denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Advances in Newly Diagnosed and Relapsed Myeloma
Introduction: Daratumumab (DARA) is a novel human CD-38-targeting monoclonal antibody in clinical development for multiple myeloma (MM). In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]), DARA monotherapy showed remarkable clinical activity and was well tolerated in heavily treated patients (pts) with relapsed and refractory (RR) MM (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl: abstr LBA8512). A combined analysis of efficacy of 16 mg/kg DARA in these two studies is presented.
Methods: GEN501, a first-in-human open-label, two-part (Part 1 dose escalation; Part 2 dose expansion) study, enrolled pts with MM that had relapsed after or were refractory to ≥2 prior therapies. Sirius, an open-label, two-part study, enrolled pts with MM with ≥3 prior therapies, including a PI or IMiD, or were refractory to both a PI and an IMiD. Eligibility criteria included pts with absolute neutrophil count ≥1000/mm3, hemoglobin ≥7.5 g/dL, platelet count ≥75×109/L (GEN501) or ≥50×109/L (Sirius), and alanine aminotransferase ≤3.5 (GEN501) or ≤2.5 (Sirius) times the upper limit of normal. In GEN501 Part 2, the first 16 mg/kg DARA infusion was followed by a 3 week rest period, and then qw for 7 weeks, q2w for 14 weeks, and q4w thereafter. In Sirius, 16 mg/kg DARA was infused qw for 8 weeks, q2w for 16 weeks, and q4w thereafter. The combined analysis comprised pts treated with 16 mg/kg DARA in Sirius and Part 2 of GEN501. In both studies overall response rates (ORR) were assessed according to IMWG response criteria.
Results: The combined analysis included 148 pts (42 and 106 pts from GEN501 and Sirius, respectively). The median (range) age was 64 (31-84) years. Median time since initial diagnosis was 5.8 and 4.8 years in GEN501 and Sirius, respectively, and 62% and 82% of pts had received >3 prior therapies, respectively. In GEN501, 76% of pts were refractory to their last therapy and 64% were refractory to both a PI and IMiD; a greater proportion of pts in Sirius were refractory to their last therapy (97%) and double refractory to a PI and IMiD (95%). The ORR was 36% in GEN501 and 29% in Sirius; the ORR for the combined analysis was 31%. Best overall response is shown in Table. Responses deepened over time and the combined rate of very good partial response (VGPR) or better was 11% with 2 pts with complete responses (CR) and 3 with stringent CRs (sCR) across the two studies. In the combined analysis, median duration of response was 7.6 months and 46% of responders remained progression free at 1-year after a median follow-up of 9.3 months. Median overall survival (OS) had not been reached at median follow-up times of 10.2 months (GEN501) and 9.3 months (Sirius). The estimated 1-year OS rate (95% CI) was 77% (58-88), 65% (51-76), and 69% (58-77) for GEN501, Sirius, and the combined analysis, respectively. Forty-four of 46 responders were still alive at the time of the primary analysis. At a subsequent data cutoff for the combined analysis, after a median follow-up of 14.8 months, the estimated median OS was 19.9 months (95% CI, 15.1 – not estimable). ORR was similar across prespecified subgroups which included age, ISS stage, number of prior therapies, and refractory status.
Conclusions: Single-agent DARA (16 mg/kg) demonstrated remarkable clinical activity (31% ORR) in a combined analysis of two studies in heavily pretreated MM pts. The quality of the observed responses (11% VGPR or better, 2 CRs, and 3 sCRs) was noteworthy in this highly refractory population. DARA shows promising activity in pts who have exhausted other approved myeloma treatment options.
Table. Best Overall Response.
|
16 mg/kg |
|
|
|
MMY2002 |
GEN501 Part 2 |
Total |
Combined analysis set |
106 |
42 |
148 |
Best response |
|
|
|
Stringent Complete Response (sCR) |
3 (2.8) |
0 |
3 (2.0) |
Complete response (CR) |
0 |
2 (4.8) |
2 (1.4) |
Very good partial response (VGPR) |
10 (9.4) |
2 (4.8) |
12 (8.1) |
Partial response (PR) |
18 (17.0) |
11 (26.2) |
29 (19.6) |
Minimal response (MR) |
5 (4.7) |
4 (9.5) |
9 (6.1) |
Stable disease (SD) |
46 (43.3) |
22 (52.4) |
68 (45.9) |
Progressive disease (PD) |
18 (17.0) |
0 |
18 (12.2) |
Not evaluable (NE) |
6 (5.7) |
1 (2.4) |
7 (4.7) |
Overall response (sCR+CR+VGPR+PR) |
31 (29.2) |
15 (35.7) |
46 (31.1) |
Disclosures: Usmani: Celgene Corporation: Consultancy , Honoraria ; Janssen: Research Funding ; Onyx: Consultancy , Honoraria , Research Funding . Weiss: Janssen and Millennium: Consultancy ; Janssen and Onclave: Research Funding . Bahlis: Johnson & Johnson: Research Funding ; Amgen: Consultancy ; Johnson & Johnson: Consultancy ; Johnson & Johnson: Speakers Bureau ; Celgene: Consultancy , Honoraria , Research Funding , Speakers Bureau . Lonial: Bristol-Myers Squibb: Consultancy , Research Funding ; Celgene: Consultancy , Research Funding ; Onyx: Consultancy , Research Funding ; Janssen: Consultancy , Research Funding ; Millennium: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding . Lokhorst: Genmab: Honoraria , Research Funding ; Janssen: Honoraria , Research Funding ; Amgen: Honoraria . Voorhees: Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy , Research Funding ; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy ; Millennium/Takeda and Novartis: Honoraria , Membership on an entity’s Board of Directors or advisory committees . Richardson: Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees ; Celgene: Membership on an entity’s Board of Directors or advisory committees ; Novartis: Membership on an entity’s Board of Directors or advisory committees ; Millennium Takeda: Membership on an entity’s Board of Directors or advisory committees ; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees . Axel: Janssen: Employment . Feng: Janssen: Employment . Uhlar: Janssen: Employment . Wang: Janssen: Employment . Khan: Janssen: Employment . Ahmadi: Janssen: Employment . Nahi: Janssen: Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Celgene: Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau .
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