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8000
Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory ...multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined. Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m
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on C1D1, 36 or 70 mg/m
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subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability. Results: Twenty-two pts (median range age, 60 34-74 y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m
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by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE pulmonary embolism; 1 PD; 4 other ASCT). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%. Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971.
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LBA8512
Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study ...(NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.
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8515
Background: Asymptomatic monoclonal gammopathies (AMG) are the most common plasma cell dyscrasia classified as either monoclonal gammopathy of undetermined significance (MGUS) or ...asymptomatic multiple myeloma (AMM). Clinical outcome in AMGs can be highly variable and there is an unmet need to identify newer clinical, genomic and imaging parameters from prospective studies to guide patient management. Methods: We analyzed clinical, genomic and imaging data from AMG patients (n=334) enrolled in a prospective observational clinical trial (S0120) conducted under the auspices of SWOG. Baseline data from clinical variables, as well as gene expression profiles of purified tumor cells and the findings on magnetic resonance imaging (MRI) were correlated with the risk of progression to symptomatic myeloma (MM) requiring therapy. Results: In addition to serum M spike, percent bone marrow plasma cells and the ratio of involved/uninvolved serum free light chains, the level of serum beta-2-microglobulin was associated with an increased risk of progression to clinical myeloma requiring therapy. Gene expression profiles (GEP) of purified tumor cells revealed that all of the known molecular GEP subtypes of human MM are also represented in the precursor phase. An increased risk score (> - 0.26) based on a 70-gene signature (GEP70) was an independent predictor of the risk of progression to clinical MM requiring therapy. The presence of focal lesions on MRI also conferred an increased risk of disease progression but was not independent of other clinical and genomic features. Conclusions: These data represent the first comprehensive evaluation of clinical, genomic and imaging features of AMGs in the context of a prospective US-cooperative group trial, and demonstrate that while all genetic subtypes of MM have a precursor phase, genetic signatures previously associated with high risk myeloma also predict the risk of progression to clinical malignancy requiring therapy. These findings suggest the need to integrate both clinical assessment of tumor bulk and genomic properties of tumor cells in the clinical management of these patients. Clinical trial information: NCT00900263.
Abstract 3955▪▪This icon denotes a clinically relevant abstract
MGUS counts for the majority of monoclonal gammopathies and can be found in approximately 3% of adults older than 50 years. MGUS ...progresses to active Multiple Myeloma (MM) at a rate of 1–2% per year, thus imparting an average risk of 25% for progression (PRO) over a lifetime once diagnosed. Unfortunately no single laboratory, molecular or imaging variable can reliably predict PRO. S0120 accrued 363 patients at 69 sites across the US between January 1, 2004 and November 1, 2011, of whom 166 had MGUS and 190 AMM, defined according to IMWG criteria, on whom laboratory, gene expression and imaging studies were collected in a prospective fashion. Here we report the results of imaging studies as predictors of progression.
262 patients with evaluable follow-up were enrolled at the University of Arkansas for Medical Sciences (UAMS) site. MRI and PET-CT studies were performed at baseline and serially thereafter until PRO to symptomatic MM defined by standard variables of M-protein, bone marrow findings and CRAB criteria, according to protocol. Lab studies were performed at three months, six months and one year after registration, then every 12 months for a total of 5 years from registration as well as within 14 days of decision to discontinue observation or within 14 days of progression. MRI parameters included the number of focal lesions (FL) recognized by short TI inversion recovery (STIR) analysis of the axial bone marrow along with an account of bone marrow background intensity compared to adjacent muscles (hypo-, iso-, hyper-intense). PET-CT parameters included number of FDG-avid focal lesions (PET-FL), SUVmax of PET-FL, presence of extra-medullary disease (EMD) as well as the FDG avidity score at L5 (SUV-L5). Evaluable baseline MRI and PET studies were available for 235 and 224 patients, respectively.
In the 262 eligible patients enrolled and followed at UAMS, the two subgroups of MGUS and AMM differed by definition in M-protein and bone marrow plasmacytosis; in addition, IgA subclass and Hyperdiploidy molecular subgroup were overrepresented in the AMM group. Patients in the AMM group also had higher risk scores defined by the GEP 70-gene risk model (GEP70). At 24 months from study entry, 18.8% of all patients had progressed to MM (25.6% of AMM patients and 8.2% of MGUS patients) and 11.5% had begun MM therapy (15.8% of AMM patients and 4.5% of MGUS patients).
Univariate Cox regression strongly indicated that age ≥ 65, serum albumin <3.5g/dL, B2M >+3.5mg/L, detection of any cytogenetic abnormalities (CA), and suppression of uninvolved light chains were adversely associated with time to PRO. The AMM-constituting features, bone marrow plasmacytosis >10%, M-protein >30g/L, and abnormal K/L ratio also conferred greater hazard of PRO. Risk scores > −0.26 and >1.5 for GEP70 and GEP80, respectively, as well as detection of focal lesions by MRI at baseline carried an elevated HR for PRO. A multivariate Cox regression showed only elevated M-protein, abnormal K/L ratio and GEP70 risk scores > =0.26 to be strongly associated with time to PRO. In the context of this MV model, disease subtype (AMM v MGUS) was insignificant. Inclusion of development of MRI-FL or and PET-FL as time-dependent variables showed that they were associated with time to PRO with HRs of 27.12 and 32.18 respectively. Abnormal K/L ratio and elevated M-protein were lost in this MV model. Analyzing variables linked to initiation of MM therapy, abnormal K/L ratio, elevated BM plasmacytosis, elevated M-protein, GEP70 risk scores >-0.26 as well as detection of MRI-FL at baseline (≥1 FL: HR=4.90; ≥3FL: HR=10.00) were univariately significant. On multivariate analysis, abnormal K/L ratio, elevated M-protein and GEP70 risk scores > – 0.26 were associated with time to treatment for MM. Inclusion of development of MRI-FL or PET-FL as a time dependent variable were associated with time to treatment with HRs of 29.12 and 36.50 respectively.
To our knowledge, this is the first comprehensive effort that has used available imaging modalities along with established laboratory and pathology investigations in an attempt to distinguish features predictive of PRO from MGUS to active MM. In addition to the established “high-risk” MGUS/AMM features, we found that presence of MRI-FL at baseline, presence of CA and GEP70 scores >-0.26 carry a higher risk of PRO.
Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.
