	65.5	0.64 (0.50-0.82)
ECOG PS
0	37/127	NE	49/123	NE	0.69 (0.45-1.06)
1	76/178	NE	110/187	58.3	0.62 (0.47-0.84)
≥2	37/63	61.9	43/59	39.0	0.64 (0.41-1.00)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; 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; Rd, lenalidomide + dexamethasone; t, translocation. ^aData are based on a median follow-up of 73.6 months. ^bHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-Rd. ^cPatients with high cytogenetic risk were positive by fluorescence in situ hybridization or karyotype testing for ≥1 of the following cytogenetic abnormalities: t(4;14), t(14;16), or del(17p).

At a median follow-up of 64.5 months, the ORR, MRD-negativity rate, and rates of sustained MRD-negativity lasting ≥12 months and ≥18 months were higher with D-Rd vs Rd treatment; see Table: Summary of ORR, MRD-Negativity Rate, and Sustained MRD-Negativity Rates in the ITT Population (MAIA).
At a median follow-up of 73.6 months, the OS was improved in patients who were MRDnegative (D-Rd, 88.9%; Rd, 78.0%) vs patients who were MRD-positive (D-Rd, 55.9%; Rd, 50.4%) in both treatment arms; however, more patients in the D-Rd arm achieved MRD-negativity.

Summary of ORR, MRD-Negativity Rate, and Sustained MRD-Negativity Rates in the ITT Population (MAIA)³

Parameter	D-Rd (n=368)^a	Rd (n=369)^a	P Value^a
ORR, n (%)	342 (92.9)	301 (81.6)	<0.0001
≥CR	188 (51.1)	111 (30.1)	<0.0001
sCR	131 (35.6)	58 (15.7)	<0.0001
CR	57 (15.5)	53 (14.4)	-
≥VGPR	300 (81.5)	210 (56.9)	<0.0001
VGPR	112 (30.4)	99 (26.8)	-
PR	42 (11.4)	91 (24.7)	-
MRD-negative, n (%)	118 (32.1)	41 (11.1)	<0.0001
Sustained MRD-negative, n (%)
Lasting ≥12 months	69 (18.8)	15 (4.1)	<0.0001
Lasting ≥18 months	62 (16.8)	12 (3.3)	<0.0001
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; VGPR, very good partial response. ^aData are based on a median follow-up of 64.5 months.

At a median follow-up of 64.5 months, a total of 128 patients in the D-Rd arm and 194 patients in the Rd arm received subsequent therapy.
- In the D-Rd vs Rd arm, 9.4% vs 23.2% of patients received DARZALEXcontaining treatment as the first subsequent therapy and 14.1% vs 48.5% of patients received DARZALEX-containing treatment in any subsequent line of therapy.

Safety

The most common TEAEs (median follow-up, 64.5 months) are summarized in the Table: Summary of Any-Grade (≥30%) and Grade 3/4 (≥20%) TEAEs in the Safety Population MAIA.
- The grade 3/4 infection rate in the D-Rd vs Rd arm was 42.6% vs 29.6%.
The most common serious TEAE in both arms was pneumonia (D-Rd, 18.7%; Rd, 10.7%).
The rate of treatment discontinuation due TEAEs in the D-Rd vs Rd arm was 14.6% vs 23.8%.

Summary of Any-Grade (≥30%) and Grade 3/4 (≥20%) TEAEs in the Safety Population (MAIA)^a,³

Event, n (%)	D-Rd (n=364)		Rd (n=365)
Event, n (%)	Any-Grade	Grade 3/4	Any-Grade	Grade 3/4
Hematologic
Neutropenia	224 (61.5)	197 (54.1)	166 (45.5)	135 (37.0)
Anemia	154 (42.3)	62 (17.0)	150 (41.1)	79 (21.6)
Nonhematologic
Diarrhea	240 (65.9)	33 (9.1)	188 (51.5)	22 (6.0)
Fatigue	164 (45.1)	33 (9.1)	114 (31.2)	17 (4.7)
Constipation	157 (43.1)	6 (1.6)	137 (37.5)	2 (0.5)
Peripheral edema	155 (42.6)	10 (2.7)	117 (32.1)	3 (0.8)
Back pain	155 (42.6)	14 (3.8)	109 (29.9)	14 (3.8)
Asthenia	136 (37.4)	19 (5.2)	101 (27.7)	18 (4.9)
Nausea	133 (36.5)	7 (1.9)	88 (24.1)	2 (0.5)
Insomnia	125 (34.3)	11 (3.0)	116 (31.8)	14 (3.8)
Bronchitis	124 (34.1)	12 (3.3)	87 (23.8)	7 (1.9)
Pneumonia	113 (31.0)	71 (19.5)	66 (18.1)	39 (10.7)
Cough	123 (33.8)	2 (0.5)	65 (17.8)	0 (0.0)
Dyspnea	119 (32.7)	12 (3.3)	63 (17.3)	4 (1.1)
Weight decreased	112 (30.8)	10 (2.7)	69 (18.9)	11 (3.0)
Muscle spasms	111 (30.5)	2 (0.5)	86 (23.6)	5 (1.4)
Peripheral sensory neuropathy	111 (30.5)	9 (2.5)	66 (18.1)	2 (0.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event. ^aData are based on a median follow-up 64.5 months.

Analysis of Clinically Important Subgroups of MAIA

Moreau et al (2022)⁵ presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

Efficacy outcomes (PFS, ORR, and MRD-negativity) were analyzed in subgroups based on the following patient characteristics:
- Age ≥75 years
- International Staging System (ISS) stage III disease
- Renal insufficiency (baseline CrCl ≤60 mL/min)
- Extramedullary plasmacytomas
- Cytogenetic risk
  - Standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], and del[17p])
  - High cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], and del[17p])
  - Revised standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
  - Revised high cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
  - Gain(1q21) (3 copies of chromosome 1q21, with or without other HRCAs)
  - Amp(1q21) (≥4 copies of chromosome 1q21, with or without other HRCAs)
  - Gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, with or without other HRCAs)
  - 1 HRCA (only 1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21])
  - Two or more HRCAs (≥2 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
  - Isolated gain(1q21) (3 copies of chromosome 1q21, without any other HRCAs)
  - Isolated amp(1q21) (≥4 copies of chromosome 1q21, without any other HRCAs)
  - Isolated gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, without any other HRCAs)
  - Gain(1q21) or amp(1q21) plus ≥1 HRCA (3 or ≥4 copies of chromosome 1q21, plus ≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], and t[14;20])

Results

Patient Characteristics

Overall, 737 patients (D-Rd, 368; Rd, 369) were included in the ITT population.
The median duration of follow-up was 64.5 months.

Efficacy

The PFS duration was longer in the D-Rd vs Rd arm in the majority of subgroups. See Table: Subgroup Analysis of PFS in the ITT Population of MAIA.
- PFS was improved in the D-Rd vs Rd arm among patients with the following characteristics:
  - Revised standard cytogenetic risk (HR, 0.50; 95% CI, 0.37-0.66; P<0.0001)
  - 1 HRCA (HR, 0.55; 95% CI, 0.40-0.76; P=0.0003)
  - Isolated gain(1q21) (HR, 0.36; 95% CI, 0.19-0.67; P=0.0008)
  - Isolated amp(1q21) (HR, 0.78; 95% CI, 0.50-1.22; P=0.2764)
- PFS was similar in the D-Rd and Rd arms among patients with ≥2 HRCAs (P=0.8477).
A more favorable result was reported in the D-Rd vs Rd arm for the following endpoints across all subgroups:
- ORR (See Table: Subgroup Analysis of ORR in the ITT Population of MAIA)
- MRD-negativity (10^-5) rate (See Table: Subgroup Analysis of MRD-negativity (10^-5) Rates in the ITT Population of MAIA)
- Sustained MRD-negativity (10^-5) lasting ≥12 months (See Table: Subgroup Analysis of Rates of Sustained MRD-Negativity (10^-5) Lasting ≥12 Months in the ITT Population)

Subgroup Analysis of PFS in the ITT Population of MAIA⁵

Subgroup	D-Rd		Rd		HR (95% CI)^a
Subgroup	n/N	Median PFS, Month	n/N	Median PFS, Month	HR (95% CI)^a
ITT (overall)	176/368	61.9	228/369	34.4	0.55 (0.45-0.67)
Baseline characteristic
Age ≥75 years	87/160	54.3	106/161	31.4	0.59 (0.44-0.79)
ISS stage III	61/107	42.4	73/110	24.2	0.61 (0.43-0.86)
Renal insufficiency	82/162	56.7	92/142	29.7	0.55 (0.41-0.75)
Extramedullary plasmacytomas	7/15	57.5	5/9	19.4	0.47 (0.15-1.50)
Cytogenetic risk
Standard cytogenetic risk	126/271	63.8	174/279	34.4	0.51 (0.41-0.64)
High cytogenetic risk	28/48	45.3	31/44	29.6	0.57 (0.34-0.96)
Revised standard cytogenetic risk	78/176	NR	115/187	35.1	0.50 (0.37-0.66)
Revised high cytogenetic risk	82/156	56.0	96/152	30.7	0.59 (0.44-0.80)
Gain(1q21)	20/53	NR	28/44	37.8	0.43 (0.24-0.76)
Amp(1q21)	48/74	40.0	45/76	26.1	0.81 (0.54-1.21)
Gain(1q21) or amp(1q21)	68/127	53.2	73/120	32.3	0.63 (0.46-0.88)
1 HRCA	68/137	61.4	86/137	31.2	0.55 (0.40-0.76)
≥2 HRCAs	14/19	24.9	10/15	24.0	0.92 (0.40-2.10)
Isolated gain(1q21)	16/47	NR	27/42	37.8	0.36 (0.19-0.67)
Isolated amp(1q21)	38/61	42.8	38/65	28.9	0.78 (0.50-1.22)
Isolated gain(1q21) or amp(1q21)	54/108	61.4	65/107	37.1	0.58 (0.40-0.83)
Gain(1q21) or amp(1q21) plus ≥1 HRCA	14/19	24.9	8/13	24.0	1.03 (0.42-2.48)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; NR, not reached; PFS, progression-free survival; Rd, lenalidomide + dexamethasone. ^aHR <1 indicates an advantage for D-Rd.

Subgroup Analysis of ORR in the ITT Population of MAIA⁵

Subgroup	D-Rd n/N (%)	Rd n/N (%)	OR (95% CI)^a
ITT (overall)	342/368 (92.9)	301/369 (81.6)	2.97 (1.84-4.79)
Baseline characteristic
Age ≥75 years	144/160 (90.0)	131/161 (81.4)	2.06 (1.07-3.95)
ISS stage III	93/107 (86.9)	86/110 (78.2)	1.85 (0.90-3.81)
Renal insufficiency	146/162 (90.1)	112/142 (78.9)	2.44 (1.27-4.70)
Extramedullary plasmacytomas	13/15 (86.7)	3/9 (33.3)	13.00 (1.70-99.37)
Cytogenetic risk
Standard cytogenetic risk	253/271 (93.4)	228/279 (81.7)	3.14 (1.78-5.54)
High cytogenetic risk	44/48 (91.7)	33/44 (75.0)	3.67 (1.07-12.55)
Revised standard cytogenetic risk	162/176 (92.0)	149/187 (79.7)	2.95 (1.54-5.66)
Revised high cytogenetic risk	147/156 (94.2)	126/152 (82.9)	3.37 (1.52-7.46)
Gain(1q21)	51/53 (96.2)	39/44 (88.6)	3.27 (0.60-17.75)
Amp(1q21)	70/74 (94.6)	63/76 (82.9)	3.61 (1.12-11.65)
Gain(1q21) or amp(1q21)	121/127 (95.3)	102/120 (85.0)	3.56 (1.36-9.30)
1 HRCA	129/137 (94.2)	114/137 (83.2)	3.25 (1.40-7.56)
≥2 HRCAs	18/19 (94.7)	12/15 (80.0)	4.50 (0.42-48.53)
Isolated gain(1q21)	46/47 (97.9)	37/42 (88.1)	6.22 (0.70-55.56)
Isolated amp(1q21)	57/61 (93.4)	55/65 (84.6)	2.59 (0.77-8.75)
Isolated gain(1q21) or amp(1q21)	103/108 (95.4)	92/107 (86.0)	3.36 (1.17-9.60)
Gain(1q21) or amp(1q21) plus ≥1HRCA	18/19 (94.7)	10/13 (76.9)	5.40 (0.49-59.02)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; OR, odds ratio; ORR, overall response rate; Rd, lenalidomide + dexamethasone. ^aOR >1 indicates an advantage for D-Rd.

Subgroup Analysis of MRD-negativity (10^-5) Rates in the ITT Population of MAIA⁵

Subgroup	D-Rd n/N (%)	Rd n/N (%)	OR (95% CI)^a
ITT (overall)	118/368 (32.1)	41/369 (11.1)	3.78 (2.55-5.59)
Baseline characteristic
Age ≥75 years	43/160 (26.9)	16/161 (9.9)	3.33 (1.79-6.21)
ISS stage III	29/107 (27.1)	12/110 (10.9)	3.04 (1.46-6.34)
Renal insufficiency	48/162 (29.6)	11/142 (7.7)	5.01 (2.49-10.11)
Extramedullary plasmacytomas	5/15 (33.3)	0/9 (0)	NE (NE-NE)
Cytogenetic risk
Standard cytogenetic risk	93/271 (34.3)	33/279 (11.8)	3.89 (2.50-6.06)
High cytogenetic risk	12/48 (25.0)	1/44 (2.3)	14.33 (1.78-115.59)
Revised standard cytogenetic risk	60/176 (34.1)	21/187 (11.2)	4.09 (2.36-7.09)
Revised high cytogenetic risk	49/156 (31.4)	15/152 (9.9)	4.18 (2.22-7.86)
Gain(1q21)	19/53 (35.8)	6/44 (13.6)	3.54 (1.27-9.89)
Amp(1q21)	23/74 (31.1)	8/76 (10.5)	3.83 (1.59-9.27)
Gain(1q21) or amp(1q21)	42/127 (33.1)	14/120 (11.7)	3.74 (1.92-7.30)
1 HRCA	44/137 (32.1)	15/137 (10.9)	3.85 (2.02-7.34)
≥2 HRCAs	5/19 (26.3)	0/15 (0)	NE (NE-NE)
Isolated gain(1q21)	17/47 (36.2)	6/42 (14.3)	3.40 (1.19-9.71)
Isolated amp(1q21)	20/61 (32.8)	8/65 (12.3)	3.48 (1.39-8.66)
Isolated gain(1q21) or amp(1q21)	37/108 (34.3)	14/107 (13.1)	3.46 (1.74-6.89)
Gain(1q21) or amp(1q21) plus ≥1 HRCA	5/19 (26.3)	0/13 (0)	NE (NE-NE)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; Rd, lenalidomide + dexamethasone. ^aOR >1 indicates an advantage for D-Rd.

Subgroup Analysis of Rates of Sustained MRD-Negativity (10^-5) Lasting ≥12 Months in the ITT Population⁵

Subgroup	D-Rd n/N (%)	Rd n/N (%)	OR (95% CI)^a
ITT (overall)	69/368 (18.8)	15/369 (4.1)	5.45 (3.05-9.72)
Baseline characteristic
Age ≥75 years	22/160 (13.8)	5/161 (3.1)	4.97 (1.83-13.49)
ISS stage III	17/107 (15.9)	3/110 (2.7)	6.74 (1.91-23.73)
Renal insufficiency	30/162 (18.5)	2/142 (1.4)	15.91 (3.73-67.89)
Extramedullary plasmacytomas	2/15 (13.3)	0/9 (0)	NE (NE-NE)
Cytogenetic risk
Standard cytogenetic risk	55/271 (20.3)	11/279 (3.9)	6.20 (3.17-12.14)
High cytogenetic risk	6/48 (12.5)	0/44 (0)	NE (NE-NE)
Revised standard cytogenetic risk	31/176 (17.6)	5/187 (2.7)	7.78 (2.95-20.52)
Revised high cytogenetic risk	32/156 (20.5)	7/152 (4.6)	5.35 (2.28-12.53)
Gain(1q21)	14/53 (26.4)	3/44 (6.8)	4.91 (1.31-18.40)
Amp(1q21)	13/74 (17.6)	4/76 (5.3)	3.84 (1.19-12.38)
Gain(1q21) or amp(1q21)	27/127 (21.3)	7/120 (5.8)	4.36 (1.82-10.44)
1 HRCA	31/137 (22.6)	7/137 (5.1)	5.43 (2.30-12.83)
≥2 HRCAs	1/19 (5.3)	0/15 (0)	NE (NE-NE)
Isolated gain(1q21)	14/47 (29.8)	3/42 (7.1)	5.52 (1.46-20.86)
Isolated amp(1q21)	12/61 (19.7)	4/65 (6.2)	3.73 (1.13-12.31)
Isolated gain(1q21) or amp(1q21)	26/108 (24.1)	7/107 (6.5)	4.53 (1.87-10.97)
Gain(1q21) or amp(1q21) plus ≥1 HRCA	1/19 (5.3)	0/13 (0)	NE (NE-NE)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; Rd, lenalidomide + dexamethasone. ^aOR >1 indicates an advantage for D-Rd.

Safety (Patients Aged ≥75 Years)

Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95.0% patients in the D-Rd vs Rd arm.
- The most common (≥20%) grade 3/4 TEAEs were neutropenia (D-Rd, 62.4%; Rd, 41.5%), lymphopenia (D-Rd, 21.0%; Rd, 12.6%), anemia (DRd, 20.4%; Rd, 25.2%), and pneumonia (D-Rd, 20.4%; Rd, 14.5%).
Serious TEAEs were reported in 80.9% vs 79.2% of patients in the D-Rd vs Rd arm, the most common of which was pneumonia (D-Rd, 19.7%; Rd, 12.6%).
TEAEs led to treatment discontinuation in 15.3% vs 27.7% of patients in the D-Rd vs Rd arm.
TEAEs resulting in death were reported in 11.5% vs 13.2% of patients in the D-Rd vs Rd arm.

Impact of Frailty on Safety and Efficacy in the MAIA Study

Facon et al (2022)⁶ reported a post hoc subgroup analysis of frailty status in patients with NDMM ineligible for transplant in the MAIA study.

Results

Patient Characteristics

Patients (D-Rd, n=368; Rd, n=369) were stratified based on frailty scores (assessed using age, Charlson comorbidity index, and baseline ECOG PS scores):
- Frail patients: 172 (46.7%) in the D-Rd arm vs 169 (45.8%) in the Rd arm
- Total non-frail (fit and intermediate combined) patients: 196 (53.3%) in the D-Rd arm vs 200 (54.2%) in the Rd arm
- Intermediate patients: 128 (34.8%) in the D-Rd arm vs 122 (33.1%) in the Rd arm
- Fit patients: 68 (18.5%) in the D-Rd arm vs 78 (21.1%) in the Rd arm
Median duration of follow-up was 36.4 months.

Efficacy

Median relative dose intensity (RDI) of DARZALEX was consistent across all frailty subgroups (≥98.0%).
Median RDI of lenalidomide was higher in the D-Rd arm (77.2% vs 65.4%) and lower in the Rd arm (86.4% vs 92.9%) for patients in the total non-frail vs frail subgroup, respectively.
Median PFS benefit was observed in all subgroups:
- For frail patients, PFS was NR in the D-Rd arm vs 30.4 months in the Rd arm (HR, 0.62; 95% CI, 0.45-0.85; P=0.003).
- For total non-frail patients, PFS was NR in the D-Rd arm vs 41.7 months in the Rd arm (HR, 0.48; 95% CI, 0.34-0.68; P<0.0001).
- For intermediate patients, PFS was NR in both the D-Rd and Rd arms (HR, 0.53; 95% CI, 0.35-0.80; P=0.0024).
- For fit patients, PFS was NR in the D-Rd arm vs 41.7 months in the Rd arm (HR, 0.41; 95% CI, 0.22-0.75; P=0.0028).
The 36-month PFS rate was higher in the D-Rd vs Rd arm, respectively, in all subgroups:
- Frail patients: 61.5% vs 39.5%
- Total non-frail patients: 73.2% vs 52.1%
- Intermediate patients: 70.4% vs 51.7%
- Fit patients: 78.3% vs 53.6%
ORR was 87.2% vs 78.1% (P=0.0265) in frail patients, 98.0% vs 84.5% (P<0.0001) in total non-frail patients, 96.9% vs 85.2% (P=0.0012) in intermediate patients, and 100.0% vs 83.3% (P=0.0004) in fit patients receiving D-Rd vs Rd, respectively.
The rate of achieving ≥CR was 43.6% vs 30.8% (P=0.0144) in frail patients, 54.6% vs 24.0% (P<0.0001) in total nonfrail patients, 53.9% vs 25.4% (P<0.0001) in intermediate patients, and 55.9% vs 21.8% (P<0.0001) in fit patients receiving D-Rd vs Rd, respectively.
The rate of achieving ≥VGPR was 74.4% vs 53.8% (P<0.0001) in frail patients, 85.2% vs 56.0% (P<0.0001) in total nonfrail patients, 84.4% vs 57.4% (P<0.0001) in intermediate patients, and 86.8% vs 53.8% (P<0.0001) in fit patients receiving D-Rd vs Rd, respectively.
The rate of MRD-negativity was 23.8% vs 10.1% (P=0.0008) in frail patients, 33.2% vs 8.5% (P<0.0001) in total non-frail patients, 32.8% vs 9.0% (P<0.0001) in intermediate patients, and 33.8% vs 7.7% (P<0.0001) in fit patients receiving D-Rd vs Rd, respectively.

Safety

Incidence of serious TEAE was higher in the frail subgroup vs all other subgroups. The most common serious TEAE in patients receiving D-Rd vs Rd, respectively, was pneumonia across all subgroups: frail, 17.9% vs 8.4%; total non-frail, 10.7% vs 9.0%; intermediate, 10.2% vs 9.8%; and fit, 11.8% vs 7.8%.
The most common (≥10%) grade 3/4 TEAEs and TEAEs with an outcome of death (>1 patient, safety population) are summarized in Table: Summary of Safety Data.

Summary of Safety Data⁶

Parameter, n (%)	Non-frail						Frail (n=334)
	Fit (n=145)		Intermediate (n=250)		Total Non-frail (n=395)		Frail (n=334)
	D-Rd (n= 68)	Rd (n= 77)	D-Rd (n= 128)	Rd (n= 122)	D-Rd (n= 196)	Rd (n= 199)	D-Rd (n= 168)	Rd (n= 166)
Total number of patients with grade 3/4 TEAEs	58 (85.3)	61 (79.2)	117 (91.4)	104 (85.2)	175 (89.3)	165 (82.9)	159 (94.6)	148 (89.2)
Hematologic TEAEs
Neutropenia	30 (44.1)	22 (28.6)	59 (46.1)	52 (42.6)	89 (45.4)	74 (37.2)	97 (57.7)	55 (33.1)
Lymphopenia	7 (10.3)	7 (9.1)	18 (14.1)	14 (11.5)	25 (12.8)	21 (10.6)	31 (18.5)	18 (10.8)
Leukopenia	7 (10.3)	2 (2.6)	11 (8.6)	10 (8.2)	18 (9.2)	12 (6.0)	22 (13.1)	9 (5.4)
Anemia	4 (5.9)	11 (14.3)	17 (13.3)	24 (19.7)	21 (10.7)	35 (17.6)	28 (16.7)	40 (24.1)
Thrombocytopenia	4 (5.9)	3 (3.9)	8 (6.3)	12 (9.8)	12 (6.1)	15 (7.5)	17 (10.1)	18 (10.8)
Nonhematologic TEAEs
Infections	16 (23.5)	22 (28.6)	46 (35.9)	30 (24.6)	62 (31.6)	52 (26.1)	70 (41.7)	46 (27.7)
Pneumonia	7 (10.3)	5 (6.5)	13 (10.2)	11 (9.0)	20 (10.2)	16 (8.0)	33 (19.6)	17 (10.2)
Cataract	10 (14.7)	8 (10.4)	11 (8.6)	9 (7.4)	21 (10.7)	17 (8.5)	13 (7.7)	19 (11.4)
Pulmonary embolism	8 (11.8)	5 (6.5)	6 (4.7)	9 (7.4)	14 (7.1)	14 (7.0)	7 (4.2)	5 (3.0)
Hypokalemia	7 (10.3)	5 (6.5)	12 (9.4)	10 (8.2)	19 (9.7)	15 (7.5)	18 (10.7)	20 (12.0)
Hyperglycemia	2 (2.9)	2 (2.6)	13 (10.2)	4 (3.3)	15 (7.7)	6 (3.0)	12 (7.1)	8 (4.8)
Total number of patients with TEAE with an outcome of death	1 (1.5)	3 (3.9)	6 (4.7)	4 (3.3)	7 (3.6)	7 (3.5)	20 (11.9)	20 (12.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatmentemergent adverse event.

The 2 most common reasons for treatment discontinuation across all subgroups were PD and AEs. Median time to treatment discontinuation was 13.4 vs 12.1 months in frail patients, 19.1 vs 12.0 months in total non-frail patients, 16.4 vs 10.4 months in intermediate patients, and 22.3 vs 17.3 months in fit patients receiving D-Rd vs Rd, respectively.
TEAEs that led to treatment discontinuation most frequently were fatigue and pulmonary embolism in the D-Rd and Rd arms, respectively. The rates of treatment discontinuation due to TEAEs were highest in the frail subgroup:
- Frail patients: 10.1% and 19.3% receiving D-Rd and Rd, respectively
- Total non-frail patients: 6.6% and 15.6% receiving D-Rd and Rd, respectively
- Intermediate patients: 6.3% and 16.4% receiving D-Rd and Rd, respectively
- Fit patients: 7.4% and 14.3% receiving D-Rd and Rd, respectively
The rates of death and TEAEs resulting in death were highest in the frail subgroup. Deaths were reported in:
- Frail patients: 33.9% and 34.3% receiving D-Rd and Rd, respectively
- Total non-frail patients: 13.3% and 23.1% receiving D-Rd and Rd, respectively
- Intermediate patients: 16.4% and 27.9% receiving D-Rd and Rd, respectively
- Fit patients: 7.4% and 15.6% receiving D-Rd and Rd, respectively
Deaths were reported due to TEAEs in frail (11.9% vs 12.0%), total non-frail (3.6% vs 3.5%), intermediate (4.7% vs 3.3%), and fit (1.5% vs 3.9%) patients receiving DRd vs Rd, respectively.

Subgroup Analysis of MAIA According to Age

Facon et al (2022)⁷ presented the efficacy results of the MAIA study according to age group.

Results

Patient Characteristics

Of the 737 randomized patients (D-Rd, n=368; Rd, n=369), 155 (21%) patients were aged <70 years and 261 (35%) patients were aged ≥70 to <75 years. Overall, 416 (56%) patients were aged <75 years.
The median duration of follow-up was 64.5 months.
The proportions of patients who discontinued treatment across arms are summarized in the Table: Patient Disposition and Treatment Discontinuations According to Age Group in the ITT Population (MAIA).

Patient Disposition and Treatment Discontinuations According to Age Group in the ITT Population (MAIA)⁷

Parameter	Age <70 Years		Age ≥70 to <75 Years		Age <75 Years
Parameter	D-Rd (n=78)	Rd (n=77)	D-Rd (n=130)	Rd (n=131)	D-Rd (n=208)	Rd (n=208)
Patients treated, n (%)^a	78 (100)	76 (98.7)	129 (99.2)	130 (99.2)	207 (99.5)	206 (99.0)
Patients who discontinued treatment, n (%)^b	37 (47.4)	64 (84.2)	79 (61.2)	106 (81.5)	116 (56.0)	170 (82.5)
Reasons for discontinuation, n (%)
PD	17 (21.8)	34 (44.7)	42 (32.6)	47 (36.2)	59 (28.5)	81 (39.3)
AE	9 (11.5)	12 (15.8)	20 (15.5)	33 (25.4)	29 (14.0)	45 (21.8)
Noncompliance with study drug	5 (6.4)	5 (6.6)	7 (5.4)	7 (5.4)	12 (5.8)	12 (5.8)
Death	5 (6.4)	2 (2.6)	5 (3.9)	7 (5.4)	10 (4.8)	9 (4.4)
Physician’s decision	1 (1.3)	9 (11.8)	3 (2.3)	7 (5.4)	4 (1.9)	16 (7.8)
Patient withdrawal	0	2 (2.6)	1 (0.8)	3 (2.3)	1 (0.5)	5 (2.4)
Other	0	0	1 (0.8)	2 (1.5)	1 (0.5)	2 (1.0)
Abbreviations: AE, adverse event; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; PD, progressive disease; Rd, lenalidomide + dexamethasone. ^aPercentages are based on number of patients randomized. ^bPercentages are based on number of patients treated.

Efficacy

The median PFS, the 60-month PFS rate, the OS, and the 60-month OS rate were greater in the D-Rd arm than the Rd arm in all age groups. See Table: Survival Outcomes According to Age Group in the ITT Population (MAIA).
The PFS and OS benefit was most pronounced in patients aged <70 years.
The ORR and the rates of ≥CR, ≥VGPR, sCR, and MRD-negativity (10^-5) were higher in the D-Rd arm than the Rd arm in all age groups. See Table: Response Outcomes According to Age Group in the ITT Population (MAIA).

Survival Outcomes According to Age Group in the ITT Population (MAIA)⁷

Parameter	Age <70 Years		Age ≥70 to <75 Years		Age <75 Years
Parameter	D-Rd (n=78)	Rd (n=77)	D-Rd (n=130)	Rd (n=131)	D-Rd (n=208)	Rd (n=208)
Median PFS, months	NR	39.2	61.9	37.5	NR	37.5
Median PFS HR (95% CI)	0.35 (0.21-0.56)		0.64 (0.45-0.89)		0.52 (0.39-0.68)
P value	<0.0001		0.0079		<0.0001
60-month PFS, %	67.2	28.7	51.6	36.6	57.4	33.6
OS HR (95% CI)	0.50 (0.27-0.90)		0.64 (0.43-0.96)		0.59 (0.43-0.83)
P value	0.0179		0.0274		0.0017
60-month OS, %	79.9	61.7	70.3	57.0	73.9	58.8
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.

Response Outcomes According to Age Group in the ITT Population (MAIA)⁷

Parameter, n (%)	Age <70 Years			Age ≥70 to <75 Years			Age <75 Years
Parameter, n (%)	D-Rd (n=78)	Rd (n=77)	P Value	D-Rd (n=130)	Rd (n=131)	P Value	D-Rd (n=208)	Rd (n=208)	P Value
ORR	73 (93.6)	62 (80.5)	0.0156	125 (96.2)	108 (82.4)	0.0004	198 (95.2)	170 (81.7)	<0.0001
≥CR	44 (56.4)	24 (31.2)	0.0016	73 (56.2)	41 (31.3)	<0.0001	117 (56.3)	65 (31.3)	<0.0001
sCR	31 (39.7)	11 (14.3)	0.0004	50 (38.5)	23 (17.6)	0.0002	81 (38.9)	34 (16.3)	<0.0001
CR	13 (16.7)	13 (16.9)	-	23 (17.7)	18 (13.7)	-	36 (17.3)	31 (14.9)	-
≥VGPR	64 (82.1)	45 (58.4)	0.0013	111 (85.4)	76 (58.0)	<0.0001	175 (84.1)	121 (58.2)	<0.0001
VGPR	20 (25.6)	21 (27.3)	-	38 (29.2)	35 (26.7)	-	58 (27.9)	56 (26.9)	-
PR	9 (11.5)	17 (22.1)	-	14 (10.8)	32 (24.4)	-	23 (11.1)	49 (23.6)	-
SD	1 (1.3)	14 (18.2)	-	3 (2.3)	20 (15.3)	-	4 (1.9)	34 (16.3)	-
PD	0	0	-	0	0	-	0	0	-
NE	4 (5.1)	1 (1.3)	-	2 (1.5)	3 (2.3)	-	6 (2.9)	4 (1.9)	-
MRD-negative (10^–5)	28 (35.9)	9 (11.7)	0.0006	47 (36.2)	16 (12.2)	<0.0001	75 (36.1)	25 (12.0)	<0.0001
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

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

Jakubowiak et al (2022)⁸ reported the results of a pooled analysis of patient-level data of transplant-ineligible patients with NDMM and high cytogenetic risk from the MAIA and ALCYONE studies.

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, ≥CR, ≥VGPR, MRD-negative CR

Results

Patient Characteristics

Overall, 101 patients (D-Rd [MAIA], n=48; DARZALEX + bortezomib + melphalan + prednisone [D-VMP; ALCYONE], n=53) were included in the pooled DARZALEX cohort and 89 patients (Rd [MAIA], n=44; bortezomib + melphalan + prednisone [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 MAIA study are summarized in Table: Summary of Baseline Characteristics in MAIA.

Summary of Baseline Characteristics in MAIA⁸

Characteristic, n (%)	D-Rd (n=48)	Rd (n=44)	Standardized Difference^a
Median age, years	74.5	74.0	-
<75 years	24 (50.0)	24 (54.5)	9.1%
≥75 years	24 (50.0)	20 (45.5)	9.1%
Male	24 (50.0)	20 (45.5)	9.1%
ECOG PS score
0	17 (35.4)	18 (40.9)	11.3%
1	18 (37.5)	17 (38.6)	2.3%
≥2	13 (27.1)	9 (20.5)	15.6%
Type of MM by immunofixation or serum FLC
IgG	35 (72.9)	28 (63.6)	20.0%
Non-IgG	13 (27.1)	16 (36.4)	20.0%
ISS stage^b
I	6 (12.5)	8 (18.2)	15.8%
II	21 (43.8)	15 (34.1)	19.9%
III	21 (43.8)	21 (47.7)	8.0%
Cytogenetic risk^c
del(17p)	25 (52.1)	29 (65.9)	28.4%
t(4;14)	21 (43.8)	12 (27.3)	35.0%
t(14;16)	4 (8.3)	5 (11.4)	10.2%
Renal impairment^d	25 (52.1)	19 (43.2)	17.9%
Abbreviations: del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; 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; Rd, lenalidomide + dexamethasone; t, translocation. ^aStandardized difference is a measure of effect size independent of sample size, where characteristics with a standardized difference <10% were considered balanced. ^bISS staging was derived based on the combination of serum β2-microglobulin and albumin. ^cCytogenetic risk was based on FISH or karyotype testing. ^dRenal 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 Studies⁸

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: CI, confidence interval; del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; PFS, progression-free survival; t, translocation. ^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 PS, 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 Rates⁸

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: CI, confidence interval; CR, complete response; del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; 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; t, translocation; 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 PS, 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).

Impact of Frailty on PROs in the MAIA Study

Perrot et al (2022)⁹ presented a post hoc analysis of PROs in a subgroup of frail patients from the MAIA study.

Study Design/Methods

Patients were categorized as frail based on age, ECOG PS, and Charlson comorbidity index.
PROs were assessed using the following sub-scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) questionnaire:
- GHS
- Functional scales: physical, role, emotional, cognitive, and social
- Symptom scales: fatigue, nausea and vomiting, and pain
The scores were transformed to values ranging from 0-100.
The questionnaires were completed at baseline; on day 1 of cycles 3, 6, 9, and 12 for year 1; and every 6 months thereafter until PD.

Results

Patient Characteristics

The baseline demographics and disease characteristics and the baseline EORTC QLQ-C30 scores of frail patients are presented in the Tables: Baseline Patient and Disease Characteristics in Frail Patients (MAIA) and Baseline EORTC QLQ-30 Scores in Frail Patients (MAIA), respectively.
The median duration of follow-up was 64.5 months.

Baseline Patient and Disease Characteristics in Frail Patients (MAIA)⁹

Characteristic		D-Rd (n=172)	Rd (n=169)
Median age (range), years		77.0 (57-90)	77.0 (45-89)
Female, n (%)		79 (45.9)	79 (46.7)
ECOG PS score, n (%)
0		20 (11.6)	18 (10.7)
1		89 (51.7)	92 (54.4)
≥2		63 (36.6)	59 (34.9)
ISS stage, n (%)^a
I		34 (19.8)	35 (20.7)
II		74 (43.0)	67 (39.6)
III		64 (37.2)	67 (39.6)
Type of measurable disease, n (%)
IgG		103 (59.9)	99 (58.6)
IgA		32 (18.6)	34 (20.1)
Cytogenetic profile, n/N (%)^b
	High risk	25/153 (16.3)	23/147 (15.6)
Abbreviations: del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IgA, immunoglobulin A; IgG, immunoglobulin G; ISS, International Staging System; Rd, lenalidomide + dexamethasone; t, translocation. ^aBased on the combination of serum β2-microglobulin and albumin. ^bPatients with high-risk cytogenetics had a del17p, t(14;16), or t(4;14) abnormality.

Baseline EORTC QLQ-30 Scores in Frail Patients (MAIA)⁹

EORTC QLQ-C30 Score, Mean (SD)	D-Rd (n=172)	Rd (n=169)
GHS	50.4 (26.1)	51.6 (24.3)
Functional scales
Physical functioning	55.2 (29.3)	57.9 (26.1)
Role functioning	49.5 (37.7)	54.6 (34.0)
Emotional functioning	68.7 (26.2)	66.3 (25.6)
Cognitive functioning	75.1 (26.9)	74.2 (24.9)
Social functioning	62.1 (36.3)	66.8 (31.5)
Symptom scales
Pain	54.5 (37.8)	51.8 (34.0)
Fatigue	49.2 (31.4)	50.2 (27.3)
Nausea/vomiting	9.0 (19.0)	9.7 (18.9)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; GHS, global health status; Rd, lenalidomide + dexamethasone; SD, standard deviation.

PROs

Larger reductions (≥20-point change) in LS mean pain score and a greater improvement in pain symptoms from baseline were reported in patients treated with D-Rd vs Rd.
Treatment with D-Rd did not increase fatigue compared with Rd.
Improvements in GHS scores from baseline were consistent over time both in patients treated with D-Rd and Rd.
Improvements in physical functioning from baseline was greater in the D-Rd vs Rd arm until cycle 42.
Improvements in emotional and social functioning from baseline was numerically higher in the D-Rd vs Rd arm at several timepoints.
Role functioning was improved from baseline in both treatment arms with no difference between D-Rd and Rd.
No meaningful changes from baseline were reported in nausea and vomiting in either treatment arm.
Overall, the median time to worsening of HRQoL scores were longer in the D-Rd vs Rd arm, particularly for physical functioning (D-Rd, 68.1 months; Rd, 39.6 months).
- At data cutoff, the median time to worsening of pain symptoms was NR in the D-Rd arm.
- Fatigue scores were maintained for a longer median duration in the Rd (35 months) vs D-Rd (22 months) arm.
- In the D-Rd vs Rd arm, cognitive symptoms worsened at 8 vs 10 months.

Subgroup Analysis in Patients with Renal Impairment and/or High Cytogenetic Risk in the MAIA Study

Facon et al (2022)¹⁰ conducted a subgroup analysis of the phase 3 MAIA study that evaluated the efficacy and PROs of D-Rd vs Rd in subgroups of patients with NDMM who had renal impairment (CrCl ≤60 mL/min) and/or high-risk cytogenetics (del17p, t[4;14], or t[14;16] abnormality).

Study Design/Methods

Renal impairment was defined as CrCl ≤60 mL/min
Patients with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality.

Results

Patient Characteristics

Overall, 368 and 369 patients were randomized to the D-Rd and Rd arms, respectively. Baseline renal function and cytogenetic risk status in the ITT population are summarized in the Table: Baseline Renal Function and Cytogenetic Risk Status.

Baseline Renal Function and Cytogenetic Risk Status¹⁰

Characteristic	D-Rd (n=368)	Rd (n=369)
Baseline renal function (CrCl), n (%)
>60 mL/min	206 (56.0)	227 (61.5)
≤60 mL/min	162 (44.0)	142 (38.5)
Cytogenetic risk,^a n	319	323
Standard risk, n (%)	271 (85.0)	279 (86.4)
High risk, n (%)	48 (15.0)	44 (13.6)
Abbreviations: CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; IMWG, International Myeloma Working Group; Rd, lenalidomide + dexamethasone; t, translocation. ^aCytogenetic risk was evaluated based on local fluorescence in situ hybridization or karyotype testing. Patients with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality per IMWG 2016 recommendations. Patients with standard cytogenetic risk had an absence of high-risk cytogenetic abnormalities.

Efficacy

Median duration of follow-up was 56.2 months.
In the overall study population and in patient subgroups based on renal function and cytogenetic risk status, median times to ≥VGPR and ≥CR were shorter and durations of ≥CR and ≥partial response or better (≥PR) were longer in the D-Rd vs Rd arm. Efficacy outcomes are summarized in the Table: Efficacy Outcomes in the Overall Study Population and in Renal Function and Cytogenetic Risk Subgroups.

Efficacy Outcomes in the Overall Study Population and in Renal Function and Cytogenetic Risk Subgroups¹⁰

Parameter	D-Rd	Rd	HR (95% CI)	P Value
Median time to ≥VGPR, months^a,b
ITT population	3.8	9.4	2.08 (1.73-2.49)	<0.0001
Renal function
CrCl ≤60 mL/min	3.8	12.5	2.26 (1.69-3.02)	<0.0001
CrCl >60 mL/min	3.8	8.5	1.82 (1.45-2.28)	<0.0001
Cytogenetic risk status
High risk	4.7	14.1	2.50 (1.44-4.36)	0.0008
Standard risk	3.8	9.3	1.96 (1.59-2.40)	<0.0001
Median time to ≥CR, months
Renal function
CrCl ≤60 mL/min	23.3	54.6	1.58 (1.07-2.33)	0.0197
CrCl >60 mL/min	17.6	43.8	1.80 (1.34-2.41)	<0.0001
Cytogenetic risk status
High risk	15.7	47.9	1.74 (0.83-3.63)	0.1372
Standard risk	20.8	42.6	1.69 (1.29-2.21)	<0.0001
48-month EFS rate in patients achieving ≥CR, %
ITT population^c,d	81.8	57.8	0.38 (0.23-0.65)	0.0002
Renal function
CrCl ≤60 mL/min	81.0	61.5	0.45 (0.20-1.04)	0.0551
CrCl >60 mL/min	82.2	55.3	0.41 (0.22-0.77)	0.0043
Cytogenetic risk status
High risk	74.7	NE	0.32 (0.09-1.16)	0.0694
Standard risk	80.0	55.1	0.42 (0.24-0.73)	0.0015
48-month EFS rate in patients achieving ≥PR, %
Renal function
CrCl ≤60 mL/min	67.2	44.4	0.50 (0.34-0.74)	0.0003
CrCl >60 mL/min	69.8	48.9	0.50 (0.36-0.70)	<0.0001
Cytogenetic risk status
High risk	48.8	29.9	0.65 (0.35-1.19)	0.1560
Standard risk	72.3	45.7	0.43 (0.32-0.57)	<0.0001
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-Rd, DARZALEX + lenalidomide + dexamethasone; EFS, event-free survival; HR, hazard ratio; ISS, International Staging System; ITT, intent-to-treat; NE, not evaluable; PR, partial response; Rd, lenalidomide + dexamethasone; VGPR, very good partial response. ^aHR and 95% CI are calculated from a Cox proportional hazards model, with treatment as the sole explanatory variable. HR >1 indicates an advantage for D-Rd. ^bP value was based on the log-rank test. ^cHR and 95% CI are calculated from a Cox proportional hazards model, with treatment as the sole explanatory variable and stratified by ISS stage (I, II, or III), region (North America vs other), and age (<75 years vs ≥75 years), as randomized. HR <1 indicates an advantage for D-Rd. ^dP value was based on a stratified log-rank test.

Among patients with renal impairment, greater improvements from baseline in patientreported pain scores, patient-reported fatigue, and nausea and vomiting symptom scores were observed in the D-Rd vs Rd arm across most time points.
- A greater meaningful reduction in pain score was reported in the D-Rd vs Rd arm, respectively, at cycle 6 day 1 (LS mean change from baseline, 14.9 vs 7.0; P=0.0241) in patients with renal impairment.
- A greater reduction in fatigue symptom score was reported in the D-Rd vs Rd arm, respectively, at cycle 24 day 1 (LS mean change from baseline, -2.9 vs 8.1; P=0.0018), cycle 30 day 1 (LS mean change from baseline, -3.7 vs 4.4; P=0.0258), and cycle 36 day 1 (LS mean change from baseline, -2.6 vs 6.5; P=0.0183) in patients with renal impairment.
- A greater reduction in nausea and vomiting symptom score was observed in the D-Rd vs Rd arm, respectively, at cycle 36 day 1 (LS mean change from baseline, 3.7 vs 3.3; P=0.0035) in patients with renal impairment.
Greater improvements from baseline in patient-reported symptoms were observed in the D-Rd vs Rd arm in patients without renal impairment (CrCl >60 mL/min).
Greater improvements from baseline in patient-reported pain score were observed in the D-Rd vs Rd arm across most time points in patients with standard and high cytogenetic risk.

Predictive and Prognostic Role of MRD-Negativity and Durability

San-Miguel et al (2022)¹¹ evaluated the predictive and prognostic role of MRD-negativity and durability in patients with NDMM ineligible for transplant.

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, 0-49.9).

Demographics and Baseline Characteristics by MRD Durability²³

Characteristic	D-Rd				Rd
	ITT (n=368)	MRD-Negative Patients			ITT (n=369)	MRD-Negative Patients
	ITT (n=368)	At Any Time (n=106)	≥12 Months (n=40)	Not ≥12 Months (n=66)	ITT (n=369)	At Any Time (n=34)	≥12 Months (n=9)	Not ≥12 Months (n=25)
Age, years
Median (range)	73.0 (50-90)	72.0 (65-87)	71.0 (66-85)	73.5 (65-87)	74.0 (45-89)	72.5 (66-87)	71.0 (69-78)	73.0 (66-87)
Distribution
<75	208 (56.5)	68 (64.2)	31 (77.5)	37 (56.1)	208 (56.4)	20 (58.8)	6 (66.7)	14 (56.0)
≥75	160 (43.5)	38 (35.8)	9 (22.5)	29 (43.9)	161 (43.6)	14 (41.2)	3 (33.3)	11 (44.0)
ISS disease stage^a
I	98 (26.6)	24 (22.6)	10 (25.0)	14 (21.2)	103 (27.9)	11 (32.4)	5 (55.6)	6 (24.0)
II	163 (44.3)	55 (51.9)	19 (47.5)	36 (54.5)	156 (42.3)	15 (44.1)	3 (33.3)	12 (48.0)
III	107 (29.1)	27 (25.5)	11 (27.5)	16 (24.2)	110 (29.8)	8 (23.5)	1 (11.1)	7 (28.0)
Cytogenetic profile^b
Patients evaluated	319	96	34	62	323	27	8	19
Standard-risk cytogenetic abnormality	271 (85.0)	85 (88.5)	29 (85.3)	56 (90.3)	279 (86.4)	26 (96.3)	8 (100.0)	18 (94.7)
High-risk cytogenetic abnormality^c	48 (15.0)	11 (11.5)	5 (14.7)	6 (9.7)	44 (13.6)	1 (3.7)	0	1 (5.3)
del(17p)	25 (7.8)	6 (6.3)	2 (5.9)	4 (6.5)	29 (9.0)	0	0	0
Abbreviations: del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; Rd, lenalidomide + dexamethasone; t, translocation. 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-Rd regimen achieved higher rates of MRD-negativity and durability compared with Rd. 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 (HR, 0.15; 95% CI, 0.09-0.26; P<0.0001).
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 vs 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 are presented in the Table: Estimated Rates of Patients Without Subsequent Therapy at 36 Months in ITT Population.
Estimated 36-month PFS2 rate (ITT; D-Rd, n=368; Rd, n=369):
- MRD-negative (10^-5) at ≥1 time point: D-Rd, 95.0% (n=106); Rd, 83.9% (n=34)
- MRD-positive: D-Rd, 65.5% (n=262); Rd, 61.5% (n=335)

Rates of Sustained MRD-negativity Status in Transplant-ineligible NDMM¹¹

MRD-Negativity (10^-5)	(N=737)
MRD-Negativity (10^-5)	D-Rd	Rd	P Value^a
ITT	n=368	n=369
MRD-negative status, n (%)	106 (28.8)	34 (9.2)	<0.0001
≥6 months sustained	55 (14.9)	16 (4.3)	<0.0001
≥12 months sustained	40 (10.9)	9 (2.4)	<0.0001
≥CR	n=182	n=100
MRD-negative status, n (%)	106 (58.2)	34 (34.0)	0.0001
≥6 months sustained	55 (30.2)	16 (16.0)	0.0097
≥12 months sustained	40 (22.0)	9 (9.0)	0.0053
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide + dexamethasone. ^aP value was calculated using Fisher’s exact test.

Estimated Rates of Patients Without Subsequent Therapy at 36 months in ITT Population¹¹

Estimated 36-Month Time to Subsequent Anticancer Therapy Rate, n (%)	D-Rd (n=368)	Rd (n=369)
MRD-negative (10^-5) at ≥1 time point	106 (96.9)	34 (90.5)
MRD-positive	262 (65.4)	335 (48.7)
Achieved and remained MRD-negative (10^-5) for ≥6 months	55 (96.1)	16 (100.0)
MRD-negativity not ≥6 months	51 (98.0)	18 (78.7)
Achieved and remained MRD-negative (10^-5) for ≥12 months	40 (94.6)	9 (100.0)
MRD-negativity not ≥12 months	66 (98.5)	25 (85.2)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; Rd, lenalidomide + dexamethasone.

Post Hoc Analysis of MAIA Study

Moreau et al (2022)¹² analyzed PFS and OS by treatment duration within the MAIA study, with a median follow-up of 56.2 months.

Study Design/Methods

OS was evaluated in patients who received treatment with D-Rd for <18 months and ≥18 months.
PFS and OS was evaluated in the following subgroups:
- Patients who received treatment with D-Rd and who discontinued either DARZALEX only or lenalidomide only with or without dexamethasone but continued remaining treatment.
- Patients who received treatment with D-Rd or Rd for ≥9 months or for ≥18 months.
- Patients who achieved VGPR by 6 months and ≥CR by 9 months or 18 months.
Patients were excluded from this analysis if the treatment with D-Rd was discontinued due to disease progression during the first 18 months.

Results

The patient demographics and disease characteristics are presented in Table: Baseline Characteristics and Demographics.

Baseline Characteristics and Demographics¹²

Characteristic, n (%)	ITT Population (D-Rd, n=368)	Discontinued only R±d^a (D-Rd, n=48)	D-Rd treatment <18 months^b (n=48)	D-Rd treatment ≥18 months^b (n=283)
Age
<65 years	4 (1.1)	0	3 (6.3)	1 (0.4)
65-74 years	204 (55.4)	26 (54.2)	18 (37.5)	167 (59.0)
≥75 years	160 (43.5)	22 (45.8)	27 (56.3)	115 (40.6)
Median (range)	73.0 (50-90)	74.0 (67-87)	75.0 (50-90)	73.0 (55-88)
Baseline ECOG PS score
0	127 (34.5)	15 (31.3)	10 (20.8)	110 (38.9)
1	178 (48.4)	25 (52.1)	25 (52.1)	132 (46.6)
≥2	63 (17.1)	8 (16.7)	13 (27.1)	41 (14.5)
ISS disease stage^c
I	98 (26.6)	14 (29.2)	8 (16.7)	84 (29.7)
II	163 (44.3)	26 (54.2)	19 (39.6)	129 (45.6)
III	107 (29.1)	8 (16.7)	21 (43.8)	70 (24.7)
Cytogenetic abnormalities^d
N	319	45	44	242
Standard risk	271 (85.0)	39 (86.7)	38 (86.4)	212 (87.6)
High risk	48 (15.0)	6 (13.3)	6 (13.6)	30 (12.4)
Frailty status
Frail	172 (46.7)	23 (47.9)	30 (62.5)	118 (41.7)
Intermediate	128 (34.8)	19 (39.6)	13 (27.1)	105 (37.1)
Fit	68 (18.5)	6 (12.5)	5 (10.4)	60 (21.2)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; R±d, lenalidomide ± dexamethasone. ^aPatients discontinued R±d but continued remaining treatment. ^bPatients who discontinued D-Rd due to disease progression during the first 18 months of treatment were excluded. ^cISS staging is derived based on the combination of serum β2-microglobulin and albumin. ^dCytogenetic abnormalities (del17p, t[14;16] or t[4;14]) were based on fluorescence in situ hybridization or karyotype testing. Percentages calculated with the number of patients in each treatment group as the denominator).

Patient Disposition

The most common reasons of lenalidomide discontinuation in the D-Rd arm is presented in the Table: Reasons for Lenalidomide Discontinuation.

Reasons for Lenalidomide Discontinuation¹²

Event, n (%)	Discontinued only R±d (D-Rd, n=48)^a
Reasons for lenalidomide discontinuation
Adverse Event	44 (91.7)
Other^b	4 (8.3)
Most common (≥5%) reasons for discontinuation of lenalidomide due to adverse events
Diarrhea	9 (18.8)
Peripheral sensory neuropathy	5 (10.4)
Neutropenia	4 (8.3)
Constipation	6 (6.3)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; R±d, lenalidomide ± dexamethasone. ^aPatients discontinued R±d but continued remaining treatment. ^bOther includes patient decision to discontinue, interruption due to adverse events caused by progressive disease or other conditions, or cumulative low-grade adverse events.

Efficacy

Median duration of DARZALEX treatment in the D-Rd arm was 58.1 months in patients who discontinued R±d but continued remaining treatment.
- The estimated 60-month PFS rate and OS rate was 97.9% and 100.0%, respectively.
Only 1 patient discontinued DARZALEX while continuing lenalidomide treatment.
- This patient was alive and progression free at the time of analysis. No further analysis was performed on this patient.
The median OS in the D-Rd arm was NR vs 20.5 months (HR, 0.16; 95% CI, 0.1-0.25; P<0.0001) in patients who received treatment for ≥18 months vs <18 months, respectively.
In patients who received D-Rd vs Rd for ≥9 months, PFS (HR, 0.49; 95% CI, 0.38-0.62; P<0.0001) and OS (HR, 0.63; 95% CI, 0.47-0.85; P=0.0025) benefits were observed.
PFS benefit in the D-Rd vs Rd arm was observed in patients who received treatment for ≥18 months (HR, 0.57; 95% CI, 0.43-0.76; P<0.0001) vs ITT population (HR, 0.53; 95% CI, 0.43-0.66; P<0.0001).
OS benefit in the D-Rd vs Rd arm was observed in patients who received treatment for ≥18 months (HR, 0.68; 95% CI, 0.47-0.98; P=0.0379) vs ITT population (HR, 0.68; 95% CI, 0.53-0.86; P=0.0013).
PFS and OS benefits in the D-Rd vs Rd arm was observed in patients who achieved a best response of VGPR by 6 months and converted to ≥CR by 9 or 18 months as presented in Table: PFS and OS in Patients who Achieved VGPR by 6 Months and Converted to ≥CR by 9 or 18 Months.
Among patients who were treated for ≥18 months, the ≥CR rate was 9.2% vs 4.4% at 6 months, 19.1% vs 11.3% at 9 months, and 49.8% vs 30.4% at 18 months in the D-Rd vs Rd arm, respectively. See Table: Response Rates in Patients Treated for ≥18 Months.

PFS and OS in Patients who Achieved VGPR by 6 Months and Converted to ≥CR by 9 or 18 Months¹²

Parameter	D-Rd	Rd	Hazard Ratio (95% CI)	P value
Patients who achieved VGPR by 6 Months and converted to ≥CR by 9 months
Median PFS, months	NR	38.4	0.15 (0.05-0.45)	<0.0001
Median OS, months	NR	53.8	0.25 (0.07-0.86)	0.0175
Patients who achieved VGPR by 6 Months and converted to ≥CR by 18 months
Median PFS, months	NR	53.6	0.34 (0.19-0.62)	0.0002
Median OS, months	NR	NR	0.33 (0.17-0.65)	0.0006
Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-Rd, DARZALEX + lenalidomide + dexamethasone; NR, not reached; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide + dexamethasone; VGPR, very good partial response.

Response Rates in Patients Treated for ≥18 Months¹²

Response Rates, %	6 months		9 months		18 months
Response Rates, %	D-Rd	Rd	D-Rd	Rd	D-Rd	Rd
ORR	98.2	93.6	98.6	96.1	99.6	98.0
P value	0.0079		0.0785		0.0828
≥CR	9.2	4.4	19.1	11.3	49.8	30.4
P value	0.0443		0.0199		<0.0001
sCR	2.5	2.9	7.1	5.4	27.2	13.7
CR	6.7	1.5	12.0	5.9	22.6	16.7
VGPR	57.2	38.2	57.2	41.7	36.7	37.3
PR	31.8	51.0	22.3	43.1	13.1	30.4
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ORR, overall response rate; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; VGPR, very good partial response.

Safety

There were no new safety signals identified.
Incidence of grade 3/4 TEAEs are presented in Table: Most Common (≥10% in Either Treatment Arm) Grade 3/4 TEAEs in Patients Who Received ≥18 Months of Treatment.
In the D-Rd arm, the rate of grade 3/4 hematologic-related TEAEs decreased over time.

Most Common (≥10% in Either Treatment Arm) Grade 3/4 TEAEs in Patients Who Received ≥18 Months of Treatment¹²

Event, n (%)	D-Rd (n=283)	Rd (n=204)
≥1 grade 3/4 TEAE	273 (96.5)	186 (91.2)
Hematologic
Neutropenia	161 (56.9)	84 (41.2)
Anemia	48 (17.0)	37 (18.1)
Lymphopenia	48 (17.0)	25 (12.3)
Leukopenia	33 (11.7)	19 (9.3)
Non-Hematologic
Pneumonia	56 (19.8)	22 (10.8)
Hypokalemia	41 (14.5)	24 (11.8)
Cataract	39 (13.8)	38 (18.6)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.

HRQoL Outcomes from the MAIA study

Perrot et al (2021)²⁴ evaluated the impact of treatment on PRO in the MAIA study at a median follow-up of 28.0 months. Perrot et al (2021)¹³ reported updated results of the HRQoL analysis of the MAIA study, with a follow-up of 56.2 months. Results from this updated analysis are summarized below.

Results

At a median follow-up of 56.2 months, patients treated with D-Rd experienced lower discontinuation rates vs those treated with Rd (56.8% vs 80.8%, respectively).
The threshold for clinically meaningful change from baseline was defined a priori for each PRO.
- A greater proportion of D-Rd-treated patients achieved a meaningful improvement vs Rd-treated patients, particularly for physical functioning (OR, 1.49; 95% CI, 1.111.99), fatigue (OR, 1.54; 95% CI, 1.14-2.07), dyspnea (OR, 1.43; 95% CI, 1.06-1.93), and constipation (OR, 1.66; 95% CI, 1.23-2.24).
- The number of patients achieving meaningful worsening was similar across arms.
Median time to meaningful improvement was shorter with D-Rd vs Rd for both physical functioning (HR, 1.13; 95% CI, 0.91-1.40) and pain (HR, 1.01; 95% CI, 0.84-1.21) and with Rd vs D-Rd for both GHS (HR, 0.94; 95% CI, 0.77-1.15) and fatigue (HR, 1.01; 95% CI, 0.84-1.21).
Median time to worsening was comparable between the D-Rd and Rd arms for fatigue, longer for D-Rd vs Rd for GHS, and significantly longer for D-Rd vs Rd for physical functioning (HR, 0.77; 95% CI, 0.62-0.96), pain (HR, 0.69; 95% CI, 0.55-0.86), and dyspnea (HR, 0.78; 95% CI, 0.63-0.96).
Differences between arms in LS mean change from baseline for select PROs favored D-Rd at most time points. For most scales, differences were significant at ≥1 time point.

PROs in the MAIA Study

Perrot et al (2021)¹⁴ reported results of post hoc analyses assessing the relationship between clinical efficacy endpoints and PROs in the MAIA study.

Results

Best clinical response, at a median follow-up of 56.2 months, is presented in Table: Best Clinical Response in the MAIA Study (Pooled Treatment Arms).

Best Clinical Response in the MAIA Study (Pooled Treatment Arms)¹⁴

Best Clinical Response	n (%)
Stringent complete response	186 (26.2)
Complete response	113 (15.9)
Very good partial response	209 (29.4)
Partial response	135 (19.0)
Stable disease	66 (9.3)
Progressive disease	1 (0.1)
N=710; best clinical response data were missing for 27/37 patients in the intent-to-treat population.

For the PROs of GHS, fatigue, and pain, the number of patients reporting clinically meaningful improvement from baseline increased with increasing depth of best clinical response.
- ORs, which compared best clinical response against stable disease, reflect this association. See Table: Odds Ratio (95% CI) for Meaningful Improvement of GHS, Fatigue, and Pain at Any Time for Each Best Clinical Response Subgroup (vs Stable Disease).

Odds Ratio (95% CI) for Meaningful Improvement of GHS, Fatigue, and Pain at Any Time for Each Best Clinical Response Subgroup (vs Stable Disease)¹⁴

	Odds Ratio (95% CI)
GHS
Partial response	2.6 (1.4-5.0)
Very good partial response	3.9 (2.1-7.2)
Complete response	4.7 (2.4-9.2)
Stringent complete response	5.9 (3.1-11.1)
Fatigue
Partial response	3.0 (1.6-5.6)
Very good partial response	4.8 (2.6-8.8)
Complete response	5.3 (2.7-10.3)
Stringent complete response	8.9 (4.7-16.8)
Pain
Partial response	2.2 (1.2-4.1)
Very good partial response	3.3 (1.8-5.8)
Complete response	4.3 (2.3-8.3)
Stringent complete response	5.0 (2.7-9.1)
Abbreviations: CI, confidence interval; GHS, global health status.

In contrast, those who experienced disease progression frequently reported meaningful worsening or no improvement of GHS, pain, and fatigue at the time of progression or following progression. See Table: Meaningful Worsening or No Improvement of GHS, Fatigue, and Pain at or Post-Progression Among Patients Who Progressed.

Meaningful Worsening or No Improvement of GHS, Fatigue, and Pain at or Post-Progression Among Patients Who Progressed¹⁴

Worsening of Select PROs, %	Patients Who Experienced Disease Progression (N=264)
GHS
Meaningful worsening	38.6
Meaningful worsening or no improvement	62.9
Fatigue
Meaningful worsening	54.9
Meaningful worsening or no improvement	69.7
Pain
Meaningful worsening	39.4
Meaningful worsening or no improvement	61.0
Abbreviations: GHS, global health status; PRO, patient-reported outcome.

Impact of Impaired Renal Function and Lenalidomide Starting Dose on Efficacy in the MAIA Study

Usmani et al (2021)¹⁵ evaluated the efficacy of D-Rd vs Rd in patients from the MAIA study that had impaired renal function, both overall and based on the starting dose of lenalidomide that was received.

Study Design/Methods

Lenalidomide 10 mg was recommended for patients with a CrCl of 30 to 50 mL/min.
Renal impairment was defined as having a baseline CrCl of ≤60 mL/min.

Results

Patient Characteristics

A total of 737 patients received either D-Rd (n=368) or Rd (n=369). Of these, 162 (44.0%) patients in the D-Rd arm and 142 (38.5%) patients in the Rd arm had baseline renal impairment.
Among patients with renal impairment, 60 (37.0%) in the D-Rd arm and 62 (43.7%) in the Rd arm received lenalidomide at a starting dose of 25 mg, and 98 (60.5%) in the DRd arm and 75 (52.8%) in the Rd arm received lenalidomide at a starting dose of <25 mg. See Table: Distribution of Patients with Renal Impairment According to Baseline CrCl and Lenalidomide Starting Dose.
- All patients received a starting lenalidomide dose of 10 mg, except for 1 DRdtreated patient who received a lenalidomide starting dose of 5 mg.

Distribution of Patients with Renal Impairment According to Baseline CrCl and Lenalidomide Starting Dose¹⁵

Baseline CrCl, n (%)	D-Rd			Rd
Baseline CrCl, n (%)	Total (n=162)^a	R Starting Dose of 25 mg (n=60)	R Starting Dose of <25 mg (n=98)	Total (n=142)^a	R Starting Dose of 25 mg (n=62)	R Starting Dose of <25 mg (n=75)
>50 to ≤60 mL/min	64 (39.5)^a	41 (68.3)	22 (22.4)	62 (43.7)^a	41 (66.1)	20 (26.7)
30 to ≤50 mL/min	91 (56.2)^a	18 (30.0)	70 (71.4)	76 (53.5)^a	20 (32.3)	52 (69.3)
<30 mL/min	7 (4.3)	1 (1.7)	6 (6.1)	4 (2.8)	1 (1.6)	3 (4.0)
Abbreviations: CrCl, creatinine clearance; D-Rd, DARZALEX + lenalidomide + dexamethasone; R, lenalidomide; Rd, lenalidomide + dexamethasone. ^aFour patients in the D-Rd arm and 5 patients in the Rd arm were randomized and had baseline CrCl results but did not receive ≥1 dose of lenalidomide.

A lenalidomide starting dose of 10 mg was recommended for patients with a baseline CrCl of ≤50 mL/min; however, this was not followed for all patients. See Table: Demographic and Baseline Disease Characteristics of Patients with Renal Impairment According to Baseline CrCl and Lenalidomide Starting Dose.
- A greater number of patients receiving lenalidomide at a starting dose of <25 mg had ISS stage III disease, were frail, and had HRCAs.

Demographic and Baseline Disease Characteristics of Patients with Renal Impairment According to Baseline CrCl and Lenalidomide Starting Dose¹⁵

Characteristics	Baseline CrCl >50 to ≤60 mL/min				Baseline CrCl ≤50 mL/min
Characteristics	R Starting Dose of 25 mg (n=82)		R Starting Dose of <25 mg (n=42)		R Starting Dose of 25 mg (n=40)	R Starting Dose of <25 mg (n=131)
Age, years
Median (range)	75.0 (65.0-85.0)		76.0 (57.0-85.0)		75.5 (67.0-88.0)	78.0 (55.0-90.0)
ISS disease stage, n (%)^a
I	19 (23.2)		4 (9.5)		7 (17.5)	9 (6.9)
II	34 (41.5)		21 (50.0)		18 (45.0)	50 (38.2)
III	29 (35.4)		17 (40.5)		15 (37.5)	72 (55.0)
Median (range) time from MM diagnosis to randomization, months	0.92 (0.1-8.1)		1.00 (0.3-6.1)		0.97 (0.2-7.1)	0.89 (0.0-8.7)
Frailty status, n (%)^b
Fit	14 (17.1)		6 (14.3)		6 (15.0)	10 (7.6)
Intermediate	33 (40.2)		8 (19.0)		11 (27.5)	27 (20.6)
Frail	35 (42.7)		28 (66.7)		23 (57.5)	94 (71.8)
Cytogenetic profile^c	n=71		n=37		n=35	n=119
Standard risk, n (%)	63 (88.7)		26 (70.3)		28 (80.0)	103 (86.6)
High risk, n (%)	8 (11.3)		11 (29.7)		7 (20.0)	16 (13.4)
del17p	6 (8.5)	3 (8.1)		6 (17.1)		11 (9.2)
t(4;14)	2 (2.8)	7 (18.9)		1 (2.9)		4 (3.4)
t(14;16)	0	1 (2.7)		0		1 (0.8)
Abbreviations: CrCl, creatinine clearance; del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MM, multiple myeloma; R, lenalidomide; t, translocation. ^aBased on the combination of serum β2-microglobulin and albumin. ^bFrailty status was determined based on scores derived from age, baseline ECOG PS score, and Charlson comorbidity index according to the frailty scale developed in a retrospective subgroup analysis of the FIRST trial. ^cCytogenetic risk was based on local fluorescence in situ hybridization or karyotype analysis. Patients with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality. Patients with standard cytogenetic risk had an absence of high-risk cytogenetic abnormalities.

Efficacy

At a median follow-up of 56.2 months, PFS benefit (median, 56.7 months vs
29.7 months; HR, 0.55; 95% CI, 0.40-0.74) and OS benefit (median, NR vs
54.8 months; HR, 0.67; 95% CI, 0.47-0.96) was observed in the D-Rd arm vs Rd arm, respectively.
PFS and OS benefits were observed with D-Rd vs Rd in renally-impaired patients who received a lenalidomide starting dose of 25 mg. PFS and OS were also prolonged with DRd vs Rd in those with renal impairment who received a lenalidomide starting dose of <25 mg. See Table: PFS and OS in Patients with Renal Impairment Based on Lenalidomide Starting Dose.

PFS and OS in Patients with Renal Impairment Based on Lenalidomide Starting Dose¹⁵

	D-Rd	Rd	HR (95% CI)	P Value
R starting dose of 25 mg	n=60	n=62	-	-
PFS
Median PFS, months	NR	35.4	0.42 (0.24-0.72)	0.0012
5-year PFS rate, %	63.1	33.3	-	-
OS
Median OS, months	NR	NR	0.37 (0.19-0.73)	0.0028
5-year OS rate, %	79.0	50.9	-	-
R starting dose of <25 mg	n=98	n=75	-	-
PFS
Median PFS, months	49.1	24.9	0.56 (0.38-0.83)	0.0029
5-year PFS rate, %	40.3	18.6	-	-
OS
Median OS, months	62.8	54.8	0.81 (0.52-1.26)	0.3468
5-year OS rate, %	54.0	44.1	-	-
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; R, lenalidomide; Rd, lenalidomide + dexamethasone.

Safety

Deaths were reported in 125 patients with renal impairment (D-Rd, n=58; Rd, n=67). See Table: Deaths Among Patients with Renal Impairment.

Deaths Among Patients with Renal Impairment¹⁵

	D-Rd	Rd	Total^a
Deaths among patients with renal impairment, n	58	67	125
R starting dose of 25 mg	n=60	n=62	n=122
Total deaths, n (%)	12 (20.0)	29 (46.8)	41 (33.6)
Deaths due to disease progression, n (%)	6 (10.0)	10 (16.1)	16 (13.1)
R starting dose of <25 mg	n=98	n=75	n=173
Total deaths, n (%)	44 (44.9)	37 (49.3)	81 (46.8)
Deaths due to disease progression, n (%)	16 (16.3)	11 (14.7)	27 (15.6)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; R, lenalidomide; Rd, lenalidomide + dexamethasone. ^aTwo patients in the D-Rd arm and 1 patient in the Rd arm who died were randomized and had renal impairment but did not receive ≥1 dose of lenalidomide.

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 03 July 2024.

References

Show

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