Faculty Bibliography

Introduction: Patients (pts) with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have poor clinical outcomes. Ide-cel is a CAR T cell therapy under development for this patient population. Literature review of published efficacy data for TCE RRMM pts identified MAMMOTH, a large, retrospective observational study (Gandhi UH, et al. Leukemia 2019;33:2266-2275). Pts in both MAMMOTH and KarMMa were TCE. This analysis aimed to compare efficacy outcomes observed with ide-cel treatment in KarMMa and conventional care (CC) receiving pts in MAMMOTH.
Method(s): Individual patient-level data (IPD) with a median follow-up of 13.3 months were available for KarMMa (data cutoff 14th Jan 2020) while study-level data were available for MAMMOTH. Unanchored matching-adjusted indirect comparisons (MAICs) were conducted to compare efficacy outcomes from the 2 studies. IPD from MAMMOTH were reconstructed based on published Kaplan-Meier curves for time-to-event outcomes. Propensity score models were used to weight the treated population from KarMMa to match the baseline characteristics of treated pts in MAMMOTH in order to predict outcomes for ide-cel in a population corresponding to the one evaluated in MAMMOTH.
Result(s): Ide-cel was associated with a significantly higher ORR compared with CC in a population matched to the one treated in MAMMOTH (odds ratio (OR) 5.11, 95% CI 2.92-8.94, P < 0.001) (Table 1). Similarly, ide-cel significantly extended PFS (hazard ratio (HR) 0.55, 95% CI 0.42-0.73, P < 0.001) and OS (HR 0.36, 95% CI 0.24-0.54, P < 0.001) versus CC. In MAMMOTH, the individual CC regimens involving targeted therapies (CFZ, DARA, and ELO) were associated with a median OS between 8.3 and 12.7 months. The weighted median OS times for ide-cel are consistently longer than those associated with the individual CC regimens in MAMMOTH (Table 2), similar to the results for the overall treated population.
Conclusion(s): Ide-cel provides clinically and statistically significant efficacy benefits over CC, including combination regimens involving targeted agents

The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM.

Autologous stem cell transplant (ASCT) remains standard of care for consolidation after induction therapy for eligible newly diagnosed myeloma patients. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on patient fitness rather than a strict age cut off. Data from the UK NCRI Myeloma XI trial, a large phase III randomised controlled trial with pathways for transplant-eligible (TE) and ineligible (TNE) patients, was used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including analysis using an agematched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the TE pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in PFS associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged.

Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal-protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852.

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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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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