DARZALEX FASPRO®
(daratumumab and hyaluronidase-fihj)
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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)
Medical Information
MMY3021 (AURIGA) Study
Last Updated: 12/17/2024
SUMMARY
- DARZALEX FASPRO for subcutaneous (SC) use is not approved by the regulatory agencies for use in combination with lenalidomide following autologous stem cell transplant (ASCT). Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
- AURIGA (MMY3021) is an ongoing, open-label, active-controlled, multicenter, randomized phase 3 study evaluating the conversion rate to minimal residual disease (MRD)-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs lenalidomide (R) alone in patients with newly diagnosed multiple myeloma (NDMM) who are anti-cluster of differentiation (CD) 38 naïve, have
a very good partial response or better (≥VGPR), and are MRD-positive following ASCT after standard-of-care induction/consolidation. A total of 200 patients were randomized (D-R, n=99; R, n=101).1 , 2 - Badros et al (2024)2-
4 reported primary results from the phase 3 AURIGA study. The MRD-negativity (10-5 ) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P<0.0001). Similarly, the MRD-negativity (10-6 ) conversion rate by 12 months from initiation of maintenance was higher with D-R vs R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P=0.0002). At a median follow-up of 32.3 months, the D-R vs R arm showed a higher overall MRD-negativity conversion rate (10-5 sensitivity, 60.6% vs 27.7%; 10-6 sensitivity, 36.4% vs 12.9%) and a higher complete response or better (≥CR) rate (75.8% vs 61.4%). Progression-free survival (PFS) favored D-R vs R with 47% reduction in the risk of disease progression or death (hazard ratio [HR], 0.53; 95% CI, 0.29-0.97). At 30 months, the estimated PFS was 82.7% vs 66.4% and the estimated overall survival (OS) for the intention-to-treat (ITT) population was 94.6% vs 91.0% in the D-R vs R arm, respectively. Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R. Serious adverse events (AEs) were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively. - Foster et al (2024)5
presented (at the 66th American Society of Hematology [ASH]Annual Meeting) a post hoc analysis of the phase 3 AURIGA study regarding clinically relevant subgroups at a median follow-up of 32.3 months. The clinically relevant subgroups included elderly and black patients, patients with high-risk disease per International Staging System (ISS) disease staging, and patients with high cytogenetic risk per standard, revised, and International Myeloma Society (IMS) 2024 high-risk criteria. The subgroup analyses of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance appeared to consistently favor D-R vs R maintenance alone regardless of age, race, ISS disease stage, or response upon study entry. D-R vs R maintenance improved MRD-negativity (10-5 sensitivity) conversion rates by 12 months in patients with ultra-high-risk disease, standard-risk disease, and patients with modified IMS 2024 high-risk disease. D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease and regardless of the number of high-risk cytogenetic abnormalities (HRCAs). D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59). No additional safety concerns were observed in patients aged ≥65 years of age or in Black patients. D-R maintenance did not increase grade 3/4 infection or cytopenia rates in patients ≥65 years of age.
- Badros et al (2024)2-
PRODUCT LABELING
- DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf
CLINICAL DATA
Study Design/Methods
- The trial enrolled 200 patients from the United States and Canada.2 The study design is presented in the Figure: AURIGA: Study Design.
Abbreviations: ASCT, autologous stem cell transplant; CD, cluster of differentiation; CR, complete response; D, daratumumab and hyaluronidase; ECOG PS, Eastern Cooperative Oncology Group performance status; HDT, high-dose therapy; HRQoL, health‑related quality of life; IMWG, International Myeloma Working Group; IV, intravenous; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NGS, nextgeneration sequencing; OS, overall survival; PFS, progression-free survival; PO, orally; PRO, patient-reported outcome; Q2W, every two weeks; Q4W, every four weeks; QD, once a day; QW, weekly; R, lenalidomide; SC, subcutaneous; sCR, stringent complete response; VGPR, very good partial response.
a
b
c
d
e
f
Badros et al (2024)2,3 reported primary results from the phase 3 AURIGA study.
Results
Patient Characteristics
- A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.2
- The median duration of treatment was 30.7 (range, 0.7-37.5) months vs 20.6
(range, 0-37.7) months in the D-R vs R arm, respectively.2 - The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the ITT Population.2
- The median follow-up was 32.3 months.
2 - Patients in the D-R vs R arm received a median of 33.0 (range, 1-36) vs 21.5
(range, 1-36) maintenance cycles, respectively.2 - Overall, 85 of 96 (88.5%) vs 77 of 98 (78.6%) patients in the D-R vs R arm completed ≥12 maintenance cycles, respectively.2
| D-R (n=99) | R (n=101) | |
|---|---|---|
| Median age (range), years | 63 (35-77) | 62 (35-78) |
| <65 years, n (%) | 61 (61.6) | 61 (60.4) |
| 65-70 years, n (%) | 23 (23.2) | 21 (20.8) |
| ≥70 years, n (%) | 15 (15.2) | 19 (18.8) |
| Sex, n (%) | ||
| Male | 61 (61.6) | 58 (57.4) |
| Female | 38 (38.4) | 43 (42.6) |
| Race, n (%) | ||
| White | 67 (67.7) | 68 (67.3) |
| Black or African American | 20 (20.2) | 24 (23.8) |
| Asian | 5 (5.1) | 1 (1.0) |
| American Indian or Alaska Native | 0 | 1 (1.0) |
| Othera | 5 (5.1) | 5 (5.0) |
| NR | 2 (2.0) | 2 (2.0) |
| ECOG PS, n (%) | ||
| 0 | 45 (45.5) | 55 (54.5) |
| 1 | 52 (52.5) | 44 (43.6) |
| 2 | 2 (2.0) | 2 (2.0) |
| ISS disease stage, n (%)b | ||
| I | 40 (44.0) | 38 (38.8) |
| II | 28 (30.8) | 37 (37.8) |
| III | 23 (25.3) | 23 (23.5) |
| Median induction cycles (range), nc | 5.0 (4.0-8.0) | 5.0 (4.0-8.0) |
| Cytogenetic risk at diagnosis, n (%)d | ||
| Standard risk | 63 (68.5) | 66 (74.2) |
| High riske | 22 (23.9) | 15 (16.9) |
| del(17p) | 13 (14.1) | 3 (3.4) |
| t(4;14) | 10 (10.9) | 12 (13.5) |
| t(14;16) | 6 (6.5) | 7 (7.9) |
| Unknown | 7 (7.6) | 8 (9.0) |
| Revised cytogenetic risk at diagnosis, n (%)f | ||
| Standard risk | 52 (55.9) | 53 (59.6) |
| High riskg | 32 (34.4) | 30 (33.7) |
| del(17p) | 13 (14.0) | 3 (3.4) |
| t(4;14) | 10 (10.8) | 12 (13.5) |
| t(14;16) | 6 (6.5) | 7 (7.9) |
| t(14;20) | 1 (1.1) | 2 (2.2) |
| gain/amp(1q21) | 16 (17.2) | 22 (24.7) |
| Unknown | 9 (9.7) | 6 (6.7) |
| Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; NR, not reported; R, lenalidomide. aPatients reporting multiple races. bD-R vs R: n=91 vs n=98, respectively. cD-R vs R: n=98 vs n=99, respectively. dD-R vs R: n=92 vs n=89, respectively. eHigh risk is defined as positive for any of del(17p), t(14;16), or t(4;14). fD-R vs R: n=93 vs n=89, respectively. gRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21). | ||
Efficacy
The MRD status and response rates in the ITT population are summarized in Table: Summary of MRD Status and Response Rates in the ITT Population.2,3 - The MRD-negativity (10-5) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; OR, 4.51; 95% CI, 2.37-8.57; P<0.0001).
- The D-R arm yielded ~2.5 times greater sustained MRD-negativity (10-5) rates at ≥6 months (35.4% vs 13.9%) and relatively higher sustained MRD-negativity (10-5 sensitivity) rates at ≥12 months (17.2% vs 5.0%) than the R arm.
- Subgroup analyses of MRD-negativity (10-5 sensitivity) conversion rates at 12 months appeared to consistently favor D-R over R across most clinically relevant subgroups, including patients with a standard or high cytogenetic risk and older patients; the results are summarized in Table: Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population.2
- At a median follow-up of 32.3 months, treatment with D-R vs R maintenance yielded a greater improvement in PFS, with 47% reduction in the risk of disease progression or death (HR, 0.53; 95% CI, 0.29-0.97; nominal P=0.0361).2,3
- At 30 months, the estimated PFS rate in the D-R vs R arm was 82.7%
(95% CI, 72.8-89.3) vs 66.4% (95% CI, 54.0-76.2), respectively.2 At 30 months, the estimated OS in the D-R vs R arm of the ITT population was
94.6% vs 91.0% (HR, 0.50; 95% CI, 0.17-1.50; P=0.2081), respectively.2,4
| Parameter | D-R (n=99) | R (n=101) | ORa (95% CI) | P-Valueb |
|---|---|---|---|---|
| Overall MRD-negativity conversion rate, n (%)c | ||||
| 10-5 sensitivity | 60 (60.6) | 28 (27.7) | 4.12 (2.26-7.52) | <0.0001 |
| 10-6 sensitivity | 36 (36.4) | 13 (12.9) | 3.91 (1.91-7.99) | 0.0001 |
| MRD-negativity conversion rate at 12 months from start of maintenance, n (%) | ||||
| 10-5 sensitivity | 50 (50.5) | 19 (18.8) | 4.51 (2.37-8.57) | <0.0001 |
| 10-6 sensitivity | 23 (23.2) | 5 (5.0) | 5.97 (2.15-16.58) | 0.0002 |
| Sustained MRD-negativity (10-5), n (%) | ||||
| ≥6 monthsd | 35 (35.4) | 14 (13.9) | 3.40 (1.69-6.83) | 0.0005 |
| ≥12 monthsd | 17 (17.2) | 5 (5.0) | 4.08 (1.43-11.62) | 0.0065 |
| Overall response, n (%) | ||||
| ≥CR | 75 (75.8) | 62 (61.4) | 2.00 (1.08-3.69) | 0.0255 |
| sCR | 50 (50.5) | 36 (35.6) | - | - |
| CR | 25 (25.3) | 26 (25.7) | - | - |
| VGPR | 24 (24.2) | 39 (38.6) | - | - |
| Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide; sCR, stringent complete response; VGPR, very good partial response. aMantel-Haenszel estimate of the common OR for stratified tables was used. The stratification factor was the baseline cytogenetic risk per investigator assessment (high vs standard/unknown) as used for randomization. An OR of >1 indicates an advantage for the D-R arm. bAll parameters, except ≥CR were assessed using Fisher’s exact test. ≥CR rates were accessed using Cochran-Mantel-Haenszel chi-squared test. cAt a median follow-up of 32.3 months.dSustained MRD-negativity at ≥6 months and ≥12 months is defined as an MRD-negative status (at 10-5 sensitivity threshold) in 2 bone marrow aspirate assessments spaced a minimum of 6 months and 12 months apart, respectively, without any assessment showing an MRD-positive status in between the assessments. | ||||
| Subgroup, n/N (%) | D-R (n=99) | R (n=101) | OR (95% CI) |
|---|---|---|---|
| ITT (overall) | 50/99 (50.5) | 19/101 (18.8) | 4.51 (2.37-8.57) |
| Sex | |||
| Male | 32/61 (52.5) | 11/58 (19.0) | 4.71 (2.06-10.78) |
| Female | 18/38 (47.4) | 8/43 (18.6) | 3.94 (1.45-10.68) |
| Age | |||
| <65 years | 30/61 (49.2) | 12/61 (19.7) | 3.95 (1.76-8.85) |
| ≥65 years | 20/38 (52.6) | 7/40 (17.5) | 5.24 (1.86-14.74) |
| Race | |||
| White | 31/67 (46.3) | 14/68 (20.6) | 3.32 (1.55-7.10) |
| Black | 12/20 (60.0) | 4/24 (16.7) | 7.50 (1.85-30.34) |
| Other | 7/12 (58.3) | 1/9 (11.1) | 11.20 (1.04-120.36) |
| Weight | |||
| ≤70 kg | 12/23 (52.2) | 4/18 (22.2) | 3.82 (0.96-15.18) |
| >70 kg | 38/76 (50.0) | 15/81 (18.5) | 4.40 (2.14-9.03) |
| Baseline ECOG PS score | |||
| 0 | 20/45 (44.4) | 9/55 (16.4) | 4.09 (1.62-10.31) |
| ≥1 | 30/54 (55.6) | 10/46 (21.7) | 4.50 (1.86-10.88) |
| ISS staging at diagnosis | |||
| I | 19/40 (47.5) | 8/38 (21.1) | 3.39 (1.25-9.19) |
| II | 13/28 (46.4) | 7/37 (18.9) | 3.71 (1.23-11.25) |
| III | 15/23 (65.2) | 3/23 (13.0) | 12.50 (2.83-55.25 |
| Cytogenetic risk at diagnosis | |||
| High riska | 7/22 (31.8) | 1/15 (6.7) | 6.53 (0.71-60.05) |
| Standard risk | 35/63 (55.6) | 14/66 (21.2) | 4.64 (2.15-10.04) |
| Revised cytogenetic risk at diagnosis | |||
| High riskb | 14/32 (43.8) | 4/30 (13.3) | 5.06 (1.43-17.88) |
| Standard risk | 28/52 (53.8) | 12/53 (22.6) | 3.99 (1.72-9.26) |
| Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide. aHigh risk is defined as positive for any of the following abnormalities: del(17p), t(14;16), or t(4;14). bRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21). | |||
Safety
- The most common AEs in the safety population are summarized in Table: Most Common AEs in the Safety Population.2
- Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R.
- Serious AEs were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.
- Any TEAEs occurred in 99.0% of patients in both the D-R and R arms.
- Grade 3/4 TEAEs occurred in 74.0% and 67.3% of patients in the D-R and R arms, respectively.
- During the analysis, 32 of 96 (33.3%) vs 47 of 98 (48.0%) patients in the D-R vs R arm, respectively, discontinued ≥1 component of the study treatment. The reasons for treatment discontinuation are summarized in Table: Reasons for Treatment Discontinuation During Analysis.2
Most Commona AEs in the Safety Population2
| AE, n (%) | D-R (n=96) | R (n=98) | ||
|---|---|---|---|---|
| Any Grade | Grade 3/4 | Any Grade | Grade 3/4 | |
| Hematologic | ||||
| Neutropenia | 62 (64.6) | 45 (46.9) | 60 (61.2) | 41 (41.8) |
| Leukopenia | 25 (26.0) | 9 (9.4) | 29 (29.6) | 6 (6.1) |
| Thrombocytopenia | 23 (24.0) | 3 (3.1) | 28 (28.6) | 2 (2.0) |
| Lymphopenia | 23 (24.0) | 10 (10.4) | 13 (13.3) | 5 (5.1) |
| Anemia | 22 (22.9) | 4 (4.2) | 17 (17.3) | 3 (3.1) |
| Nonhematologic | ||||
| Diarrhea | 59 (61.5) | 3 (3.1) | 54 (55.1) | 5 (5.1) |
| Fatigue | 44 (45.8) | 2 (2.1) | 46 (46.9) | 3 (3.1) |
| Upper respiratory tract infection | 40 (41.7) | 0 (0) | 26 (26.5) | 0 (0) |
| Cough | 37 (38.5) | 0 (0) | 36 (36.7) | 0 (0) |
| Hypokalemia | 33 (34.4) | 7 (7.3) | 36 (36.7) | 6 (6.1) |
| Arthralgia | 32 (33.3) | 1 (1.0) | 36 (36.7) | 1 (1.0) |
| Back pain | 31 (32.3) | 0 (0) | 20 (20.4) | 1 (1.0) |
| COVID-19 | 28 (29.2) | 1 (1.0) | 29 (29.6) | 3 (3.1) |
| Nausea | 26 (27.1) | 0 (0) | 26 (26.5) | 0 (0) |
| Nasal congestion | 25 (26.0) | 0 (0) | 19 (19.4) | 0 (0) |
| Headache | 24 (25.0) | 1 (1.0) | 17 (17.3) | 0 (0) |
| Constipation | 22 (22.9) | 0 (0) | 26 (26.5) | 0 (0) |
| Muscle spasms | 22 (22.9) | 0 (0) | 21 (21.4) | 0 (0) |
| Pain in extremity | 22 (22.9) | 1 (1.0) | 17 (17.3) | 0 (0) |
| Rash maculopapular | 21 (21.9) | 1 (1.0) | 17 (17.3) | 2 (2.0) |
| Hypertension | 14 (14.6) | 7 (7.3) | 10 (10.2) | 4 (4.1) |
| Pneumonia | 10 (10.4) | 5 (5.2) | 14 (14.3) | 4 (4.1) |
| Infusion-related reactions | 13 (13.5) | 0 (0) | - | - |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; R, lenalidomide. aAEs of any grade that occurred in ≥20% of patients and grade 3/4 AEs that occurred in ≥5% of patients in either treatment group. | ||||
| Reasons for Discontinuation, n | D-R (n=96)a | R (n=98)b |
|---|---|---|
| Discontinuation of R | 32 | 47 |
| Progressive disease | 11 | 23 |
| AE | 12 | 8 |
| Patient withdrawal | 3 | 4 |
| Death | 2 | 1 |
| Physician decision | 2 | 4 |
| Patient refused further study treatment | 1 | 5 |
| Protocol deviation | - | 1 |
| Other | 1 | 1 |
| Discontinuation of D | 27 | - |
| Progressive disease | 13 | - |
| AE | 6 | - |
| Patient withdrawal | 3 | - |
| Death | 2 | - |
| Physician decision | 2 | - |
| Patient refused further study treatment | 1 | - |
| Abbreviations: AE, adverse event; D, DARZALEX FASPRO; D-R, DARZALEX FASPRO + lenalidomide; R, lenalidomide.aOf the patients randomized to the D-R (n=99) arm, 3 patients were not treated due to physician decision, study schedule being too intense, and protocol deviation (n=1 each). bOf the patients randomized to the R arm (n=101), 3 patients were not treated due to study tests being too hard, patient not wanting to be on the lenalidomide only treatment arm, and patient withdrawal of consent (n=1 each). | ||
Clinically Relevant Subgroup Analysis
Results
Demographics and Disease Characteristics
- A total of 200 patients were randomized into the D-R maintenance (n=99) vs R alone maintenance (n=101) groups.5
- The median follow-up was 32.3 months.5
- The demographics and disease characteristics of the intention-to-treat (ITT) population are presented in Table: Demographics and Disease Characteristics of the ITT Population.
| D-R (n=99) | R (n=101) | |
|---|---|---|
| Age, years, n (%) | ||
| <65 years, | 61 (61.6) | 61 (60.4) |
| ≥65 years, | 38 (38.4) | 40 (39.6) |
| Race, n (%) | ||
| White | 67 (67.7) | 68 (67.3) |
| Black | 20 (20.2) | 24 (23.8) |
| ISS disease stage, n (%) | ||
| n | 91 | 98 |
| I | 40 (44.0) | 38 (38.8) |
| II | 28 (30.8) | 37 (37.8) |
| III | 23 (25.3) | 23 (23.5) |
| Patient response category at baseline, n (%)a | ||
| <CR (VGPR) | 71 (71.7) | 71 (70.3) |
| ≥CR | 28 (28.3) | 30 (29.7) |
| Cytogenetic risk at diagnosis per standard definition, n (%)b,c | ||
| n | 92 | 89 |
| Standard-risk | 63 (68.5) | 66 (74.2) |
| High-risk | 22 (23.9) | 15 (16.9) |
| Unknown | 7 (7.6) | 8 (9.0) |
| Cytogenetic risk at diagnosis per revised definition, n (%)d | ||
| n | 93 | 89 |
| Revised standard risk (0 HRCAs) | 52 (55.9) | 53 (59.6) |
| Revised high-risk (≥1 HRCA) | 32 (34.4) | 30 (33.7) |
| 1 HRCA | 21 (22.6) | 20 (22.5) |
| ≥2 HRCAs | 11 (11.8) | 10 (11.2) |
| Gain/amp(1q21) | 16 (17.2) | 22 (24.7) |
| Isolated gain/amp(1q21) | 10 (10.8) | 15 (16.9) |
| Unknown | 9 (9.7) | 6 (6.7) |
| Cytogenetic risk per modified IMS 2024 criteria, n (%)e | ||
| n | 93 | 90 |
| Modified IMS 2024 standard-risk | 67 (72.0) | 68 (75.6) |
| Modified IMS 2024 high-risk | 17 (18.3) | 8 (8.9) |
| ≥20% del(17p) | 10 (10.8) | 2 (2.2) |
| t(4;14)/(14;16)/(14;20) + gain/amp(1q21) and/or del(1p32) | 5 (5.4) | 6 (6.7) |
| Del(1p32) + gain/amp(1q21) | 4 (4.3) | 0 (0.0) |
| Unknown | 9 (9.7) | 14 (15.6) |
| Abbreviations: CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; HRCA, high-risk cytogenetic abnormalities; IMS, International Myeloma Society; IMWG, International Myeloma Working Group; ISS, International Staging System; ITT, intention-to-treat; R, lenalidomide; VGPR, very good partial response. aPer IMWG 2016 criteria. bHigh-risk cytogenetics per the standard definition are defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16). cThe imbalance in cytogenetic risk between arms, especially a higher number of patients with del(17p) for patients randomized to the D-R arm, was since some assessments were made on cytogenetic data at screening and some on cytogenetic data at the time of diagnosis. dRevised high-risk cytogenetics per the revised definition are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21).eHigh risk per the modified IMS 2024 criteria is defined as the presence of ≥20% del(17p); or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32) [in the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32)]. | ||
Efficacy
- A subgroup analyses of MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance showed improvement for D-R vs R regardless of age, race, ISS disease stage, or response upon study entry.5 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment.
- D-R vs R improved MRD-negativity (10-5 sensitivity) conversion rates by 12 months of maintenance in patients with ultra-high-risk disease and standard-risk disease.5 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment by Risk Status.
- D-R vs R improved MRD-negative (10-5 sensitivity) conversion rate by 12 months of maintenance among patients with modified IMS 2024 high-risk disease.5 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Rate from Baseline to 12 Months of Maintenance Treatment by Modified IMS 2024 Criteria.
- D-R vs R maintenance showed a PFS benefit across various definitions of high cytogenetic risk, in addition to patients with standard-risk disease. The HR and 95% CI values presented below are derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.5
- Standard criteria: High-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16).
- Standard-risk: HR, 0.59; 95% CI, 0.23-1.49.
- High-risk: HR, 0.60; 95% CI, 0.21-1.70.
- Revised criteria: Revised high-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21).
- Revised standard-risk: HR, 0.69; 95% CI, 0.24-1.95.
- Revised high-risk: HR, 0.53; 95% CI, 0.21-1.31.
- Modified IMS 2024 criteria: High risk per the modified IMS 2024 criteria was defined as the presence of ≥20% del(17p); or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32). In the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32).5
- Modified IMS 2024 standard-risk: HR, 0.42; 95% CI, 0.16-1.07.
- Modified IMS 2024 high-risk: HR, 0.45; 95% CI, 0.13-1.53.
- Standard criteria: High-risk cytogenetics was defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16).
- D-R vs R maintenance demonstrated a PFS benefit regardless of the number of HRCAs. The HRCA numbers presented below were defined as number of abnormalities from del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21). Cytogenetic results at diagnosis (based on case report forms collected data from local laboratories) were used in the analysis. The HR and 95% CI were derived from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-R maintenance.5
- 0 HRCAs: HR, 0.69; 95% CI, 0.24-1.95.
- 1 HRCAs: HR, 0.36; 95% CI, 0.09-1.45.
- ≥2 HRCAs: HR, 0.61; 95% CI, 0.17-2.25.
- D-R vs R maintenance improved PFS among patients with gain/amp(1q21), irrespective of other HRCAs (HR, 0.46; 95% CI, 0.13-1.59).5
| Subgroup, n/N (%) | D-R | R | ORb (95% CI) |
|---|---|---|---|
| ITTc | 50/99 (50.5) | 19/101 (18.8) | 4.51 (2.37-8.57) |
| Age | |||
| <65 years | 30/61 (49.2) | 12/61 (19.7) | 3.95 (1.76-8.85) |
| ≥65 years | 20/38 (52.6) | 7/40 (17.5) | 5.24 (1.86-14.74) |
| Race | |||
| White | 31/67 (46.3) | 14/68 (20.6) | 3.32 (1.55-7.10) |
| Black | 12/20 (60.0) | 4/24 (16.7) | 7.50 (1.85-30.34) |
| ISS staging at diagnosis | |||
| I | 19/40 (47.5) | 8/38 (21.1) | 3.39 (1.25-9.19) |
| II | 13/28 (46.4) | 7/37 (18.9) | 3.71 (1.23-11.25) |
| III | 15/23 (65.2) | 3/23 (13.0) | 12.50 (2.83-55.25) |
| Baseline response statusd | |||
| <CR | 27/71 (38.0) | 11/71 (15.5) | 3.35 (1.50-7.46) |
| ≥CR | 23/28 (82.1) | 8/30 (26.7) | 12.65 (3.58-44.64) |
| Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; IMWG, International Myeloma Working Group; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; NGS, nextgeneration sequencing; OR, odds ratio; R, lenalidomide. aDefined as the proportion of patients who achieved MRD-negative status (at 10–5 bMantel-Haenszel estimate of the common OR for stratified tables is used for ITT; Mantel-Haenszel estimate of the common OR for unstratified tables is used for subgroups. An OR >1 indicates an advantage for D-R.cITT analysis set is defined as all patients who were randomized to treatment.dResponse status upon entering the study as assessed by IMWG 2016 criteria. | |||
| Subgroup, n/N (%) | D-R | R | ORb (95% CI) |
|---|---|---|---|
| Cytogenetic risk at diagnosis | |||
| Standard risk | 35/63 (55.6) | 14/66 (21.2) | 4.64 (2.15-10.04) |
| High riskc | 7/22 (31.8) | 1/15 (6.7) | 6.53 (0.71-60.05) |
| Revised cytogenetic risk at diagnosis | |||
| Revised standard risk (0 HRCAs) | 28/52 (53.8) | 12/53 (22.6) | 3.99 (1.72-9.26) |
| Revised high-risk (≥1 HRCA)d | 14/32 (43.8) | 4/30 (13.3) | 5.06 (1.43-17.88) |
| 1 HRCA | 8/21 (38.1) | 4/20 (20.0) | 2.46 (0.60-10.04) |
| ≥2 HRCAs | 6/11 (54.5) | 0/10 (0) | NE (NE-NE)e |
| Gain/amp(1q21) | 10/16 (62.5) | 3/22 (13.6) | 10.56 (2.17-51.42) |
| Isolated gain/amp(1q21) | 7/10 (70.0) | 3/15 (20.0) | 9.33 (1.46-59.48) |
| Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; HRCA, high-risk cytogenetic abnormalities; MRD, minimal residual disease; NE, not estimable; NGS, nextgeneration sequencing; OR, odds ratio; R, lenalidomide. aDefined as the proportion of patients who achieved MRD-negative status (at 10–5) by NGS by 12 months after maintenance treatment and prior to progressive disease or subsequent antimyeloma therapy.bMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-R.cHigh-risk cytogenetics per the standard definition are defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16). dRevised high-risk cytogenetics per the revised definition are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21). eNot evaluable because no patient in the R group had MRD-negative conversion. | |||
| Subgroup, n/N (%) | D-R | R |
|---|---|---|
| Modified IMS 2024 standard-risk | 34/67 (50.7) | 16/68 (23.5) |
| Modified IMS 2024 high-risk | 7/17 (41.2) | 0/8 (0.0) |
| ≥20% del(17p) | 2/10 (20.0) | 0/2 (0.0) |
| t(4;14)/(14;16)/(14;20) + gain/amp(1q21) and/or del(1p32) | 2/5 (40.0) | 0/6 (0.0) |
| Del(1p21) + gain/amp(1q21) | 3/4 (75.0) | 0/0 (0.0) |
| Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; IMS, International Myeloma Society; MRD, minimal residual disease; R, lenalidomide. aHigh risk per the modified IMS 2024 criteria is defined as the presence of ≥20% del(17p), or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32) [in the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32)]. bDefined as the proportion of patients who achieved MRD-negative status (at 10–5) by NGS by 12 months after maintenance treatment and prior to progressive disease or subsequent antimyeloma therapy. cDefined as the proportion of patients who achieved MRD-negative status any time after the date of randomization. | ||
Safety
- No unexpected safety concerns were observed in patients ≥65 years or Black patients.5
- The median duration of therapy was 25.0 months (D-R, 30.5 vs R, 23.5 months) for patients <65 years and 24.4 months (D-R, 32.7 vs R, 19.2 months) for patients ≥65 years. The safety results for patients with ≥1 TEAE based on age is summarized in Table: Safety Results for Patients With ≥1 TEAE Based on Age.
- The median duration of therapy was 23.7 months (D-R, 29.3 vs R, 18.9 months) for White patients and 25.4 months (D-R, 28.3; R, 25.4 months) for Black patients. The safety results for patients with ≥1 TEAE based on race is summarized in Table: Safety Results for Patients With ≥1 TEAE Based on Race.
- D-R maintenance did not increase grade 3/4 infection or cytopenia rates in patients ≥65 years of age.5
| Patients with ≥1 TEAE, n (%) | D-R | R | ||
|---|---|---|---|---|
| <65 years (n = 59) | ≥65 years (n = 37) | <65 years (n = 58) | ≥65 years (n = 40) | |
| Grade 3/4 TEAEs | 45 (76.3) | 26 (70.3) | 37 (63.8) | 29 (72.5) |
| Most commona | ||||
| Neutropeniab | 26 (44.1) | 19 (51.4) | 25 (43.1) | 16 (40.0) |
| Lymphopenia | 7 (11.9) | 3 (8.1) | 3 (5.2) | 2 (5.0) |
| Hypertension | 6 (10.2) | 1 (2.7) | 3 (5.2) | 1 (2.5) |
| Leukopenia | 6 (10.2) | 3 (8.1) | 2 (3.4) | 4 (10.0) |
| Hypokalemia | 4 (6.8) | 3 (8.1) | 2 (3.4) | 4 (10.0) |
| Pneumonia | 1 (1.7) | 4 (10.8) | 1 (1.7) | 3 (7.5) |
| Grade 3/4 cytopenias | 31 (52.5) | 21 (56.8) | 27 (46.6) | 19 (47.5) |
| Grade 3/4 infections | 11 (18.6) | 7 (18.9) | 6 (10.3) | 7 (17.5) |
| Serious TEAEs | 14 (23.7) | 15 (40.5) | 7 (12.1) | 15 (37.5) |
| COVID-19 events | ||||
| Any grade | 19 (32.2) | 9 (24.3) | 22 (37.9) | 7 (17.5) |
| Grade 3/4 | 1 (1.7) | 0 (0.0) | 3 (5.2) | 0 (0.0) |
| TEAEs leading to discontinuation of any treatment componentc | 7 (11.9) | 7 (18.9) | 4 (6.9) | 4 (10.0) |
| Death due to TEAEs | 0 (0.0) | 2 (5.4) | 0 (0.0) | 1 (2.5) |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; TEAE, treatment-emergent adverse event; R, lenalidomide. aOccurring in ≥10% of patients in either treatment group in either age category. bPreferred term grouping. cIncludes those who had adverse events with action taken as drug withdrawn to ≥1 component of study treatment on “AE” complete report form page. | ||||
| Patients with ≥1 TEAE, n (%) | D-R | R | ||
|---|---|---|---|---|
| White (n = 64) | Black (n = 20) | White (n = 65) | Black (n = 24) | |
| Grade 3/4 TEAEs | 49 (76.6) | 15 (75.0) | 46 (70.8) | 16 (66.7) |
| Most commona | ||||
| Neutropeniab | 29 (45.3) | 10 (50.0) | 28 (43.1) | 11 (45.8) |
| Lymphopenia | 9 (14.1) | 0 (0.0) | 5 (7.7) | 0 (0.0) |
| Hypokalemia | 6 (9.4) | 1 (5.0) | 3 (4.6) | 3 (12.5) |
| Leukopenia | 5 (7.8) | 3 (15.0) | 4 (6.2) | 2 (8.3) |
| Diarrhea | 2 (3.1) | 1 (5.0) | 2 (3.1) | 3 (12.5) |
| Fatigue | 0 (0.0) | 2 (10.0) | 2 (3.1) | 1 (4.2) |
| Grade 3/4 cytopenias | 35 (54.7) | 10 (50.0) | 31 (47.7) | 12 (50.0) |
| Grade 3/4 infections | 13 (20.3) | 4 (20.0) | 8 (12.3) | 5 (20.8) |
| Serious TEAEs | 20 (31.3) | 6 (30.0) | 14 (21.5) | 7 (29.2) |
| COVID-19 events | ||||
| Any grade | 18 (28.1) | 7 (35.0) | 20 (30.8) | 5 (20.8) |
| Grade 3/4 | 1 (1.6) | 0 (0.0) | 1 (1.5) | 2 (8.3) |
| TEAEs leading to discontinuation of any treatment componentc | 14 (21.9) | 0 (0.0) | 7 (10.8) | 1 (4.2) |
| Death due to TEAEs | 2 (3.1) | 0 (0.0) | 1 (1.5) | 0 (0.0) |
| Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; TEAE, treatment-emergent adverse event; R, lenalidomide. aOccurring in ≥10% of patients in either treatment group in either racial group. bPreferred term grouping. cIncludes those who had adverse events with action taken as drug withdrawn to ≥1 component of study treatment on “AE” complete report form page. | ||||
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
10 December 2024.
References
| 1 | Janssen Research & Development, LLC. A study of daratumumab plus lenalidomide versus lenalidomide alone as maintenance treatment in participants with newly diagnosed multiple myeloma who are minimal residual disease positive after frontline autologous stem cell transplant (AURIGA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 December 10]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03901963 NLM Identifier: NCT03901963. |
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