Miguel, Jesús F. San

Abstract The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus <CR. Persistent MRD in the 10−6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

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.

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.

Abstract We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10−5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

Abstract In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

8016 Background: Patients (pts) with RRMM previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and CD38 antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T cell therapy, showed frequent, deep, and durable responses in heavily pretreated pts with RRMM in the pivotal KarMMa trial (Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503). Here, we present updated data. Methods: Pts with ≥ 3 prior regimens (including immunomodulatory agent, PI, and CD38 mAb) and refractory to their last regimen per IMWG criteria were eligible (NCT03361748). Pts received 150─450 × 106 CAR+ T cells (target dose range) after 3 days of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2). Endpoints included overall response rate (ORR; primary) and complete response (CR) rate (key secondary). Additional secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: KarMMa enrolled 140 pts, and 128 received ide-cel. Pts had a median age of 61 years and a median of 6 (range, 3-16) prior regimens; 84% were triple-class refractory, and 26% were penta-class refractory (lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab). Most pts (88%) had bridging therapy. Median follow-up was 15.4 mo (data cutoff, 7 Apr 2020). ORR was 73% and median PFS was 8.8 mo in all treated pts; both increased with higher dose (Table). At the highest target dose (450 × 106 CAR+ T cells), the ORR was 81%, the CR rate was 39%, and the median PFS increased to 12.2 months with longer follow-up. Responses were observed in all subgroups including difficult-to-treat subsets (eg, extramedullary disease [ORR, 70%], high tumor burden [71%], and R-ISS stage III disease [48%]). OS continues to mature and the median has not been reached; the 15-month event-free rate for OS was 71%. Cytopenias (97%) and cytokine release syndrome (CRS; 84%) were the most common any-grade toxicities. CRS was mostly grade 1/2; 5 pts (4%) had grade 3, 1 had grade 4 (at 300 × 106), and 1 had grade 5 (at 300 × 106). Investigator-identified neurotoxicity was reported in 23 pts (18%); 4 pts (3%) had grade 3 and 0 had grade ≥ 4. Tocilizumab was used in 67 and 3 pts with CRS and neurotoxicity, respectively. Conclusions: Updated results from the KarMMa trial continue to demonstrate deep, durable responses with ide-cel in heavily pretreated pts with RRMM. Efficacy and safety reflect prior reports and support a favorable clinical benefit-risk profile for ide-cel across the target dose range. Clinical trial information: NCT03361748. [Table: see text]

Abstract Background: The randomized phase 3 ASPIRE study demonstrated that the addition of the proteasome inhibitor carfilzomib to Rd resulted in significantly improved progression-free survival (PFS) compared with Rd alone in patients with RRMM (median 26.3 vs 17.6 months; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.57-0.83; 2-sided P=0.0001; Stewart AK, et al. N Engl J Med . 2015;372:142-52; Table). OS data were immature at the time of the PFS analysis but showed a trend in favor of the KRd group (HR=0.79). Hereby, results from the planned final analysis of OS in ASPIRE are presented. Methods: Adults with RRMM who received 1─3 prior lines of therapy were eligible. Patients were randomized (1:1) to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or the occurrence of unacceptable toxicity. Randomization was stratified according to β2-microglobulin level (<2.5 mg per liter vs. ≥2.5 mg per liter), previous therapy with bortezomib, and previous therapy with lenalidomide. Carfilzomib was given as a 10-minute infusion (starting dose of 20 mg/m2 on days 1 and 2 of cycle 1; target dose of 27 mg/m2 thereafter) on days 1, 2, 8, 9, 15, and 16 during cycles 1─12 and on days 1, 2, 15, and 16 (cycles 13─18). Lenalidomide (25 mg) was administered on days 1-21 and dexamethasone (40 mg) was administered on days 1, 8, 15, and 22. After cycle 18 of carfilzomib, patients randomized to the KRd arm received Rd treatment only. In total, 510 deaths were required to provide 85% power to detect a reduction in the risk of death for KRd vs Rd, with a 1-sided significance level of 0.025. OS was compared between treatment arms using a stratified log-rank test. HRs were estimated using a stratified Cox model. Results: As of the data cutoff date (April 28, 2017) for the planned final OS analysis, median treatment durations were 72 weeks for carfilzomib (per protocol, carfilzomib was discontinued after cycle 18), 85 weeks (KRd arm) and 57 weeks (Rd arm) for lenalidomide, and 80 weeks (KRd arm) and 49 weeks (Rd arm) for dexamethasone. The median follow up was 67 months for both arms. Median OS (95% CI) was 48.3 (42.4-52.8) months for KRd vs 40.4 (33.6-44.4) months for Rd (HR, 0.79; 95% CI, 0.67-0.95; 1-sided P=0.0045; Table and Figure). Median OS was 11.4 months longer for KRd vs Rd in patients receiving 1 prior line (47.3 vs 35.9 months [HR, 0.81; 95% CI, 0.62-1.06]) and 6.5 months longer for patients receiving ≥2 prior lines (48.8 vs 42.3 months; [HR, 0.79; 95% CI, 0.62-0.99]). Among patients with 1 prior line of therapy, OS was improved with KRd vs Rd regardless of whether patients had received prior bortezomib; in patients with 1 prior line, median OS was improved by 12 months in the prior bortezomib group (45.9 vs 33.9 months [HR, 0.82; 95% CI, 0.56-1.19]) and 7.9 months in the no prior bortezomib group (48.3 vs 40.4 months [HR, 0.80; 95% CI, 0.55-1.17]). With respect to risk, OS by Revised International Staging System (R-ISS) stage was assessed. For R-ISS stage I (KRd, n=42; Rd, n=46), median OS was not reached for KRd and was 58.0 months for Rd (HR, 0.49; 95% CI, 0.26-0.92). For patients with R-ISS stage II (KRd, n=194; Rd, n=195), median OS was 45.4 months for KRd and 41.2 months for Rd (HR, 0.86; 95% CI, 0.68-1.10). For the small number of patients with R-ISS stage III (KRd, n=37; Rd, n=47), median OS was 23.3 months for KRd and 18.8 months for Rd (HR, 1.05; 95% CI, 0.66-1.68). For the overall study population, treatment discontinuation due to an adverse event (AE) occurred in 19.9% (KRd) and 21.5% (Rd) of patients. Fatal AEs were reported in 11.5% (KRd) and 10.5% (Rd) of patients. Grade ≥3 AE rates were 87.0% (KRd) and 83.0% (Rd). Selected grade ≥3 AEs of interest (grouped terms; KRd vs Rd) included acute renal failure (3.8% vs 3.3%), cardiac failure (4.3% vs 2.1%), ischemic heart disease (3.8% vs 2.3%), hypertension (6.4% vs 2.3%), and hematopoietic thrombocytopenia (20.2% vs 14.9%). Conclusions: KRd demonstrated a statistically significant and clinically meaningful 21% reduction in the risk of death vs Rd. KRd should be considered a standard of care in RRMM. Disclosures Stewart: Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Roche: Consultancy. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Ludwig: Bristol-Meyers: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Facon: Amgen, Celgene: Speakers Bureau. Goldschmidt: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jakubowiak: Amgen Inc., BMS, Celgene, Janssen, Karypharm, Millennium-Takeda, Sanofi, SkylineDX: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Chicago: Employment. San Miguel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Obreja: Amgen: Employment, Equity Ownership. Blaedel: Amgen: Employment, Equity Ownership. Dimopoulos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria.