Background
B-cell maturation antigen (BCMA) is a transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily involved in the regulation of B cell proliferation and survival as well ...as maturation/differentiation into plasma cells. In multiple myeloma cells, overexpression of BCMA has been shown to activate mitogen activated protein kinase pathways (AKT, ERK1/2, and NF-κB) and upregulates anti-apoptotic proteins (MCL1, BCL2, BCL-xL) resulting in cellular proliferation. Immunotherapeutic strategies targeting BCMA are showing great promise in heavily pre-treated refractory multiple myeloma.
Light Chain Amyloidosis (AL) is a multisystem disorder of clonal plasma cells that results in the production of an abnormal light chain which misfolds and deposits in the organs leading to disruption of tissue architecture, cellular stress, dysfunction and eventually, death. The smaller burden and lower proliferative potential of the offending clonal plasma cells in amyloidosis may potentially lend itself favorably to immunotherapeutic strategies targeting BCMA. Given the efficacy of this approach in MM, the evaluation of BCMA expression on the surface of amyloidogenic plasma cells is warranted.
Methods
All patients diagnosed with Light chain Amyloidosis at Memorial Sloan Kettering Cancer Center, NY between January 1, 2012, and December 31, 2018, who had unstained bone marrow samples were identified. These unstained BM biopsy samples were prospectively stained for BCMA expression using Immunohistochemistry (IHC). We utilized a clinical-grade assay (clone D6; catalog sc-390147; company Santa-Cruz; monoclonal antibody; dilution 1:400) in a CLIA compliant setting. We scored the biopsies for BCMA expression, intensity, and site of staining. We also obtained their demographic details, staging, and cytogenetic information for the patients with available samples.
Results
During the queried period, 28 unstained samples were available for testing from the time of disease diagnosis. The median age of the population was 63 years (range 41-73). 64% of patients were male and consistent with the literature; a majority of patients (75%) had lambda-typic clonal plasma cells. Cytogenetic abnormalities using fluorescence in situ hybridization (FISH) were reviewed, t(11;14) was seen in 36% patients, and chromosome 1q and del 13q were each seen in 32% of patients. No patient had t(4;14) or del 17p.
The median clonal PC burden in BM at diagnosis was 10% (range2-80%) and 36% had > 10% plasma cells. In clonal PCs, the median BCMA expression was 80% (range 20-100%). Only one patient had a staining intensity under 50% (20%). Membranous staining was noted in 82% of patients and a Golgi pattern in 11%. The median staining intensity was 2 (range 1-3).
Of the patients with baseline diagnostic samples available for testing, six patients had additional unstained bone marrow samples for staining at the time of relapse. The majority of patients (83%) who relapsed had >10% plasma cells with a higher median plasma cell burden of 35% (range 10-80). The median BCMA expression was 65% (range 50-80) with no patient having <50% expression. The staining pattern was membranous in 50%, Golgi in 17%, and Golgi-membranous in 33%. At the time of relapse, the median clonal PC burden was 13% (range 5-30). BCMA expression continued to be present at the time of relapse with a median 75% (range 50-100) with predominantly membranous staining (83%). The median staining intensity in both diagnostic and relapsed tissue within the six samples studied was 1.
Conclusions
Our study represents the first description of BCMA expression on the surface of amyloidogenic plasma cells to our knowledge. BCMA is uniformly expressed by pathologic PCs in AL amyloidosis both at the time of diagnosis and relapse. Given the efficacy of BCMA directed therapy in multiple myeloma, further investigation of these agents in light-chain amyloidosis are warranted and may provide an effective therapeutic strategy in this devastating disease.
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Dogan:Corvus Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding. Giralt:Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy; Novartis: Consultancy; Actinium: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy. Hassoun:Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Background
Multiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated ...with drug resistance and shorter survival.
Methods
Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, (>4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH.
Results
We identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH.
385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019).
In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days.
Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days.
There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009).
We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups.
Conclusion
Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy.
No relevant conflicts of interest to declare.
Background
Multiple Myeloma (MM) is a heterogeneous disorder of clonal plasma cells. Genetic aberrations are important in heterogeneity and have prognostic and perhaps therapeutic implications. ...Elevated Lactate Dehydrogenase (LDH) has been associated with drug resistance and short survival. The biologic basis of this observation is uncertain. In this study, we sought to define the genomic landscape of MM patients with high LDH to understand pathophysiology and identify therapeutic targets.
Methods
Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12), which includes over 1000 newly-diagnosed MM patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing (RNA-seq), we identified a cohort of patients with baseline LDH values and RNA-seq data available for inclusion. High LDH was defined as LDH greater than upper limit of normal (>4.68 microkatals/L). The RNA-seq data was analyzed to predict differentially expressed genes, then gene set enrichment analyses using GSEA and ClueGO were performed to assess for highly enriched pathways and gene ontologies (GO). Thereafter we analyzed to see if there was an enrichment of high risk cytogenetic changes within the high LDH group. Overall survival (OS) was estimated by Kaplan Meier method and a log-rank test.
Results
We identified 871 patients who met inclusion criteria (High LDH N=143; Normal LDH N=728). LDH continued to remain a poor prognostic factor consistent with prior literature, with median survival 660 days vs 795 days (p=0.02852).
Among the patients who underwent autologous transplant (N=385), LDH continued to be associated with poor prognosis with median overall survival (800.5 vs 878.8 days, p=0.01933). Patient characteristics and other clinical variables are submitted separately (Bal et al. ASH 2018).
There was no difference in the non-synchronous mutations between the two groups when stratified by baseline LDH levels.
To assess for enrichment of the known cytogenetic changes, we performed the hypergeometric test on the samples with both baseline LDH and cytogenetic information. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset compared to normal LDH. (18.48% vs 10.36%) while there was no statistically significant difference in the presence of t(4;14) (p=0.16, 15.65% vs 11.8%) and t(14;16) (p=0.21, 6% vs 4%).
GSEA detected 572 gene sets significantly up-regulated in the high LDH group (FDR q < 25%) compared to those with normal LDH including genes involved in the processing of capped intron containing pre-mRNA, recruitment of mitotic centrosome proteins and complexes, mRNA splicing and the proliferation signal in solid tumors leading to metastatic potential. No significantly down-regulated gene set was detected at same significance level.
The ClueGO analysis using two separate sets of up-regulated DEGs (fold > 1.5x or fold > 2x, FDR < 0.05 for both) revealed upregulated molecular signatures in similar functional categories as the GSEA in patients with high LDH. The first gene set (fold > 1.5x) showed significant enrichments (p < 0.005) in cell cycle-related pathways, including microtubule cytoskeleton organization, polo-like kinase mediated events, regulation of cell cycle phase transition, regulation of nuclear division and kinesins which provide the myeloma cells with a proliferative advantage. The second gene set (fold > 2x) was strongly associated (p < 0.005) with sympathetic nervous system development (NELL2, NTRK1, and SOX11), collagen biosynthesis (ADAMTS family) and O-linked glycosylation (COL11A family). These genes play a role in lymphocyte differentiation, anti-apoptosis, local invasion, and metastasis.
Conclusion
Elevated LDH was confirmed as a poor prognostic factor in the MMRF CoMMpass cohort. Overrepresentation of Del17p in this population likely contributes to poor prognosis. In MM, the bone marrow microenvironment is crucial in the differentiation, migration, proliferation and survival. Overexpression of proteolytic and cell adhesion signatures, evasion/suppression of host immune system along with hyper-proliferative signatures via cell division and RTK pathways in MM patients with high LDH offers insight into the aggressive disease in these patients. Targeting tumor microenvironment and RTK pathways may provide novel therapeutic strategies in this subtype of MM
No relevant conflicts of interest to declare.
Jettison-MS of Nucleic Acid Species Wang, Poguang; Shah, Gunjan L; Landau, Heather ...
Journal of the American Society for Mass Spectrometry,
08/2020, Letnik:
31, Številka:
8
Journal Article
Recenzirano
While MALDI-MS of intact genomic DNA is unheard of, actually many DNA adducts can be detected in this way under certain MALDI conditions: relatively high molar ratio of DNA nucleobases to matrix ...(0.01 to 0.3), hot matrix (CCA), and high laser fluence. This is because many DNA adducts create “bubbles” on dsDNA (disruption of base pairing), making it easier for these adducts as modified nucleobases to be jettisoned by the laser-derived energy of MALDI (jettison mass spectrometry or JeMS). The method also works for other nucleic acid species, namely nucleobases, nucleosides, nucleotides, and RNA. Examples of what we have detected in this way are as follows: methyladenine in E. coli DNA, 5-hydroxymethylcytosine in human brain DNA, melphalan-adenine in leukocyte DNA from patients on corresponding chemotherapy, wybutosine in tRNA, benzyl DNA adducts in E. coli cell culture treated with benzyl bromide, and various DNA adducts formed in test tube exposure experiments with calf thymus DNA. Noteworthy, in the chemotherapy study, principle component analysis of the data encourages the hypothesis that patient DNA undergoes much more damage than just melphalan adducts. Overall, our work leads to the preliminary generalization that about 5 fmol of a nucleobase deficient in base pairing, and present in a MALDI spot, will be detected by JeMS (on the equipment that we used), irrespective of the type of nucleic acid species which houses it, as long as the nucleobase is relatively basic such as A, C, or G.
•Telehealth use for follow-up care delivery is feasible across different hematopoietic cell transplantation types.•Patients report greater satisfaction with telehealth use compared with ...providers.•Feedback is essential to optimize telehealth usability and provider satisfaction.
Telehealth involves the use of telecommunication and information technology for the delivery of clinical care and may be a mechanism to alleviate the burden of visits faced by patients undergoing hematopoietic cell transplantation (HCT). Few studies have evaluated the feasibility and acceptability of telehealth visits in the care of HCT patients. We conducted 27 telehealth visits with 25 patients undergoing HCT using a videoconferencing system that allows for real-time, 2-way interactions and administered satisfaction surveys to patients and providers. Of the 25 patients included in the study, 20 (80%) and 5 (20%) were undergoing autologous and allogeneic HCT, respectively. The telehealth visits were distributed as follows: 3 inpatient visits upon admission for HCT; 11 inpatient visits between 2 and 14 days post-HCT; 4 inpatient visits prior to discharge after HCT; 8 outpatient, post-HCT follow-up visits; and 1 handoff to a community oncologist. Out of a total of 54 provider assessments, 7 providers (13%) were unable to complete some part of the physical examination, but no provider reported being unable to manage patients’ symptoms through telehealth. Eighty-one percent of patients were either satisfied or very satisfied with the telemedicine session. Overall satisfaction was higher among patients than providers (mean scores 4.12 versus 2.64; scale 1 to 5, with 1 = very poor to 5 = excellent). Technological barriers resulting in delays and suboptimal physical examination were largely responsible for provider dissatisfaction. The use of telehealth to deliver comprehensive follow-up care to HCT patients is feasible across different HCT types but is dependent upon quality of data streaming and videoconferencing technologies.
Introduction
Systemic immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys. Management of the disease relies ...primarily on off-label use of multiple myeloma therapies. No treatments are approved for AL amyloidosis in the relapsed/refractory setting. In the phase 3, open-label TOURMALINE-AL1 trial (NCT01659658), patients with relapsed/refractory AL amyloidosis were randomized 1:1 to receive either oral ixazomib plus dexamethasone (Id) or physician's choice (CH) in 28-day cycles, and followed until progression or unacceptable toxicity. An interim analysis demonstrated that Id was well tolerated and, although the primary endpoint of hematologic response rate was not met, time-to-event efficacy analyses consistently favored Id. We report an analysis of patient-reported outcome (PRO) data on health-related quality of life (HRQOL) and AL amyloidosis symptoms from TOURMALINE-AL1; such data for AL amyloidosis in general have been limited.
Methods
Four PRO instruments were used to collect data to support PRO-related secondary endpoints during the treatment period: the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), an amyloidosis symptom questionnaire (ASQ), the EuroQoL 5-Dimension 3-Level (EQ-5D-3L), and the Visual Analogue Scale (EQ VAS) were collected at screening, day 1 of each cycle, and end of treatment (EOT), and the 36-item Short Form General Health Survey version 2 (SF-36v2) was collected at screening, day 1 of every third cycle, and EOT. Analysis of PRO data included descriptive summaries of means and change from baseline and a linear mixed model (LMM) for repeated measures for patients in the intent-to-treat (ITT) population with a baseline and at least one postbaseline PRO-specific assessment. No adjustment was made for multiple comparisons. Data cutoff date was 20 February 2019.
Results
The ITT population included 168 patients (Id: n=85; CH: n=83), who completed up to 58 cycles (Id) and up to 43 cycles (CH); median treatment duration was 11.7 vs 5.0 months, respectively. PRO compliance in the treatment period was high for all instruments (Figure).
Baseline HRQOL as measured by the SF-36v2 and EQ VAS was similar between treatment arms. During the treatment period, SF-36v2 Mental and Physical Component Summary (MCS and PCS) scores remained stable relative to baseline and were similar between arms; the 8 subscale scores were also generally maintained over time, and mostly similar between arms. Least-squares (LS) mean changes from baseline were significantly higher (better HRQoL) for Id compared with CH at several cycles in the SF-36v2 Role Physical and Vitality subscales (p<0.05) (Figure); no subscales demonstrated significant differences favoring CH.
Symptom burden as measured by the FACT/GOG-Ntx and ASQ was low at baseline, leaving little room for improvement. FACT/GOG-Ntx scores were generally maintained over time. In the treatment period, there were small but significant differences in LS mean changes from baseline favoring Id over CH at multiple cycles for 7 of the 11 individual items and the neurotoxicity and sensory summary scores; there were small but significant differences favoring CH over Id for 1 individual item (trouble hearing) at a few later cycles.
The ASQ total score trended downward slightly (lower burden) during treatment after the first few cycles in both arms. There were significant differences per the LMM favoring Id over CH at cycles 7 and 21 (p<0.05).
In both arms, EQ VAS scores trended upward (better HRQoL) during treatment and then declined slightly at EOT. (LMM analyses were not conducted for EQ-5D.)
At EOT, a slight deterioration from baseline was observed in actual scores for SF-36v2 domains and summary scales, FACT/GOG-Ntx neurotoxicity and sensory subscales, and ASQ items and total score for both Id and CH.
Conclusions
Relapsed/refractory AL amyloidosis patients treated with Id experienced HRQOL and symptoms that were similar to or trended better than patients treated with CH. These data suggest that treatment with Id, although with a substantially longer treatment duration, did not have a negative impact on HRQOL in patients with relapsed/refractory AL amyloidosis, a population with currently no approved treatment options.
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Sanchorawala: Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Janssen: Consultancy; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria. Kim: Janssen, BMS: Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Fiona: Pfizer: Research Funding. Suzuki: Janssen: Consultancy, Honoraria; Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Comenzo: Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding. Cherepanov: Takeda: Current Employment, Current equity holder in publicly-traded company. Hayden: Takeda: Current Employment, Current equity holder in publicly-traded company. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Labotka: Takeda: Current Employment. Faller: Takeda Pharmaceuticals Co.: Current Employment; Viracta Therapeutics, Inc: Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Briacell, Inc: Current holder of stock options in a privately-held company. Kastritis: Amgen, Genesis Pharma, Janssen, Takeda: Consultancy; Amgen, Janssen, Pfizer: Research Funding; Amgen, Genesis Pharma, Janssen, Takeda, Pfizer: Honoraria.
•Carfilzomib (K) can be safely combined with MEL200 as an autologous hematopoietic cell transplantation (auto-HCT) preparative regimen.•K-MEL auto-HCT yields promising efficacy in patients with ...relapsed multiple myeloma (MM).•Carfilzomib is well-tolerated maintenance after salvage auto-HCT in MM.
We performed a phase 1/2 trial to investigate the safety and activity of the second-generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2 (MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36 mg/m2 days 1, 8, and 15 (schedule A) or days 1, 2, 15, and 16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). The patients had received a median of 3 previous lines of therapy, 56% had undergone previous AHCT, and 51% had received previous K therapy. During phase 1 (n = 15), the maximum tolerated dose of K in combination with MEL200 was not reached, so the maximum tested dose of 27 mg/m2 (on day -3) and 56 mg/m2 (on day -2) was used in phase 2. The rate of very good partial response after K-MEL therapy (n = 44) was 59.2%, compared with 13.7% before K-MEL therapy. Among patients starting maintenance therapy (n = 27), 12-month progression-free survival was 66.7% and 12-month overall survival was 88.1%. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in patients with MM.
Background: Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival (OS) in AL amyloidosis. Achieving at least a very good ...partial response (VGPR) defined by a dFLC <4mg/dL is an accepted goal of therapy based on favorable outcomes, including improved renal survival (REF: Palladini JCO 2012, Palladini Blood 2014). Recently more profound clonal suppression as indicated by no evidence of minimal residual plasma cell disease (MRD) in bone marrow (BM) (Muchtar Blood 2017) and achieving dFLC <1mg/dL (Manwani Blood 2018) have shown additional benefit. While depth of hematologic response by standard criteria are important, this study assessed additional factors that influence renal response and time to renal response.
Methods: All patients (pts) with AL and renal involvement (biopsy proven renal tissue diagnosis and/or 24hr proteinuria >500mg/day) undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up less than 12 months post RA-ASCT, hemodialysis prior to RA-ASCT and Waldenstrom macroglobulinemia were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise (Landau Leukemia 2013). Hematologic response was assessed at 3 and 12 months (mos) post RA-ASCT (Palladini JCO 2012) and those with less than complete response (CR) were offered consolidation therapy with bortezomib and dexamethasone (BD). All pts underwent serial organ function assessment (Palladini Blood 2014). Logistic regression models were used to assess association with renal response by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance.
Results: Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 pts died within a year post RA-ASCT were excluded. Median age (range) was 61 years (44-73), M:F 49%:51%, white 90% and 34% had cardiac involvement. Median (IQR) 24 hr proteinuria pre RA-ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre RA-ASCT was 9% (IQR 2-14%). 46% pts received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11%. 46% pts received BD consolidation.
Hematologic response at 3 mos post RA-ASCT was CR 44%, VGPR 29%, partial response (PR) 20% and stable disease (SD) 7%. MRD in BM by 10-color flow cytometry was assessed in 33 pts and 13 (39%) were MRD negative. dFLC <1mg/dL was achieved in 63% of pts. Renal response by 12 mos following RA-ASCT was achieved in 32 pts (53%). Median (IQR) time to renal response in these pts was 5.8 mos (5.1 - 11.3). Amongst renal responders, 50% were in CR, 53% had MRD negative BM (of 15 pts) and 78% with dFLC <1mg/dL early post RA-ASCT. In pts who achieved dFLC <1mg/dL early post RA-ASCT, 66% had renal response.
By univariate analysis (Table 1) OR (95% CI) Mayo cardiac Stage (2004) II and III 0.23 (0.07-0.83, p=0.025), early post RA-ASCT dFLC <1mg/dL 3.00 ( 1.01-8.93, p=0.048), VGPR early post RA-ASCT 7.80 (1.69-36.06, p=0.009), dFLC <1mg/dL at 12 mos 7.20 (2.14-24.21, p=0.001) and CR at 12 mos 10.27 (1.14-92.26, p=0.038) were significantly associated with renal response. Neither renal stage, Mayo stage (2012), MRD negativity, melphalan dose nor consolidation was associated with renal response. By multivariate analysis (Table 2), early post RA-ASCT dFLC <1mg/dL continued to be the most significant factor predicting renal response, OR (95% CI) 4.52 (1.26-16.24, p=0.021), when adjusted for renal amyloid stage and Mayo cardiac stage (2004).
Conclusion: In this single center study, we report that RA-ASCT results in renal response in more than half (53%) of the patients at 1 year. Achieving dFLC <1mg/dL early post ASCT is significantly associated with renal response. Renal response is independent of baseline proteinuria and BM plasma cells or MRD status post ASCT. Our study supports that pathologic entity in organ damage is not the plasma cells but rather light chains. Further studies using dFLC <1mg/dL should be evaluated in organ response. Mass spectrometric light chain monitoring may even be more sensitive and could potentially serve as a non-invasive way to measure disease burden.
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Shah:Janssen: Research Funding; Amgen: Research Funding. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Introduction
Belantamab mafodotin is an antibody drug conjugate targeting B-cell maturation antigen (BCMA) on plasma cells and was the first BCMA-targeted drug approved by the FDA. Single agent ...effect was around 31-34% in a recent phase II study (Lonial et al, Lancet Oncology 2020). Side effects, including keratopathy and reduced visual acuity, necessitate dose reduction and dose delays that may limit efficacy.
Patients enrolled on clinical trials, however, often do not reflect a real-world population due to eligibility criteria that limit comorbidities and include wash-out periods not typical of clinical practice. The aim of this study was to assess response rates, dose modifications, and frequency of ocular adverse events in patients treated with belantamab mafodotin in a real-world setting.
Methods
All patients treated with commercial drug belantamab mafodotin at Memorial Sloan Kettering Cancer Center since October 2020 were included in the study. Descriptive statistics were used to assess patient characteristics, response rates, and rate of adverse events.
Results
Forty-two relapsed/refractory multiple myeloma patients were treated with belantamab mafodotin between October 2020 and the data cut off July 2021, including 55% (N=23) women; median age was 67 years. Twelve patients had been included in the Expanded Access Program with belantamab mafodotin prior to transitioning to commercial drug. Thirty patients (71%) had high risk cytogenetics, including gain 1q, t(4;14), t(14;16), t(14;20), complex karyotype, and MYC-translocations.
Patients had been treated with a median of 7 (range 4-14) prior lines of therapy. All patients had received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Eleven patients had received a BCMA-targeted agent in clinical trials, including bi-specific antibodies, chimeric antigen receptor (CAR) T cells, and one patient had received prior trial therapy with belantamab mafodotin.
Patients received a median of 3 cycles (range 1-17) of belantamab mafodotin. The majority, 95% (N=40) as single agent, while two patients were treated with belantamab mafodotin in combination with other standard myeloma treatments.
The overall response rate (ORR) in all patients was 43%; 18/42 patients. Of these, 7 achieved a partial response (PR); 5 patients achieved a very good partial response (VGPR), 4 patients achieved a complete response (CR) and 1 patient achieved a stringent CR (Table 1). Median duration of response for patients in the ORR cohort was 11 months (95% confidence interval: 9.1-not reached). Three patients achieved a minimal response (MR), 6 patients had stable disease (SD), and 1 patient was not evaluable for response assessment. After a median follow up of 7.5 months, 14 patients had progressive disease and 10 patients had died. Sixteen patients continued on belantamab mafodotin therapy at the time of data cutoff, July 31 st 2021.
In a separate analysis of patients not included in the Expanded Access Program, the ORR was 33%; 5 achieved a PR, 4 patients VGPR, 1 patient CR. Two patients achieved a MR, 3 patients had SD, and 14 patients had progressive disease.
Twenty-seven patients (64%) had any grade of ocular toxicity on ophthalmology exam. Using the Keratopathy and Visual Acuity (KVA) scale, 12 patients had grade 1 keratopathy, 7 had grade 2, and 8 had grade 3 keratopathy. Fourteen patients had presence of corneal microcysts. Eighteen patients experienced a decline in best corrected visual acuity (BCVA); 10 patients had grade 1, 5 had grade 2, and 3 patients had grade 3 decline in BCVA.
The dose of belantamab mafodotin was reduced from the starting dose of 2.5 mg/kg to 1.92 mg/kg in 17 patients: 16 patients due to ocular toxicity and 1 patient due to baseline cytopenia. Additionally, one or more doses were delayed in 9 patients due to keratopathy; the majority of patients (N=8) were able to continue therapy with maintained response on a lower dose after the delay.
Conclusion
In this heavily pre-treated multiple myeloma population, the ORR was 33-43% which is similar or better than reported in a recent phase II study. The rate of ocular toxicity (64% keratopathy) was also comparable to previous reports. These data demonstrate encouraging results for belantamab mafodotin treatment in the real-world setting with responses and toxicities comparable to clinical trial subjects. Additional patients and updated follow up will be reported at the meeting.
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Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Peterson: GlaxoSmithKline: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Evicore: Consultancy; Legend Biotech: Consultancy. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker. Landgren: Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Giralt: CELGENE: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Lesokhin: Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria; bristol myers squibb: Research Funding; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; Serametrix, Inc: Patents & Royalties.
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