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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)
Medical Information
DARZALEX FASPRO - Use in High-Risk Multiple Myeloma
Last Updated: 06/03/2026
SUMMARY
- Johnson & Johnson does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
- This response includes information on high-risk subgroups from studies that include patients with newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM).
Newly Diagnosed Multiple Myeloma
- PERSEUS is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) induction and consolidation followed by maintenance with lenalidomide and daratumumab (D-R) in DVRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for autologous stem cell transplant (ASCT).1
- Bertamini et al (2026)2
presented a post hoc analysis of the PERSEUS study evaluating patients based on the International Myeloma Society/International Myeloma Working Group (IMS/IMWG) Consensus Genomic Staging (CGS) high-risk criteria. Progression-free survival (PFS) was higher in the D-VRd vs VRd arms for both standard risk (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.20-0.74; P=0.005) and high risk (OR, 0.54; 95% CI, 0.31-0.95; P=0.03) patients. - Dimopoulos et al (2024)3
, 4 presented an expanded subgroup analysis of PERSEUS clinical outcomes based on the second revised International Staging System (R2-ISS) and the presence of high risk cytogenetic abnormalities (HRCAs), including gain(1q21) and amp(1q21). At a median follow-up of 47.5 months, hazard ratio (HR) point estimates for PFS favored D-VRd vs VRd for revised standard risk (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027). D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II (HR, 0.29; 95% CI, 0.14-0.57) and III (HR, 0.46; 95% CI, 0.29-0.75). - Bertamini et al (2024)5
presented results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTCs) as a biomarker in transplant-eligible NDMM patients. D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. There was no improvement in outcomes for patients with high cytogenetic risk combined with high CTC levels.
- Bertamini et al (2026)2
- CEPHEUS is a phase 3 study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are
transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).6 - Usmani et al (2026)7
presented the final efficacy and safety results of the TIE population of the CEPHEUS study at a median follow-up of 76.0 months. MRD negativity (10-5 ) in patients with complete response or better (≥CR) was achieved in 50% of patients with high cytogenetic risk in both the D-VRd and VRd arms (OR, 1.00; 95% CI, 0.28-3.57). Median PFS for patients with high risk cytogenetics was 58.0 months in the D-VRd arm vs 31.7 months in the VRd arm.
- Usmani et al (2026)7
- AURIGA is a phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs lenalidomide (R) alone in patients with 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.8 ,9 - Badros et al (2025)9 reported primary results from the phase 3 AURIGA study at a median follow-up of 32.2 months. MRD-negativity (10-5) conversion rate after 12 months of maintenance treatment was improved with D-R vs R for both the high risk cytogenetics group (31.8% vs 6.7%; OR, 6.53; 95% CI, 0.71-60.05) and the revised high risk cytogenetics group (43.8% vs 13.3%; OR, 5.06; 95% CI, 1.43-17.88).
- Anderson et al (2025)10
presented updated efficacy and safety results from the phase 3 AURIGA study at 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months. Subgroup analyses of MRD-negativity (10-5) conversion rates consistently favored D-R over R in all patient subgroups regardless of risk status. - Chung et al (2025)11
presented an analysis of MRD dynamics in post-transplant patients with NDMM from the AURIGA study at a median follow up of 40.3 months. At the median follow up, there were higher rates of MRD-negative (10-5) conversion in high risk patients in the D-R arm (50%) vs R alone (20%). MRD-negative (10-6 ) conversion rates in high risk patients in the D-R arm were higher at (27.3%) compared to R alone (13.3%). - Foster et al (2024)12
presented a post hoc analysis of the AURIGA study that evaluated clinically relevant subgroups at a median follow-up of 32.3 months. The subgroup analysis of MRD-negativity (10-5) conversion rates by 12 months of maintenance consistently favored D-R vs R maintenance, regardless of age, race, ISS disease stage, or response upon study entry. D-R vs R maintenance improved MRD-negativity (10-5) conversion rates by 12 months in patients with ultra high-risk disease, standard-risk disease, and patients with modified IMS 2024 high-risk disease.
Relapsed/Refractory Multiple Myeloma
- APOLLO is a phase 2 study evaluating the safety of pomalidomide + lenalidomide (Pd) vs DARZALEX FASPRO + Pd (D-Pd) in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a proteasome inhibitor (PI).13
,14 - Sonneveld et al (2021)15
presented updated efficacy and safety data at a median follow-up of 30.7 months. PFS favored D-Pd vs Pd across subgroups, including ISS stage and cytogenetic risk status.
- Sonneveld et al (2021)15
CLINICAL studies – newly Diagnosed Multiple Myeloma
Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TIE NDMM
Post Hoc Analysis of IMS/IMWG CGS Risk Criteria in the PERSEUS Study
Study Design/Methods
- A post hoc analysis of the phase 3 PERSEUS study evaluated patients based on the IMS/IMWG CGS high-risk criteria utilizing the next generation sequencing (NGS)-based unique molecular assay (UMA) panel.2
- Per the IMS/IMWG CGS criteria, high risk was defined as the presence of at least one of the following2 :
- del(17p) and/or TP53 mutation
- t(4;14) or t(14;16) or t(14;20) with additional amp(1q) or biallelic del(1p)
- Monoallelic del(1p) with additional amp(1q), or biallelic del(1p)
- High β2M with normal renal function
Results
Patient Characteristics
- A total of 709 patients were enrolled and randomized in the PERSEUS study, of which 434 patients were risk-evaluable based on the IMS/IMWG CGS criteria.2
- Of these risk-evaluable patients, 152 (35%) were classified as high risk.
- del(17p) and/or TP53 mutation was the most common genetic lesions identified by UMA-NGS (14% [n=59]).
- When comparing to the per-protocol FISH criteria, 17% of patients were reclassified from standard to high risk and 4% were reclassified from high to standard risk with the IMS/IMWG CGS criteria.2
- Baseline characteristics among risk-evaluable patients were generally balanced across treatment arms and comparable to the PERSEUS ITT population. See Table: Baseline Characteristics (IMS/IMWG CGS Risk-Evaluable Population).2
| Characteristic | D-VRd (n=209) | VRd (n=225) |
|---|---|---|
| IMS/IMWG CGS, high risk, n (%) | 69 (33.0) | 81 (36.0) |
| Female, n (%) | 86 (41.1) | 95 (42.2) |
| Median age (IQR), years | 61 (53-65) | 60 (54-65) |
| ISS, n (%) | ||
| I | 105 (50.2) | 113 (50.2) |
| II | 69 (33.0) | 79 (35.1) |
| III | 35 (16.7) | 32 (14.2) |
| Per protocol FISH cytogenetics, high risk, n (%) | 49 (23.4) | 44 (19.6) |
| Abbreviations: CGS, Consensus Genomic Staging; D-VRd, DARZALEX FASPRO +bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in-situ hybridization; IMS/IMWG, International Myeloma Society/International Myeloma Working Group; IQR, interquartile range; ISS, International Staging System; VRd, bortezomib + lenalidomide + dexamethasone. | ||
Efficacy
- Overall and sustained MRD negativity rates were higher in the D-VRd vs VRd arm in both IMS/IMWG CGS standard and high risk patients as summarized in Table: Summary of MRD negativity (≥CR) Ratesby IMS/IMWG CGS Risk Criteria.2
| Parameter | Standard risk | High Risk | ||||||
|---|---|---|---|---|---|---|---|---|
| D-VRd (n=138) | VRd (n=144) | OR (95% CI) | P-value | D-VRd (n=71) | VRd (n=81) | OR (95% CI) | P-value | |
| Overall MRD negativity (≥CR) rate, n (%)a,b | ||||||||
| 10-5 threshold | 106 (76.8) | 78 (54.2) | 2.79 (1.68-4.71) | <0.0001 | 52 (73.2) | 37 (45.7) | 3.22 (1.64-6.50) | 0.0006 |
| 10-6 threshold | 93 (67.4) | 56 (38.9) | 3.23 (1.99-5.30) | <0.0001 | 40 (56.3) | 21 (25.9) | 3.64 (1.85-7.35) | 0.0001 |
| Sustained MRD negativity (≥CR) for ≥12 months, n (%)a,c | ||||||||
| 10-5 threshold | 95 (68.8) | 55 (38.2) | 3.55 (2.18-5.86) | <0.0001 | 42 (59.2) | 19 (23.5) | 4.65 (2.34-9.57) | <0.0001 |
| 10-6 threshold | 73 (52.9) | 31 (21.5) | 4.06 (2.43-6.91) | <0.0001 | 26 (36.6) | 14 (17.3) | 2.73 (1.30-5.96) | 0.0069 |
| Abbreviations: CGS, Consensus Genomic Staging; CI, confidence interval, CR, complete response; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; IMS/IMWG, International Myeloma Society/International Myeloma Working Group; MRD, minimal residual disease; NGS, next generation sequencing; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. a b c | ||||||||
- PFS was higher in the D-VRd vs VRd arms for both standard risk (OR, 0.38; 95% CI, 0.20-0.74; P=0.005) and high risk (OR, 0.54; 95% CI, 0.31-0.95; P=0.03) patients.2
- Patients who achieved sustained MRD negativity (10-5 and 10-6) for ≥12 months had a higher PFS rate than those that did not, regardless of risk status as defined by IMS/IMWG CGS criteria.2
Expanded Analysis of the PERSEUS Study Based on R2-ISS and HRCAs
Study Design/Methods
- A total of 709 patients were randomized 1:1 into D-VRd (n=355) vs VRd (n=354) arm.1
- Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).
Results
Patient Characteristics
- Baseline characteristics are summarized in Table: Demographics and Baseline Clinical Characteristics of the High-Risk ITT Population.3,4
| D-VRd (n=355) | VRd (n=354) | |
|---|---|---|
| Cytogenetic abnormalities, n (%) | ||
| del(17p) | 36 (10.1) | 34 (9.6) |
| t(4;14) | 33 (9.3) | 38 (10.7) |
| t(14;16) | 11 (3.1) | 14 (4) |
| Gain(1q21)b | 59 (16.6) | 71 (20.1) |
| Amp(1q21)c | 28 (7.9) | 36 (10.2) |
| Cytogenetic risk profiled | ||
| Standard risk | 264 (74.4) | 266 (75.1) |
| High risk | 76 (21.4) | 78 (22) |
| del(17p) | 36 (10.1) | 34 (9.6) |
| t(4;14) | 33 (9.3) | 38 (10.7) |
| t(14;16) | 11 (3.1) | 14 (4) |
| Indeterminate | 15 (4.2) | 10 (2.8) |
| Revised cytogenetic riske | ||
| Revised standard risk | 174 (49) | 167 (47.2) |
| Revised high risk | 130 (36.6) | 148 (41.8) |
| Indeterminate | 51 (14.4) | 39 (11) |
| ISS disease stage, n/N (%) | ||
| I | 186/355 (52.4) | 178/353 (50.4) |
| II | 114/355 (32.1) | 125/353 (35.4) |
| III | 55/355 (15.5) | 50/353 (14.2) |
| R2-ISS disease stage, n (%) | ||
| Low (I) | 116 (32.7) | 114 (32.2) |
| Low-intermediate (II) | 111 (31.3) | 106 (29.9) |
| Intermediate-high (III) | 108 (30.4) | 115 (32.5) |
| High (IV) | 20 (5.6) | 19 (5.4) |
| Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; FISH; fluorescence in situ hybridization; ISS, International Staging System; ITT, intent-to-treat; R2-ISS, second revised International Staging System; VRd, bortezomib + lenalidomide + dexamethasone. aThe ITT population was defined as all patients who underwent randomization. bGain(1q21) was defined as the presence of 3 copies of chromosome 1q21. cAmp(1q21) was defined as the presence of 4 or more copies of chromosome 1q21. dCytogenetic risk was based on FISH; high risk was defined as the presence of del(17p), t(4;14), or t(14;16). eRevised cytogenetic risk was defined as the presence of del(17p), t(4;14), t(14;16), gain(1q21), or amp(1q21). | ||
Efficacy
- Across all cytogenetic risk subgroups, PFS was favored for D-VRd followed by D-R maintenance vs VRd followed by R maintenance and is summarized in Table: Cytogenetic Risk Subgroup Analysis of PFS in the ITT Population.4
- HR point estimates for PFS favored D-VRd vs VRd for revised standard (HR, 0.29; 95% CI, 0.15-0.56; P=0.0001) and revised high cytogenetic risk (HR, 0.53; 95% CI, 0.35-0.81; P=0.0027).3,4
- Irrespective of other HRCAs, HR point estimates for PFS also favored D-VRd vs VRd in patients with the presence of gain(1q21), amp(1q21), and gain(1q21) or amp(1q21).4
| Subgroup | D-VRd | D-VRd | VRd | VRd | HR (95% CI) | P Value |
|---|---|---|---|---|---|---|
| n/N | Median PFS, Months | n/N | Median PFS, Months | |||
| Standard riska | 25/264 | NE | 62/266 | NE | 0.35 (0.22-0.56) | <0.0001 |
| High riskb | 24/76 | NE | 38/78 | 44.1 | 0.59 (0.36-0.99) | 0.0439 |
| Revised standard riskc | 12/174 | NE | 35/167 | NE | 0.29 (0.15-0.56) | 0.0001 |
| Revised high riskd | 33/130 | NE | 62/148 | NE | 0.53 (0.35-0.81) | 0.0027 |
| gain(1q21)e | 15/59 | NE | 26/71 | NE | 0.62 (0.33-1.18) | 0.1400 |
| amp(1q21)f | 6/28 | NE | 17/36 | 46.7 | 0.37 (0.15-0.94) | 0.0306 |
| gain(1q21)/ amp(1q21)g | 21/87 | NE | 43/107 | NE | 0.52 (0.31-0.88) | 0.0133 |
| Isolated gain(1q21)h | 8/37 | NE | 15/47 | NE | 0.57 (0.24-1.36) | 0.2004 |
| Isolated amp(1q21)i | 1/17 | NE | 9/23 | NE | 0.11 (0.01-0.87) | 0.0115 |
| 1 revised HRCA | 21/97 | NE | 43/110 | NE | 0.47 (0.28-0.79) | 0.0035 |
| ≥2 revised HRCAs | 12/33 | NE | 19/38 | 44.1 | 0.73 (0.35-1.50) | 0.3878 |
| Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ITT, intent-to-treat; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone. aStandard risk (per protocol), defined as none of the following HRCAs: del(17p), t(4;14), t(14;16). bHigh risk (per protocol), defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16). cDefined as none of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21). dDefined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21). eDefined as the presence of 3 copies of chromosome 1q21, with or without other HRCAs. fDefined as the presence of 4 or more copies of chromosome 1q21, with or without other HRCAs. gDefined as the presence of gain(1q21) or amp(1q21), with or without other HRCAs. hDefined as the presence of 3 copies of chromosome 1q21, without any other HRCAs. iDefined as the presence of 4 or more copies of chromosome 1q21, without any other HRCAs. | ||||||
- D-VRd increased PFS irrespective of the R2-ISS disease stage with a pronounced effect for R2-ISS stages II and III and is summarized in Table: Subgroup Analysis of PFS Based on R2-ISS Disease Stage.3
| Subgroup | D-VRd | D-VRd | VRd | VRd | HR (95% CI) |
|---|---|---|---|---|---|
| n/N | Median PFS, Months | n/N | Median PFS, Months | ||
| Low (I) | 6/116 | NE | 13/114 | NE | 0.42 (0.16-1.11) |
| Low-intermediate (II) | 11/111 | NE | 30/106 | NE | 0.29 (0.14-0.57) |
| Intermediate-high (III) | 25/108 | NE | 50/115 | NE | 0.46 (0.29-0.75) |
| High (IV) | 8/20 | NE | 10/19 | 39.8 | 0.63 (0.25-1.61) |
| Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone. | |||||
- Regardless of high-risk cytogenetic markers, a subgroup analysis of overall and sustained (≥12 months) MRD negativity (at 10-5 and 10-6 sensitivity) ≥CR rates based on cytogenetic risk markers favored treatment with D-VRd followed by D-R maintenance over VRd followed by R maintenance and is summarized in Table: Subgroup Analysis of MRD Negativity.3,4
| Subgroup | D-VRd | VRd | OR (95% CI) | P Value |
|---|---|---|---|---|
| n/N (%) | n/N (%) | |||
| MRD negativity (10-5) with ≥CR | ||||
| Standard riska | 204/264 (77.3) | 128/266 (48.1) | 3.67 (2.52-5.33) | <0.0001 |
| High riskb | 52/76 (68.4) | 37/78 (47.4) | 2.40 (1.24-4.63) | 0.0086 |
| Revised standard riskc | 131/174 (75.3) | 79/167 (47.3) | 3.39 (2.14-5.37) | <0.0001 |
| Revised high riskd | 95/130 (73.1) | 73/148 (49.3) | 2.79 (1.68-4.62) | <0.0001 |
| gain(1q21)e | 41/59 (69.5) | 33/71 (46.5) | 2.62 (1.27-5.41) | 0.0086 |
| amp(1q21)f | 24/28 (85.7) | 20/36 (55.6) | 4.80 (1.38-16.69) | 0.0104 |
| gain(1q21)/amp(1q21)g | 65/87 (74.7) | 53/107 (49.5) | 3.01 (1.63-5.56) | 0.0004 |
| Isolated gain(1q21)h | 27/37 (73) | 23/47 (48.9) | 2.82 (1.12-7.10) | 0.0268 |
| Isolated amp(1q21)i | 16/17 (94.1) | 13/23 (56.5) | 12.31 (1.39-109.10) | 0.0093 |
| 1 revised HRCA | 73/97 (75.3) | 55/110 (50) | 3.04 (1.68-5.51) | 0.0002 |
| ≥2 revised HRCAs | 22/33 (66.7) | 18/38 (47.4) | 2.22 (0.85-5.83) | 0.1044 |
| Low (I) | 92/116 (79.3) | 55/114 (48.2) | 4.11 (2.30-7.35) | - |
| Low-intermediate (II) | 84/111 (75.7) | 49/106 (46.2) | 3.62 (2.03-6.45) | - |
| Intermediate-high (III) | 79/108 (73.1) | 55/115 (47.8) | 2.97 (1.70-5.21) | - |
| High (IV) | 12/20 (60) | 9/19 (47.4) | 1.67 (0.47-5.93) | - |
| Sustained MRD negativity (10-5) lasting ≥12 months | ||||
| Standard riska | 183/264 (69.3) | 83/266 (31.2) | 4.98 (3.45-7.20) | <0.0001 |
| High riskb | 37/76 (48.7) | 20/78 (25.6) | 2.75 (1.40-5.42) | 0.0032 |
| Revised standard riskc | 115/174 (66.1) | 53/167 (31.7) | 4.19 (2.67-6.59) | <0.0001 |
| Revised high riskd | 77/130 (59.2) | 41/148 (27.7) | 3.79 (2.30-6.26) | <0.0001 |
| gain(1q21)e | 37/59 (62.7) | 21/71 (29.6) | 4 (1.92-8.34) | 0.0002 |
| amp(1q21)f | 20/28 (71.4) | 10/36 (27.8) | 6.50 (2.17-19.48) | 0.0006 |
| gain(1q21)/amp(1q21)g | 57/87 (65.5) | 31/107 (29) | 4.66 (2.54-8.56) | <0.0001 |
| Isolated gain(1q21)h | 25/37 (67.6) | 15/47 (31.9) | 4.44 (1.77-11.17) | 0.0012 |
| Isolated amp(1q21)i | 15/17 (88.2) | 6/23 (26.1) | 21.25 (3.71-121.61) | 0.0001 |
| 1 revised HRCA | 60/97 (61.9) | 31/110 (28.2) | 4.13 (2.31-7.41) | <0.0001 |
| ≥2 revised HRCAs | 17/33 (51.5) | 10/38 (26.3) | 2.97 (1.10-8.04) | 0.0303 |
| Low (I) | 82/116 (70.7) | 38/114 (33.3) | 4.82 (2.76-8.43) | - |
| Low-intermediate (II) | 76/111 (68.5) | 27/106 (25.5) | 6.35 (3.51-11.49) | - |
| Intermediate-high (III) | 63/108 (58.3) | 36/115 (31.3) | 3.07 (1.77-5.32) | - |
| High (IV) | 9/20 (45) | 4/19 (21.1) | 3.07 (0.75-12.59) | - |
| MRD negativity (10-6) with ≥CR | ||||
| Standard riska | 177/264 (67) | 88/266 (33.1) | 4.12 (2.87-5.91) | <0.0001 |
| High riskb | 44/76 (57.9) | 24/78 (30.8) | 3.09 (1.60-6.00) | 0.0007 |
| Revised standard riskc | 115/174 (66.1) | 56/167 (33.5) | 3.86 (2.47-6.05) | <0.0001 |
| Revised high riskd | 82/130 (63.1) | 48/148 (32.4) | 3.56 (2.17-5.84) | <0.0001 |
| gain(1q21)e | 36/59 (61) | 22/71 (31) | 3.49 (1.69-7.20) | 0.0006 |
| amp(1q21)f | 21/28 (75) | 15/36 (41.7) | 4.20 (1.42-12.39) | 0.0082 |
| gain(1q21)/amp(1q21)g | 57/87 (65.5) | 37/107 (34.6) | 3.59 (1.98-6.52) | <0.0001 |
| Isolated gain(1q21)h | 24/37 (64.9) | 15/47 (31.9) | 3.94 (1.58-9.80) | 0.0028 |
| Isolated amp(1q21)i | 14/17 (82.4) | 9/23 (39.1) | 7.26 (1.62-32.60) | 0.0069 |
| 1 revised HRCA | 63/97 (64.9) | 35/110 (31.8) | 3.97 (2.23-7.08) | <0.0001 |
| ≥2 revised HRCAs | 19/33 (57.6) | 13/38 (34.2) | 2.61 (1.00-6.83) | 0.0500 |
| Low (I) | 78/116 (67.2) | 37/114 (32.5) | 4.27 (2.46-7.41) | - |
| Low-intermediate (II) | 76/111 (68.5) | 31/106 (29.2) | 5.25 (2.94-9.38) | - |
| Intermediate-high (III) | 65/108 (60.2) | 40/115 (34.8) | 2.83 (1.65-4.88) | - |
| High (IV) | 12/20 (60) | 6/19 (31.6) | 3.25 (0.87-12.14) | - |
| Sustained MRD negativity (10-6) lasting ≥12 months | ||||
| Standard riska | 137/264 (51.9) | 54/266 (20.3) | 4.24 (2.88-6.22) | <0.0001 |
| High riskb | 23/76 (30.3) | 11/78 (14.1) | 2.64 (1.18-5.90) | 0.0160 |
| Revised standard riskc | 87/174 (50) | 35/167 (21) | 3.77 (2.34-6.07) | <0.0001 |
| Revised high riskd | 55/130 (42.3) | 23/148 (15.5) | 3.99 (2.27-7.01) | <0.0001 |
| gain(1q21)e | 25/59 (42.4) | 11/71 (15.5) | 4.01 (1.76-9.15) | 0.0007 |
| amp(1q21)f | 17/28 (60.7) | 6/36 (16.7) | 7.73 (2.42-24.63) | 0.0003 |
| gain(1q21)/amp(1q21)g | 42/87 (48.3) | 17/107 (15.9) | 4.94 (2.53-9.63) | <0.0001 |
| Isolated gain(1q21)h | 19/37 (51.4) | 9/47 (19.1) | 4.46 (1.69-11.77) | 0.0020 |
| Isolated amp(1q21)i | 13/17 (76.5) | 3/23 (13) | 21.67 (4.15-113.02) | <0.0001 |
| 1 revised HRCA | 45/97 (46.4) | 18/110 (16.4) | 4.42 (2.32-8.42) | <0.0001 |
| ≥2 revised HRCAs | 10/33 (30.3) | 5/38 (13.2) | 2.87 (0.87-9.51) | 0.0797 |
| Low (I) | 58/116 (50) | 24/114 (21.1) | 3.75 (2.10-6.69) | - |
| Low-intermediate (II) | 56/111 (50.5) | 18/106 (17) | 4.98 (2.65-9.34) | - |
| Intermediate-high (III) | 47/108 (43.5) | 22/115 (19.1) | 3.26 (1.79-5.94) | - |
| High (IV) | 7/20 (35) | 2/19 (10.5) | 4.58 (0.81-25.80) | - |
| Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. aStandard risk (per protocol), defined as none of the following HRCAs: del(17p), t(4;14), t(14;16). bHigh risk (per protocol), defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16). cRevised standard risk, defined as none of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21). dRevised high risk, defined as 1 or more of the following HRCAs: del(17p), t(4;14), t(14;16), gain(1q21), amp(1q21). eDefined as the presence of 3 copies of chromosome 1q21, with or without other HRCAs. fDefined as the presence of 4 or more copies of chromosome 1q21, with or without other HRCAs. gDefined as the presence of gain(1q21) or amp(1q21), with or without other HRCAs. hDefined as the presence of 3 copies of chromosome 1q21, without any other HRCAs. iDefined as the presence of 4 or more copies of chromosome 1q21, without any other HRCAs. | ||||
Results
Patient Characteristics
- The CTC testing was performed at screening in 451 patients from the PERSEUS study (D-VRd, 231/355 [65.1%] vs VRd, 220/354 [62.1%] patients). The baseline patient characteristics were balanced between the treatment groups and are summarized in Table: Baseline Characteristics in Patients from the PERSEUS Study - CTC Subgroup.
| Characteristic | D-VRd (n=231) | VRd (n=220) | P Value |
|---|---|---|---|
| ISS disease stage, % | |||
| I | 53.2 | 50.9 | 0.76 |
| II | 31.6 | 35 | 0.76 |
| III | 15.2 | 14.1 | 0.76 |
| High LDH, n (%) | 63 (27.3) | 42 (19.1) | 0.04 |
| Cytogenetic high riska, n (%) | 51 (22.1) | 49 (22.3) | 0.86 |
| Abbreviations: CTC, circulating tumor cell; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; LDH, lactate dehydrogenase; VRd, bortezomib + lenalidomide + dexamethasone. aHigh-risk cytogenetics was defined by the presence of t(4;14), and/or t(14;16) and/or del17p by fluorescence in situ hybridization. | |||
Efficacy
- D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in the outcomes for patients with high cytogenetic risk combined with high CTC levels.5 The prognostic impact of CTC and other risk factors on PFS is presented in Table: Prognostic Impact of CTC and Other Risk Factors on PFS.
- D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).5
| Risk Factor | HR (95% CI) | P Value |
|---|---|---|
| CTC (log10) | 1.36 (1.15-1.6) | ≤0.05 |
| Cytogenetics high riska | 2.71 (1.76-4.17) | ≤0.05 |
| ISS stage II | 1.31 (0.81-2.12) | >0.05b |
| ISS stage III | 2.5 (1.45-4.32) | ≤0.05 |
| Elevated LDH | 1.04 (0.65-1.68) | >0.05b |
| Abbreviations: CI, confidence interval; CTC, circulating tumor cell; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase; PFS, progression-free survival. aComparison with standard risk. High-risk cytogenetics is defined by the presence of t(4;14) and/or t(14;16) and/or del17p by fluorescence in situ hybridization. Absence of those is considered standard risk. bNot significant. | ||
Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TIE NDMM
Final Analysis of TIE Patients in the CEPHEUS Study
Results
Patient Characteristics
- Of the 395 patients enrolled in the study, 298 were ineligible for transplant (D-VRd, n=144; VRd, n=145).7
- The baseline characteristics of TIE patients are summarized in Table: Select Baseline Characteristics of TIE Population.16
| Characteristic | D-VRd (n=144) | VRd (n=145) |
|---|---|---|
| ISS disease stagec, n (%) | ||
| I | 50 (34.7) | 48 (33.1) |
| II | 54 (37.5) | 57 (39.3) |
| III | 40 (27.8) | 40 (27.6) |
| Cytogenetic risk profiled, n (%) | ||
| Standard | 105 (72.9) | 111 (76.6) |
| High | 20 (13.9) | 18 (12.4) |
| Unevaluable or missing | 19 (13.2) | 16 (11.0) |
| Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; IFM, Intergroupe Francophone du Myelome; Ig, immunoglobulin; IMWG, International Myeloma Working group; ISS, International Staging System; TIE, transplant-ineligible; VRd, bortezomib + lenalidomide + dexamethasone. aECOG PS is scored on a scale of 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability. bTotal additive frailty is scored on a scale of 0-5 based on age, comorbidities, and cognitive and physical conditions, with 0 indicating fit, 1 indicating intermediate fitness, and ≥2 indicating frail, per the Myeloma Geriatric Assessment score (http://www.myelomafrailtyscorecalculator.net/). cBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease. dBased on fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16). | ||
Efficacy
- Subgroup analyses of MRD negativity (≥CR; 10-5) and PFS were generally consistent across prespecified subgroups. See Tables: Prespecified Subgroup Analysis of MRD Negativity (TIE Subgroup) and Prespecified Subgroup Analysis of PFS (TIE Subgroup).7
| Subgroup | D-VRd | VRd | OR (95% CI) |
|---|---|---|---|
| MRD negativity (≥CR; 10-5), n/N (%) | |||
| Baseline ISS | |||
| I | 33/50 (66.0) | 20/48 (41.7) | 2.72 (1.20-6.17) |
| II | 32/54 (59.3) | 26/57 (45.6) | 1.73 (0.82-3.68) |
| III | 23/40 (57.5) | 12/40 (30.0) | 3.16 (1.26-7.94) |
| Cytogenetic Risk | |||
| High risk | 10/20 (50.0) | 9/18 (50.0) | 1.00 (0.28-3.57) |
| Standard risk | 67/105 (63.8) | 44/111 (39.6) | 2.68 (1.55-4.66) |
| Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance score; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone. | |||
| Subgroup | D-VRd | VRd | OR (95% CI) | ||
|---|---|---|---|---|---|
| Events/N | Median PFS, months | Events/N | Median PFS, months | ||
| Baseline ISS | |||||
| I | 17/50 | NE | 25/48 | 60.5 | 0.52 (0.28-0.97) |
| II | 19/54 | NE | 30/57 | 49.4 | 0.50 (0.28-0.88) |
| III | 18/40 | 66.4 | 21/40 | 43.8 | 0.66 (0.35-1.24) |
| Cytogenetic Risk | |||||
| High risk | 11/20 | 58.0 | 12/18 | 31.7 | 0.82 (0.36-1.87) |
| Standard risk | 35/105 | NE | 50/111 | 61.6 | 0.58 (0.38-0.89) |
| Abbreviations: CI, confidence interval; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance score; ISS, International Staging System; NE, not estimable; OR, odds ratio; PFS, progression-free survival; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone. | |||||
Safety
- Grade 3/4 TEAEs occurred in 93.8% of patients in the D-VRd arm vs 88.7% in the VRd arm as summarized in Table: Safety Overview (TIE Subgroup).7
| Event, n (%) | D-VRd (n=144) | VRd (n=142) |
|---|---|---|
| Any TEAE | 144 (100.0) | 142 (100.0) |
| Grade 3/4 | 135 (93.8) | 126 (88.7) |
| Grade 5 non-COVID-19 | 18 (12.5) | 13 (9.2) |
| Grade 5 COVID-19a | 6 (4.2) | 1 (0.7) |
| Any serious TEAE | 109 (75.7) | 99 (69.7) |
| TEAE leading to discontinuation of study treatment | 14 (9.7) | 33 (23.2) |
| Exposure-adjusted grade 5 TEAE rate, patient-monthsb | 0.30/100 | 0.26/100 |
| Second primary malignancies | 20 (13.9) | 20 (14.1) |
| Most common (≥5%) grade 3/4 TEAEs of interest | ||
| Neutropenia | 65 (45.1) | 47 (33.1) |
| Thrombocytopenia | 44 (30.6) | 33 (23.2) |
| Anemia | 16 (11.1) | 14 (9.9) |
| Diarrhea | 20 (13.9) | 15 (10.6) |
| Fatigue | 13 (9.0) | 15 (10.6) |
| COVID-19c | 14 (9.7) | 5 (3.5) |
| Pneumonia | 26 (18.1) | 19 (13.4) |
| Peripheral sensory neuropathy | Any grade: 86 (59.7) Grade 3/4: 14 (9.7) | Any grade: 91 (64.1) Grade 3/4: 12 (8.5) |
| Abbreviations: D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone. aDeaths on or within 30 days of treatment. bExposure-adjusted incidence rate: number of subjects with event per 100 patient-months at risk. Patient-months at risk = sum of exposure time until first TEAE occurrence or end of treatment for subjects without the event.cGroup term. | ||
Phase 3 Study of D-R Maintenance in Patients with NDMM
Primary Analysis of the AURIGA Study
Badros et al (2024)9 reported primary results from the phase 3 AURIGA study at a median follow up of 32.3 months.
Study Design/Methods
- The trial enrolled 200 patients from the United States and Canada.9
- Primary endpoint: MRD-negativity conversion rate from baseline by 12 months.9
- MRD was assessed at 12, 18, 24, and 36 months.
- Key secondary endpoints: Safety, PFS, overall MRD-negativity conversion rate, sustained MRD-negativity rate (≥6 months), response rates including CR/sCR as assessed by International Myeloma Working Group (IMWG) 2016 criteria, duration of ≥CR, OS, health-related quality of life (HRQoL) changes based on patient reported outcomes.9
Results
Patient Characteristics
- A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.9
- The baseline demographics and disease characteristics of the intention-to-treat (ITT) population are presented in Table: Baseline Demographics and Disease Characteristics of the High-Risk ITT Population.9
- 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.9
- Patients in the D-R vs R arm received a median of 33 (range, 1-36) vs 21.5 (range, 1-36) maintenance cycles, respectively.9
- 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.9
| D-R (n=99) | R (n=101) | |
|---|---|---|
| ISS disease stagea, n (%) | ||
| I | 40 (44) | 38 (38.8) |
| II | 28 (30.8) | 37 (37.8) |
| III | 23 (25.3) | 23 (23.5) |
| Median induction cycles (range)b, n | 5 (4-8) | 5 (4-8) |
| Cytogenetic risk at diagnosisc, n (%) | ||
| Standard risk | 63 (68.5) | 66 (74.2) |
| High riskd | 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) |
| Revised cytogenetic risk at diagnosise, n (%) | ||
| Standard risk | 52 (55.9) | 53 (59.6) |
| High riskf | 32 (34.4) | 30 (33.7) |
| del(17p) | 13 (14) | 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; ISS, International Staging System; ITT, intent-to-treat; NR, not reported; R, lenalidomide. aD-R vs R: n=91 vs n=98, respectively. bD-R vs R: n=98 vs n=99, respectively. cD-R vs R: n=92 vs n=89, respectively. dHigh risk is defined as positive for any of del(17p), t(14;16), or t(4;14). eD-R vs R: n=93 vs n=89, respectively. fRevised 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
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 High-Risk ITT Population.9
| Subgroup, n/N (%) | D-R (n=99) | R (n=101) | OR (95% CI) |
|---|---|---|---|
| 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) | 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; ISS, International Staging System; ITT, intent-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
- 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.9
- Serious AEs were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.9
- Any TEAEs occurred in 99% of patients in both the D-R and R arms.9
- Grade 3/4 TEAEs occurred in 74% 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%) patients in the D-R vs R arm, respectively, discontinued ≥1 component of the study treatment.9
Updated Efficacy and Safety Analysis of Phase 3 AURIGA Study
Results
Treatment Disposition
- The median duration of study treatment was 33.1 months (range, 0.7-37.5) for the D-R group and 24.9 months (range, 0-37.7) for R group.
Efficacy
- Subgroup analyses of MRD-negativity (10-5) conversion rates consistently favored D-R over R in all patient subgroups regardless of risk status; the results are summarized in Table: Subgroup Analysis of MRD-Negativity (10-5) Conversion Rates in Patient Subgroups.10
| Subgroup, n/N (%) | D-R | R | OR (95% CI) |
|---|---|---|---|
| ISS staging at diagnosis | |||
| I | 22/40 (55.0) | 14/38 (36.8) | 2.10 (0.85-5.19) |
| II | 15/28 (53.6) | 11/37 (29.7) | 2.73 (0.98-7.59) |
| III | 18/23 (78.3) | 3/23 (13.0) | 24.00 (5.01-114.97) |
| Cytogenetic risk at diagnosis | |||
| High riska | 11/22 (50.0) | 3/15 (20.0) | 4.00 (0.88-18.22) |
| Standard risk | 40/63 (63.5) | 20/66 (30.3) | 4.00 (1.92-8.33) |
| Revised cytogenetic risk at diagnosis | |||
| High riskb | 19/32 (59.4) | 6/30 (20.0) | 5.85 (1.87-18.27) |
| Standard risk | 32/52 (61.5) | 18/53 (34.0) | 3.11 (1.40-6.90) |
| Cytogenic risk per IMS 2024 criteria | |||
| High riskc | 9/17 (52.9) | 0/8 (0) | NE (NE-NE) |
| Standard risk | 42/67 (62.7) | 25/68 (36.8) | 2.89 (1.44-5.81) |
| Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ISS, International Staging System; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; R, lenalidomide. aHigh-risk cytogenetics are defined as ≥1 abnormality including del(17p), t(4;14), and/or t(14;16). bRevised high-risk cytogenetics are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), and/or gain/amp(1q21). cHigh 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)]. | |||
Safety
- No new safety concerns were identified with the addition of DARZALEX FASPRO to R maintenance.10
- The most common treatment-emergent adverse events (TEAEs) in the safety population are summarized in Table: Most Common TEAEs.10
- Grade 3/4 TEAEs occurred in 72/96 (75%) of patients in the D-R arm, and 72/98 (73.5%) in the R arm.
- Serious TEAEs were reported in 31.3% vs 25.5% of patients in the D-R vs R arm, respectively.
| Patients with ≥1 TEAE, n (%) | D-R (n=96) | R (n=98) |
|---|---|---|
| Grade 3/4 TEAEsa | 72 (75.0) | 72 (73.5) |
| Neutropenia | 47 (49.0) | 45 (45.9) |
| Leukopenia | 10 (10.4) | 7 (7.1) |
| Lymphopenia | 10 (10.4) | 6 (6.1) |
| Hypokalemia | 7 (7.3) | 7 (7.1) |
| Hypertension | 7 (7.3) | 4 (4.1) |
| Pneumonia | 6 (6.3) | 5 (5.1) |
| Diarrhea | 3 (3.1) | 5 (5.1) |
| Grade 3/4 infections | 19 (19.8) | 14 (14.3) |
| Serious TEAEsb | 30 (31.3) | 25 (25.5) |
| Pneumonia | 5 (5.2) | 5 (5.1) |
| Diarrhea | 3 (3.1) | - |
| TEAEs leading to discontinuation of any treatment componentc | 14 (14.6) | 10 (10.2) |
| TEAEs leading to discontinuation of treatmentd | 12 (12.5) | 9 (9.2) |
| Death due to TEAEse | 2 (2.1) | 1 (1.0) |
| TEAE, treatment-emergent adverse event. aOccurring in ≥5% of patients in either treatment group. bOccurring in ≥3% of patients in either treatment group. cIncludes patients who had adverse events with action taken as drug withdrawn to ≥1 component of study treatment on adverse event case report form page. dIncludes patients with treatment discontinuation due to adverse events per treatment disposition case report form page. | ||
Analysis of MRD Dynamics from the Phase 3 AURIGA Study
Results
Efficacy
- MRD-negative conversion and MRD-positive recurrence rates by cytogenetic risk at diagnosis are summarized in Table: Summary of MRD Negative Conversion and MRD Positive Recurrence (10-5, 10-6, and 10-5 only) Rates by Cytogenetic Risk at Diagnosis.11
| Patients, n/N (%) | D-R (n=99) | R (n=101) |
|---|---|---|
| MRD-negative conversiona,d | ||
| 10-5 sensitivityb | 60/99 (60.6) | 30/101 (29.7) |
| Standard riskc | 45/70 (64.3) | 25/74 (33.8) |
| High risk | 11/22 (50.0) | 3/15 (20.0) |
| 10-6 sensitivitye | 36/99 (36.4) | 14/101 (13.9) |
| Standard riskc | 27/70 (38.6) | 12/74 (16.2) |
| High risk | 6/22 (27.3) | 2/15 (13.3) |
| 10-5 only sensitivityf | 24/99 (24.2) | 16/101 (15.8) |
| Standard riskc | 18/70 (25.7) | 13/74 (17.6) |
| High risk | 5/22 (22.7) | 1/15 (6.7) |
| MRD-positive recurrenced | ||
| 10-5 sensitivity | ||
| Standard riskc | 9/45 (20.0) | 8/25 (32.0) |
| High risk | 6/11 (54.5) | 1/3 (33.3) |
| 10-6 sensitivity | ||
| Standard riskc | 3/27 (11.1) | 5/12 (41.7) |
| High risk | 2/6 (33.3) | 1/2 (50.0) |
| 10-5 only sensitivity | ||
| Standard riskc | 7/18 (38.9) | 6/13 (46.2) |
| High risk | 5/5 (100) | 1/1 (100) |
| Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; MRD, minimal residual disease; R, lenalidomide. aIncludes patients with ≥1 negative MRD test at the 10–5 bOf the 11 high-risk patients in the D-R group, 6 had del(17p), 4 had t(4;14), and 4 had t(14;16); all 3 high-risk patients in the R group had only t(4;14). cFor this analysis, the standard-risk subgroups included patients with an incomplete cytogenetic panel. dMRD-negative conversion and MRD-positive recurrence rates are among patients with cytogenetic results for del(17p), t(4;14), and/or t(14;16) at diagnosis. One patient with MRD-positive recurrence in the D-R arm had no cytogenetic test results for del(17p), t(4;14), or t(14;16). eOf the 6 high-risk patients in the D-R group, 3 had del(17p), 3 had t(4;14), and 3 had t(14;16); both high-risk patients in the R group had only t(4;14). fOf the 5 high-risk patients in the D-R group, 3 had del(17p), 1 had t(4;14), and 1 had t(14;16); the 1 high-risk patient in the R group had only t(4;14). | ||
Clinically Relevant Subgroup Analysis of the Phase 3 AURIGA Study
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.12
- The median follow-up was 32.3 months.12
- The demographics and disease characteristics of the ITT population are presented in Table: Demographics and Disease Characteristics of the ITT Population.
| D-R (n=99) | R (n=101) | |
|---|---|---|
| ISS disease stage, n (%) | ||
| n | 91 | 98 |
| I | 40 (44) | 38 (38.8) |
| II | 28 (30.8) | 37 (37.8) |
| III | 23 (25.3) | 23 (23.5) |
| Cytogenetic risk at diagnosis per standard definitiona,b, n (%) | ||
| 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) |
| Cytogenetic risk at diagnosis per revised definitionc, n (%) | ||
| 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 criteriad, n (%) | ||
| n | 93 | 90 |
| Modified IMS 2024 standard-risk | 67 (72) | 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) |
| Unknown | 9 (9.7) | 14 (15.6) |
| Abbreviations: 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. aHigh-risk cytogenetics per the standard definition are defined as ≥1 abnormality including del(17p), t(4;14), or t(14;16). bThe 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. cRevised 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). dHigh 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 analysis 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.12 The results are summarized in Table: Subgroup Analysis of MRD-negativity (10-5 Sensitivity) Conversion Ratea from Baseline to 12 Months of Maintenance Treatment.
| 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) | 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) | 12.50 (2.83-55.25) |
| Baseline response statusd | |||
| <CR | 27/71 (38) | 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) 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 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. | |||
- 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.12 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.
| 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) | 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) | 3/15 (20) | 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. | |||
- 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.12 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.
| 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) |
| ≥20% del(17p) | 2/10 (20) | 0/2 (0) |
| t(4;14)/(14;16)/(14;20) + gain/amp(1q21) and/or del(1p32) | 2/5 (40) | 0/6 (0) |
| Del(1p21) + gain/amp(1q21) | 3/4 (75) | 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. | ||
- 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.12
- 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).
- 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.12
- 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).12
CLINICAL STUDIES – RELAPSED/REFRACTORY MULTIPLE MYELOMA
Phase 3 Study of DARZALEX FASPRO in Combination with Pd in Patients with RRMM
Updated Efficacy and Safety Analysis of the APOLLO Study
Results
Patient Characteristics
- The key baseline characteristics are summarized in Table: Key Baseline Characteristics in the ISS and Cytogenetic Profile Subgroups (APOLLO).
| D-Pd (n=151) | Pd (n=153) | |
|---|---|---|
| ISS disease stagea, n (%) | ||
| I | 68 (45) | 69 (45.1) |
| II | 50 (33.1) | 51 (33.3) |
| III | 33 (21.9) | 33 (21.6) |
| Cytogenetic profileb | ||
| N | 103 | 108 |
| Standard-risk, n (%) | 64 (62.1) | 73 (67.6) |
| High-risk, n (%) | 39 (37.9) | 35 (32.4) |
| Abbreviations: D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; ISS, International Staging System; Pd, pomalidomide + dexamethasone. aBased on the combination of serum β2-microglobulin and albumin. bBased on fluorescence in situ hybridization. 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 30.7 months, PFS favored D-Pd vs Pd (median 12.1 months vs 7 months, respectively; HR, 0.63; 95% CI, 0.48-0.83; P=0.0007).
- The PFS benefit associated with D-Pd vs Pd was consistent across subgroups. See Table: PFS in the ISS Staging and Cytogenetic Profile Subgroups (APOLLO).
| Events/Patients | Median PFS, Months | HR (95% CI)a | |||
|---|---|---|---|---|---|
| D-Pd | Pd | D-Pd | Pd | ||
| Overall | 100/151 | 120/153 | 12.09 | 7.03 | 0.63 (0.48-0.83) |
| ISS disease staging | |||||
| I | 40/68 | 50/69 | 19.32 | 10.12 | 0.66 (0.43-1) |
| II | 36/50 | 41/51 | 12.25 | 6.08 | 0.52 (0.33-0.82) |
| III | 24/33 | 29/33 | 6.05 | 5.03 | 0.67 (0.39-1.17) |
| Revised ISS disease staging | |||||
| I | 14/26 | 19/25 | 17.54 | 11.17 | 0.61 (0.30-1.22) |
| II | 54/74 | 72/88 | 12.25 | 6.47 | 0.58 (0.41-0.83) |
| III | 16/19 | 12/14 | 2.83 | 3.38 | 1.17 (0.55-2.51) |
| Cytogenetic risk at study entry | |||||
| High-risk | 32/39 | 28/35 | 5.78 | 3.98 | 0.88 (0.53-1.46) |
| Standard-risk | 39/64 | 58/73 | 17.54 | 8.54 | 0.56 (0.37-0.84) |
| Abbreviations: CI, confidence interval; D-Pd, DARZALEX FASPRO + pomalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; Pd, pomalidomide + dexamethasone; PFS, progression-free survival. aHRs and 95% CIs were calculated from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-Pd. | |||||
Safety
- Grade ≥3 TEAEs were reported in 133 (89.3%) D-Pd-treated patients vs 123 (82%) Pd-treated patients.
- Grade 3/4 TEAEs occurring in ≥15% of patients in the D-Pd vs Pd arm were
neutropenia (69.1% vs 50.7%), infections (31.5% vs 23.3%), anemia (18.1% vs 21.3%), thrombocytopenia (18.1% vs 18.7%), and leukopenia (16.8% vs 4.7%). - Treatment discontinuation due to TEAEs was low among both treatment groups (D-Pd, 2%; Pd, 4%).
Literature Search
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 02 June 2026. In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.
References
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