Faculty Bibliography

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.

Introduction: The oral proteasome inhibitor ixazomib is approved for the treatment of RRMM pts who have received >=1 prior therapy. We report on a pooled analysis of IRd therapy from the INSIGHT MM study and the Czech Registry of Monoclonal Gammopathies (RMG), to evaluate the efectiveness of IRd in RRMM in routine clinical practice.
Method(s): INSIGHT MM is a large, prospective, observational study which has enrolled over 4,200 adult MM pts. The RMG comprises clinical data for >6,000 MM pts enrolled at 19 Czech and 4 Slovak centers. Individual pt level data on demographics, disease characteristics, treatment history, efectiveness, and safety from both registries were integrated and analyzed.
Result(s): At data cutof, 217 pts (83 INSIGHT; 134 RMG) from 11 countries were included. At diagnosis, 32% of pts had ISS Stage III disease, 78% had bone lesions, 46% had anemia, and 12% had elevated creatinine. At study start, median age was 67 years (12% >75 years); 58%/14% of pts had ECOG PS 1/2. Prior therapies included: bortezomib (90%), stem cell transplant (60%), thalidomide (47%), lenalidomide (26%), carflzomib (8%), daratumumab (6%), and pomalidomide (2%). Median time from diagnosis to start of IRd therapy was 42.1 mos. The most common reasons for starting IRd were relapse/progression (87%) and insufcient response (10%). Median duration of follow-up was 12.6 mos. At data cutof, 54% pts had discontinued IRd; median DOT was 11.9 (95% CI: 9.4-15.2) mos; at 12 mos, 49% (41.3-56.2) of pts were still on treatment (KM estimates). Best response to therapy was available for 152 pts. ORR was 74%, with 36% >=VGPR. Median time to first response was 1.2 mos (RMG); median time to best response was 3.7 mos (INSIGHT). Median PFS (mPFS) was 21.6 (95% CI: 13.6-26.7) mos. PFS rate at 12 mos was 62%, and 86 (40%) pts had progressed at data cutof. Median time to next therapy (TTNT) was 31.5 (95% CI: 24.5-35.9) mos, with a 12-month rate of 74%. At data cutof, 53 (24%) pts had died. Median OS was 36.7 (95% CI: 24.4-NR) mos, with 79% of pts alive at 12 mos (Figure). Ixazomib and lenalidomide dose reductions were required in 16% and 36% of pts, including 10% and 21% who required dose reductions due to AEs.
Conclusion(s): The efectiveness of IRd in routine clinical practice (ORR 74%, mPFS 21.6 mos) seen here is comparable to the efficacy reported in TOURMALINE MM1 (ORR 78%, mPFS 20.6 mos). IRd is well tolerated with no new safety signals, and low rates of dose reductions due to AEs

UNLABELLED:= 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome. SIGNIFICANCE:.

Introduction: Patients (pts) with relapsed and refractory multiple myeloma who are triple-class exposed to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies (mAbs) have limited treatment (Tx) options. The BCMA-targeted CAR T cell therapy, ide-cel, is being developed to address the unmet need in this setting. An SLR identifed 2 phase 2 clinical trials investigating the efficacy and safety of specific therapies under US FDA evaluation in this setting, namely Sd (NCT02336815) and BM 2.5 mg/kg (NCT03525678). Here we compare the efficacy outcomes of ide-cel from the KarMMa study with Sd from STORM part 2 and BM from DREAMM-2.
Method(s): Unanchored matching-adjusted indirect Tx comparisons (MAICs) were performed based on individual pt-level data from 128 infused pts in KarMMa, and study-level data from STORM part 2 and DREAMM-2. Individual pt data were reconstructed based on the published Kaplan-Meier curves for time-to-event outcomes from the studies. Between-study diferences were summarized, and the most relevant differences in pt characteristics were identifed based on clinical expertise. Propensity score models were used to weight pts in KarMMa to predict outcomes in a population corresponding to each study. ORs were calculated for ORR using weighted logistic regression models. HRs were calculated for PFS and OS using weighted Cox proportional hazard models. Sensitivity analyses were performed to explore the relative Tx efects with other cohorts from the KarMMa trial, including the enrolled pts (N=140) and pts receiving the target dose of 450x10⁶ CAR+ T cells (N=54).
Result(s): Ide-cel was associated with a higher ORR vs both Sd and BM in a population matched to each trial (Table). Similarly, ide-cel extended PFS and OS vs both Sd and BM. Results were generally consistent in the sensitivity analyses using the KarMMa enrolled population and across different doses for both indirect MAICs, although the efective sample size was reduced in some cases.
Conclusion(s): Tese data suggest that ide-cel ofers improvements in ef-cacy vs both Sd and BM, the only therapies for which there are currently phase 2 data in pts with RRMM afer anti-CD38 mAb Tx

Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine >500umol/L, urine output <400ml/day or dialysis). The Modification of Diet in Renal Disease formula was used to calculate the baseline estimated glomerular filtration rate (eGFR). Renal function was normal, eGFR >=60 ml/min/1.73m², moderately impaired 30-59 or severely impaired <30. Potentially nephrotoxic LC were considered those with a difference of >=500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of >=25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high (>=500) or low (<500) dFLC were examined. Consistent with the findings in the contemporaneous group, KRdc was associated with a significant improvement in PFS compared to Rdc in both the normal and renal function impaired groups. Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC>=500 68.6% v dFLC<500 53.2%). Interestingly the rate of renal recovery was similar between KRdc and Rdc in the high dFLC group (KRdc 71.1% v Rdc 67.5%) suggesting the improved PFS seen with KRdc in the group with renal impairment is not due to an increased rate of renal recovery. Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. [Formula presented] Disclosures: Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies: Celgene, Amgen, Merck: Research Funding. Davies: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cook: Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory: Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner: Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones: Celgene: Honoraria, Research Funding. Kaiser: Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen: Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan: Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson: Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns: Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma
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Aims: To evaluate AMG 701, a BiTE molecule binding BCMA on MM cells and CD3 on T cells, in RR MM (Amgen, NCT03287908); primary objective was to evaluate safety and tolerability and estimate a biologically active dose; secondary objectives were to characterize pharmacokinetics (PK), anti-myeloma activity per IMWG criteria, and response duration.
Method(s): Patients with MM RR or intolerant to >=3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses >=1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. Exclusion criteria included: solely extramedullary disease; prior allogeneic stem cell transplant (SCT) in the past 6 months; prior autologous SCT in the past 90 days; CNS involvement; prior anti-BCMA therapy. The first 3 cohorts (dose 5-45 mug) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, <=10^-5 per IMWG) or flow cytometry (<=3x10^-5).
Result(s): As of July 2, 2020, 75 patients received AMG 701. Patients had a median age of 63 years, a median time since diagnosis of 5.9 years, and a median (range) of 6 (1-25) prior lines of therapy; 27% of patients had extramedullary disease, 83% prior SCT, and 93% prior anti-CD38 Ab; 68% were triple refractory to a PI, an IMiD, and an anti-CD38 Ab. Median (Q1, Q3) treatment duration was 6.1 (3.1, 15.3) weeks and median follow-up on treatment was 1.7 (1.0, 3.7) months. Patients discontinued drug for PD (n=47), AEs (adverse events, n=4, 3 CRS, 1 CMV / PCP pneumonia), withdrew consent (4), other therapy (1), investigator discretion (1), and CNS disease (1); 17 patients remain on AMG 701. The most common hematological AEs were anemia (43%), neutropenia (23%), and thrombocytopenia (20%). The most common non-hematological AEs were CRS (61%), diarrhea (31%), fatigue (25%), and fever (25%). CRS was mostly grade 1 (n=19) or 2 (n=21) per Lee Blood 2014 criteria. All grade 3 CRS (n=5, 7%) were assessed as dose-limiting toxicities (DLTs); all were reversible with corticosteroids and tocilizumab, with median duration of 2 days. CRS grade 3 drivers included transient LFT increases in 3 patients and hypoxia in 2 patients. Other DLTs were 1 case each of transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia. Serious AEs (n=29, 39%) included infections (13), CRS (7), and asymptomatic pancreatic enzyme rise (2, no imaging changes, 1 treatment related). There were 4 deaths from AEs, none related to AMG 701 (2 cases of sepsis, 1 of retroperitoneal bleeding, and 1 of subdural hematoma). Reversible treatment-related neurotoxicity was seen in 6 patients, with median duration of 1 day, all grade 1-2, and associated with CRS in 4 patients. The response rate was 36% (16/45) at doses of 3-12 mg; at <=1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values.
Summary: In this FIH study with ongoing dose escalation, AMG 701, an anti-BCMA BiTE molecule, demonstrated a manageable safety profile, encouraging activity, and a favorable PK profile in patients with heavily pre-treated RR MM, supporting further evaluation of AMG 701. [Formula presented] Disclosures: Harrison: Janssen: Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Haemalogix: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria. Minnema: Amgen: Honoraria; Servier: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Janssen Cilag: Honoraria. Lee: Celgene: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding. Spencer: AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Pharmamar: Research Funding. Kapoor: Cellectar: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Madduri: Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Larsen: Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ailawadhi: Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Amgen: Research Funding; Takeda: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding. Kaufman: Amgen: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Raab: Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari: BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Iida: AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Davies: Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lesley: Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Upreti: Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Sharma: Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Minella: Amgen Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Beam Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lentzsch: Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Sanofi: Research Funding; Karyopharm: Research Funding; Celularity: Consultancy; Sorrento: Consultancy. OffLabel Disclosure: AMG 701, a half-life extended BiTE (bispecific T-cell engager) molecule is an investigational agent for multiple myeloma.
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Background: Therapeutic advances in multiple myeloma (MM) have greatly improved the rate and depth of response. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that has synergistic activity with carfilzomib (K) and dexamethasone (d), and is currently under investigation as a targeted therapy in relapsed/refractory (R/R) MM. Using next-generation sequencing (NGS) and ¹⁸F-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), we aimed to comprehensively evaluate minimal residual disease (MRD) in R/R MM patients (pts) treated with VenKd.
Method(s): In this phase 2, dose-escalation study (NCT02899052), R/R MM (1 - 3 prior lines of therapy and no prior K exposure) pts received VenKd: Ven 400 mg/day + K 27 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,8,15,22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 d1,8,15 + d 40 mg d1,8,15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,2,8,9,15,16,22,23 (Cohort 4). The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR and cytogenetic abnormalities by interphase fluorescence in situ hybridization. MRD assessments by NGS (clonoSEQ) were performed on bone marrow aspirates at cycle 3 day 1 in pts achieving VGPR or better, time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR with negativity determined at <10^-5 threshold. FDG-PET/CT imaging was performed on a subset of pts at baseline, cycle 3 day 1, and confirmation of CR or sCR, which corresponded to the bone marrow MRD evaluations by NGS. Lesions assessed by PET/CT were guided by standard of care imaging (i.e., x-ray, CT), and FDG-uptake was measured by maximum standardized uptake value. Pts were excluded from subsequent FDG-PET imaging based on proximity of evaluable lesions to anticipated areas of high normal FDG uptake (e.g., brain), or PET negative based on baseline FDG-PET imaging. MRD negativity (NGS and/or Imaging) was evaluated in the ITT population and key biomarker-defined subgroups (t(11;14) and BCL2^high). Pts with missing or indeterminate assessments were considered MRD positive. Correlation with PFS, DOR, OS, and patient-reported outcomes (e.g., physical functioning, pain scores, fatigue) will be presented.
Result(s): As of 14 Feb 2020, 49 pts were enrolled (4 in cohort 1, 3 in cohort 2, 7 in cohort 4 and 35 in cohort 3 + expansion). Pts had received a median of 2 (1-3) prior lines of therapy, 96% were exposed to PI (57% refractory), 90% exposed to IMiD (71% refractory), and 86% exposed to PI + IMiD (45% double refractory). Median age was 60 years (37 - 79), 61% had ISS II/III disease, 27% had t(11;14), and 45% were BCL2^high. Of note, 8 out of the 22 (36.4%) BCL2^high pts were t(11;14) positive. Overall response rate (ORR) was 80% (>=PR), including 65% >= VGPR and 41% >=CR (Table 1). Among t(11;14) pts, ORR was 92%, >= VGPR 85%, and >=CR 54%; while among BCL2^high pts ORR was 86%, >= VGPR 77%, and >=CR 41%. Of the 19 pts assessed for MRD by NGS, 15 (79%) had clonotypes identified at baseline. Of these 15 pts, 6 (40%) achieved MRD negativity (<10^-5) by NGS in the bone marrow after VenKd treatment. Of the 12 pts who participated in the FDG-PET sub-study, 10 (83%) were FDG-PET positive at baseline, and 8 (67%) completed post-treatment FDG-PET imaging. Of these 8 pts, 3 (38%) achieved complete metabolic response (CMR) by FDG-PET imaging after VenKd treatment. While only 4 pts were evaluated concurrently for MRD by NGS and FDG-PET/CT imaging, the assessments were concordant for 3 pts (2 positive, 1 negative). The discordant result (NGS negative, FDG-PET/CT positive lymph node) indicated clearance of disease in the bone marrow while the presence of a potential soft tissue plasmacytoma remaining after treatment with VenKd. Of the 19 pts evaluated by either NGS or FDG-PET/CT, 8 (42%) achieved MRD negativity by NGS in the bone marrow or CMR by FDG-PET/CT after VenKd treatment. The highest rates of MRD negativity were observed in t(11;14) and BCL2^high subgroups (Table).
Conclusion(s): The combination of VenKd demonstrates promising efficacy in pts with R/R MM, including high rates of MRD, particularly in the t(11;14) and BCL2^high subgroups. Overall, MRD assessments by NGS and FDG-PET/CT were highly concordant in this study and may be complementary for assessment of disease clearance in MM. [Formula presented] Disclosures: Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Burwick: AbbVie: Research Funding. Jakubowiak: AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Kaufman: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cabanillas: AbbVie: Research Funding. Dail: Genentech: Current Employment, Current equity holder in publicly-traded company. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Masud: AbbVie: Current Employment, Other: may hold stock or stock options. Yang: Abbvie: Current Employment, Current equity holder in publicly-traded company. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mudd: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company. Davies: Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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