Rajkumar, S. Vincent

SummaryBelantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to < 100, or clonal BMPCs > 50% to < 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.

8054 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. Herein we provide survival outcomes on the first randomized trial in newly diagnosed HRMM, S1211, to follow-up on the previously reported progression-free survival (PFS) (NCT01668719, Usmani SZ et al, Lancet Haem 2021). Methods: S1211 is a randomized phase II trial comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab (RVd-Elo). Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14;16), t(14;20), del(17p), amplification 1q21, primary plasma cell leukemia (pPCL), or elevated serum LDH (> 2X ULN). Median PFS was the primary endpoint, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n=54, RVd-Elo n=49. 74% had ISS II/III, 48% amp1q21, 38% del(17p), 11% t(14;16), 9% GEPhi, 7% pPCL, 5% t(14;20) and 4% elevated LDH (17% >1 feature). With median follow-up of 72 months (mos.), no difference in median PFS was observed [RVd-Elo=29 mos., RVd= 34 mos., HR = 1.11 (80% CI=0.82, 1.49, p=0.66]. No difference in OS was observed [RVd-Elo = median not reached (NR), RVd= 68 mos., HR = 0.85 (80% CI: 0.59, 1.23), p-value = 0.58]. 76% pts had >Grade 3 AEs, no differences in the safety profile were observed. Amongst patients with gain/amp 1q21, median PFS was [RVd-Elo=31 mos., RVd= 37 mos., HR = 1.48 (80% CI= 0.95, 2.31), p=0.25], median OS was [RVd-Elo = 61 mos., RVd= 68 mos., HR = 1.23 (80% CI: 0.72, 2.10), p-value = 0.63]. In patients with del(17p), median PFS was RVd-Elo=41 mos., RVd= 30 mos.[HR = 0.98 (80% CI= 0.60, 1.58), p=0.95], median OS RVd-Elo = NR, RVd= 72 mos., [HR = 0.77 (80% CI: 0.40, 1.48), p-value = 0.61]. Conclusions: In the first randomized HRMM study reported to date, the addition of Elo to RVd induction and maintenance did not improve PFS and OS with a median follow-up of 6 years. Although the median PFS for Del17p subgroup on RVd-Elo arm is higher than RVd, it did not achieve statistical significance. The PFS and OS observed for gain/amp 1q21 and del17p in the RVd control arm may serve as important benchmarks for future enrichment design HRMM clinical trials. The PFS and OS in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination induction/maintenance therapy for this population. Clinical trial information: NCT01668719.

e20001 Background: High dose melphalan followed by autologous stem cell transplant (HDM-ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) despite advances in treatments. Achievement of complete response (CR) is associated with improved overall survival (OS) and progression-free survival (PFS); Minimal Residual Disease (MRD) negativity (-) using next generation flow cytometry with a sensitivity of 10-5 is strongly associated with improved PFS and OS. We investigated the rates of conversion to MRD(-), especially MRD(-) CR following HDM-ASCT in patients with NDMM. Methods: We retrospectively reviewed patients with NDMM who underwent early HDM-ASCT at Mayo Clinic Rochester from May 2018 to July 2019. Response assessment was conducted after induction and within 100 days post-ASCT based on 2016 IMWG criteria, except for using Mass-Fix instead of immunofixation. MRD was assessed in bone marrow using the established Euro Flow protocol with sensitivity of 10-5. The FISH assay was used to risk-stratify patients as high-risk (HR) and standard risk (SR) cytogenetics as per the mSMART guidelines. Primary outcome measure was the conversion to MRD(-) CR after ASCT. Secondary outcomes include the overall conversion to MRD(-) irrespective of IMWG response, the impact of HR cytogenetics and pre-ASCT IMWG response on conversion to MRD(-) CR. Results: Two-hundred and ten patients were included; 126 (60%) were male and median age 62 years (range 32–77 years). There were 78 (44%) patients with HR cytogenetics. Pre-ASCT, 23 patients (11%) achieved MRD(-) CR, and 66 (31%) patients achieved MRD(-) CR post ASCT. Of 187 patients not in MRD(-) CR pre-ASCT, 45 (24%) converted to MRD(-) CR. Table provides a breakdown of the conversion rate of pre-ASCT IMWG response category to MRD(-) CR post ASCT and patients with MRD(+) CR had the highest rate (78%) of conversion. The presence of HR cytogenetics did not impact rates of MRD(-) CR achievement post ASCT irrespective of pre-ASCT IMWG response (p = 1.0). Overall, irrespective of IMWG response, 43 (20%) patients were MRD(-) pre-ASCT (19 in VGPR, 24 in CR or better) and 102 (49%) patients were MRD(-) post-ASCT (36 in VGPR, 66 in CR or better). Among 85 patients in VGPR post-ASCT, 36 were MRD(-) of which 8 (22%) progressed, while 49 were MRD(+) of which 24 (49%) progressed (p = 0.014). Conclusions: Upfront HDM-ASCT in patients with NDMM leads to deeper responses with 24% converting to MRD(-) CR and more than doubling of the total rate of MRD(-) irrespective of IMWG response. [Table: see text]

110 Background: Sarcopenia or a loss of muscle mass increases with aging and is associated with increased overall mortality in patients with cancer. Recent advances in machine learning–based CNN algorithms have allowed for the rapid processing of digital images to produce image classifications of body composition. Since incidence of MM is highly associated with aging, we sought to determine if the presence of sarcopenia, as determined by utilizing this machine learning–based CNN algorithm on CT images, had prognostic value in patients with NDMM. Methods: We identified all patients with NDMM from January 2003 to July 2019 who had a standard-dose CT scan that included the L3 vertebral level performed within 6 months of diagnosis. Using a machine learning–based CNN-algorithm, abdominal CT images were analyzed to measure muscle area. These measurements were normalized by dividing the area values by the height of the patient squared (m2) to obtain skeletal muscle index (SMI) values. Patients were categorized as sarcopenic according to international gender-specific consensus cutoffs for SMI (male: < 55 cm2/m2 and female: < 39 cm2/m2). Patients with the following FISH cytogenetics were considered high risk (HR): t(4;14), t(14;16), t(14;20), and deletion 17p/monosomy 17 whereas the remainder were standard risk (SR). Survival analysis was performed using the Kaplan-Meier method and compared via the log-rank method. Results: The study cohort consisted of 344 patients. 68 (20%) were categorized as HR based on FISH cytogenetics.187 (54%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. Sarcopenic patients were more likely to have ISS-3 disease (45% vs. 30%; p =.023), be male (73% vs. 48%; p <.001), and be ≥ age 75 (27% vs. 14%; p =.002) compared to non-sarcopenic patients. The median OS for patients with HR FISH and ISS 2 / 3 disease was 40 months and 57 months respectively compared to 90 months and 119 months for those with SR FISH and ISS-1 disease respectively (FISH: p <.004; ISS: p <.001). The median OS for sarcopenic patients was 44 months compared to 90 months for those not sarcopenic (p <.001). The time to next therapy (TTNT) for sarcopenic patients was 39 months compared to 45 months for those not sarcopenic (p =.05). In a multivariable model, the presence of sarcopenia (HR 1.64, 95% CI, 1.05–2.56; p =.03) retained significance in the presence of HR FISH, ISS 2 / 3 disease, and age ≥ 75. Conclusions: Gender-specific sarcopenia identified by a machine learning–based CNN algorithm significantly affects OS in patients with NDMM and is independent of age, ISS stage, and cytogenetic status. Future studies utilizing this machine learning–based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

PURPOSE: Patients' concerns regarding clinical trial (CT) participation include apprehension about side effects, quality of life (QoL), financial burden, and quality of care. METHODS: We prospectively evaluated the experience of patients with multiple myeloma or lymphoma who were treated on CTs (CT group, n = 35) versus patients treated with standard approaches (non-CT group, n = 88) focusing on QoL, financial burden of care, and patients' perception of quality of care over a 1-year period. RESULTS: There were no significant differences in any of the patient-reported outcomes in CT versus non-CT groups. We observed an initial decline in overall QoL in the first 3 months across both groups, driven primarily by physical and functional well-being. QoL gradually improved and was above baseline by month 12. Patients reported highest improvement in the functional well-being subdomain. Patients in both groups reported high satisfaction with the quality of care received, and there were no differences in overall satisfaction, communication with team, or access to care. At baseline, 16%-19% of patients reported financial burden, which increased to a peak of 33% in the CT group and to 49% in the non-CT group over the course of 1 year. There was no significant difference in financial burden in the two groups overall. Most of the patients reported getting all the care that was deemed medically necessary in both groups. However, a significant proportion of patients reported having to make other kinds of financial sacrifices because of their cancer (CT group: 33% of patients at baseline and 21%-40% over 1 year; non-CT group: 19% at baseline and 25%-36% over 1 year). CONCLUSION: Patients treated on CTs reported comparable QoL and quality of care with the non-CT group. A high proportion of patients reported financial burden over time in both groups. Our findings can serve as a guide to educate patients regarding CT participation and highlight the need to address the significant financial burden experienced by patients with cancer.

Abstract Disease Overview Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy‐proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hyper c alcemia, r enal failure, a nemia, or lytic b one lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Risk Stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high‐risk multiple myeloma. The presence of any two high risk factors is considered double‐hit myeloma, and three or more high risk factors is triple‐hit myeloma. Risk‐Adapted Initial Therapy In patients who are candidates for autologous stem cell transplantation, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3–4 cycles followed by autologous stem cell transplantation (ASCT). In high‐risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara‐VRd) is an alternative to VRd. Selected standard‐risk patients can collect stem cells, get additional cycles of induction therapy, and delay transplant until first relapse. Patients who are not candidates for transplant are treated with VRd for approximately 8–12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. Maintenance Therapy Standard‐risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high‐risk myeloma. Management of Relapsed Disease A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse.

Abstract Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P &lt; .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P &lt; .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P = .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P = .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P = .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P = .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

Abstract Mass-spectrometry (MS) assays detect lower levels of monoclonal proteins and result in earlier detection of monoclonal gammopathy of undetermined significance (MGUS). We examined heavy chain MGUS prevalence using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS among 3 risk groups, ages 50 or older: 327 African Americans (AA) and 1223 European Americans (EA) from a clinical biobank and 1093 unaffected first-degree relatives (FDR) of patients with hematologic disorders. Age- and sex-adjusted prevalence rates were directly standardized to 2010 United States population. Prevalence ratios were estimated for comparisons of AA and FDR to the EA group using the Poisson distribution. Results were also compared with population-based prevalence using conventional gel-based methods. Risk groups had similar sex and age distributions. MALDI-TOF MGUS prevalence was higher in the AA (16.5% [95% confidence interval (CI), 12.2%, 20.8%]) and FDR (18.3% [95% CI, 16.6%, 21.6%]) than in EA (10.8% [95% CI, 8.8%, 12.7%]), translating to prevalence ratios of 1.73 (95% CI, 1.31, 2.29) and 1.90 (95% CI, 1.55, 2.34), respectively. MALDI-TOF EA prevalence was over threefold higher than conventional estimates but showed similar age trends. Thus, the MALDI-TOF assay found greater numbers with MGUS but similar relative differences by race, family history, and age as prior studies.