Rajkumar, S. Vincent

BackgroundThere exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population‐based analysis of long‐term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT).MethodsThe National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD‐O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi‐square tests.ResultsA total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long‐term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high‐volume facilities were associated with long‐term survival.ConclusionsKey differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long‐term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high‐volume facilities might prolong patient survival.

Abstract The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P &lt; .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

Background:Maintenance therapy (MT) in NDMM has been increasingly used to prolong duration of response achieved by ASCT. TOURMALINE‐MM3 is a phase 3, double‐blind, placebo‐controlled study, where ixazomib improved PFS, and is the first study to evaluate the impact of MT on HRQoL post ASCT in NDMM (Dimopoulos et al., Lancet 2019;393:253). HRQoL is an important consideration during MT in NDMM patients with minimal disease burden post ASCT (Anderson et al., Leukemia 2008;22:231).Aims:To assess HRQoL in patients randomized to ixazomib vs. placebo MT in TOURMALINE‐MM3.Methods:In TOURMALINE‐MM3, NDMM patients post ASCT were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo. HRQoL was assessed by EORTC QLQ‐C30 (overall/subscale score range, 1–100) at screening, the start of every cycle (1–26), end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. MM‐specific symptoms were assessed by EORTC QLQ‐MY20 (subscale score range, 1–100) at screening, the start of every 3 cycles between cycles 1–25, end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. For both instruments, higher scores for global and functional domains indicate better HRQoL, while higher scores on symptom scales represent higher levels of symptomatology. Change from study entry in subscale scores, defined in terms of 30 four‐week intervals, was analyzed using a linear mixed‐effects model among patients who reported HRQoL outcomes at study entry and completed at least one post‐study entry assessment.Results:Characteristics at study entry were well balanced between ixazomib (n = 386) and placebo (n = 251) arms; median age: 58 years; ECOG performance status 0–1: 97%; 79% had at least a very good partial response post ASCT at study entry. At study entry, least squares (LS) mean scores for ixazomib vs. placebo on the EORTC QLQ‐C30 were: Global Health Status/QoL, 69.8 vs. 69.1; Physical Functioning, 82.1 vs. 82.0; Pain, 25.3 vs. 25.7; Nausea/Vomiting, 2.3 vs. 2.0; Diarrhea, 5.9 vs. 6.0; and on the EORTC QLQ‐MY20 were: Disease Symptoms, 20.3 vs. 19.2; Peripheral Neuropathy, 25.0 vs. 25.6. Compliance with study assessments, averaged across cycles, was high in the treatment phase (≥94%) and similar between treatment groups.Changes in subscale scores across the 4‐week intervals were generally similar between the ixazomib and placebo groups, with treatment differences not reaching the established minimal important difference (MID) of 10 in MM (Kvam et al., Eur J Haematol 2011;87:330). LS mean (95% CI) score changes at interval 24 (week 96) for ixazomib vs. placebo on the EORTC QLQ‐C30 included: Global Health Status/QoL, –0.4 (–3.4, 2.7) vs. 1.8 (–1.7, 5.2); Physical Functioning, 0.7 (–1.8, 3.1) vs. 3.0 (0.3, 5.8); Pain, 4.1 (0.5, 7.7) vs. –1.4 (–5.5, 2.7); and on the EORTC QLQ‐MY20 were: Disease Symptoms, 5.1 (2.4, 7.9) vs. 0.8 (–2.3, 3.8); Peripheral Neuropathy, –0.7 (–5.1, 3.7) vs. –6.2 (–11.1, –1.3). EORTC QLQ‐C30 Nausea/Vomiting and Diarrhea subscales, while consistently worse for ixazomib than placebo (LS mean [95% CI] change at interval 24, 5.0 [3.0, 7.0] vs. 1.0 [–1.3, 3.3] and 4.0 [1.1, 6.8] vs. 0.5 [–2.8, 3.8], respectively), were in line with the ixazomib toxicity profile; treatment differences did not exceed the MID.Summary/Conclusion:In addition to improvements in PFS with ixazomib, HRQoL was maintained during the protocol‐defined treatment period in both arms, and active treatment with ixazomib did not have an adverse impact on HRQoL.

Background:Venetoclax is a B cell lymphoma 2 (BCL‐2) inhibitor that has shown activity as a single agent and in combination with other therapies in patients with multiple myeloma, particularly those harboring t(11;14) associated with high BCL‐2 expression. Although early clinical trial data is encouraging (monotherapy response rate of 21% and 40% amongst t(11;14) and a response rate of 97% when used in combination with bortezomib and dexamethasone), data on outcomes in patients treated outside of clinical trial setting are sparse.Aims:We aimed to identify the efficacy of venetoclax in patients with multiple myeloma treated outside clinical trial.Methods:We conducted a retrospective review of all patients with multiple myeloma treated with venetoclax between December 2016 and February of 2019 at the Mayo Clinic outside of a clinical trial setting.Results:A total of 29 patients that were treated with venetoclax for relapsed or refractory multiple myeloma were identified. Characteristics of the cohort are reported in Table 1. Two thirds of the cohort had t(11;14) detected on cytogenetic studies and 48% (n = 14) had presence of high risk abnormalities. Median number of prior therapies was 6 (range 1–15) and 21% (n = 6) of patients had received ≥10 prior lines of therapy. Eighty three percent (n = 24) of patients had received prior autologous transplant and 76% (n = 22) were penta refractory or exposed. Median time from diagnosis of myeloma to initiation of venetoclax therapy was 5.3 years (range 0.8–23.6 years).Venetoclax used as monotherapy or a doublet in combination with dexamethasone in 59% (n = 17) of patients and a triplet or quadruplet in 41% (n = 12) given at 800 mg (55%) or 400 mg (35%) daily. Triplet and quadruplet regimens combined venetoclax with a variety of proteasome inhibitors or daratumumab. One patient had a quadruplet of venetoclax, carfilzomib, pomalidomide and dexamethasone. 93% (n = 27) patients were refractory to at least on proteasome inhibitor and immunomodulatory drug. Dose titration and escalation was used in 31% (n = 9) of patients. None of the patients experienced tumor lysis syndrome. At last follow‐up 55% (n = 16) of patients remain on venetoclax therapy. Overall response rate in the 24 patients evaluable for response was 46% (21% CR, 8% VGPR, 17% PR). Patients with t(11;14) had a numerically higher response rate than those without (50% vs 33%, p = 0.64). Patients with high risk cytogenetic abnormalities were less likely to respond (ORR 69% for standard risk vs 18% for high risk, p = 0.019). Median time to response was 2.6 months (range 1.1–6.9 months). Median duration of response was 5.2 months (range 2.2–12.9 months). After a median follow‐up time of 7.2 months for the cohort, the median PFS and OS are 5.8 and 14.6 months, respectively, Figure 1A/B. High risk cytogenetic abnormalities were associated with a shorter PFS (median PFS 3 months vs 14 months for standard risk, p = 0.002). The outcomes with venetoclax monotherapy and combination therapies are reported separately in the Table.Summary/Conclusion:Venetoclax is an effective oral agent in relapsed and/or refractory myeloma and can produce deep and durable responses in heavily pretreated patients. Further studies are needed to elucidate its role earlier in the disease and its effectiveness in combination with other anti‐myeloma therapies.image

Background:Previous literature has established “long‐term survivors” as patients who survive greater than 10 years from diagnosis of active multiple myeloma (MM). With the rapid discovery and evolving use of novel therapeutic agents, a greater proportion of patients are reaching this milestone. Although these patients share in their extended survival, they also constitute a heterogeneous group in terms of treatments and outcomes.Aims:The aim of this study is to examine a large cohort of long‐term survivors with protracted follow‐up as an attempt to identify a subset of patients within ten‐year survivors who have longstanding disease remission, and examine the predictors of their especially exceptional prognosis.Methods:All patients with active MM evaluated at Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study. Patients with MGUS, smoldering MM, and solitary plasmacytoma were excluded. The overall survival (OS) was calculated from time of symptomatic disease requiring treatment. Patients with greater than 10 year survival from diagnosis were then divided into three cohorts based upon treatment and remission status: Cohort 1 included patients off therapy ≥ 5 years and in sustained remission, Cohort 2 included patients on maintenance therapy ≥ 5 years and in sustained remission, and Cohort 3 included patients who had relapsed within the past 5 years. Differences between the groups were compared using Wilcoxon, Chi‐square, and Fisher's exact test as applicable. “Early” stem cell transplant was defined as patients who received a stem cell transplant within one year of diagnosis.Results:During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. Three‐hundred ninety nine (19%) had survived at least 10 years from diagnosis. Among these patients, based on the available data regarding remission and ongoing treatment status, 332 patients were categorized into three cohorts, seen in Table 1. Sixty patients (18% of long‐term survivors) comprised Cohort 1, 48 patients (14% of long‐term survivors) comprised Cohort 2, and 224 patients (68% of long‐term survivors) comprised Cohort 3. Sex difference was statistically significant between the groups, with more females constituting Cohorts 1 and 2 (p = 0.03). Within Cohort 1, 77% of patients underwent an autologous stem cell transplant (ASCT). The median progression free survival following ASCT in this cohort was not reached (95% CI 15–NR, p < 0.001). In addition, patients in Cohort 1 and Cohort 2 were more likely to undergo an early ASCT as compared to patients in Cohort 3 (p = 0.002). There were no significant differences in high or intermediate risk FISH/cytogenetics at diagnosis, ISS at diagnosis, or induction therapies used at diagnosis among the three groups.Summary/Conclusion:Our study identified a small subset (3% of all patients diagnosed with active MM) of long‐term survivors who are off of therapy and remain in sustained longstanding remission. Female sex, progression free survival following ASCT, and receiving an early ASCT were factors that portended a positive prognosis amongst long term survivors.image

Background:Deepened response has been associated with prolonged progression‐free (PFS) and overall survival in multiple myeloma, including in the maintenance therapy setting. In the Myeloma XI trial, post‐ASCT maintenance with lenalidomide vs observation resulted in improved responses in 15.8% vs 11.0% of patients (pts) and a median PFS of 56.9 vs 30.1 months (Jackson et al, ASH 2017). In the phase 3, double‐blind, placebo‐controlled TOURMALINE‐MM3 study (NCT02181413), post‐ASCT maintenance therapy with the oral proteasome inhibitor (PI) ixazomib vs placebo resulted in a 39% improvement in PFS (median 26.5 vs 21.3 months; HR 0.72; 95% CI: 0.58–0.89; p = 0.002), with a favorable safety profile (Dimopoulos et al, Lancet 2019). We report improvements in depth of response and the impact on outcomes in TOURMALINE‐MM3.Aims:To evaluate the rates and timing of response improvement during ixazomib vs placebo maintenance and the impact on PFS in TOURMALINE‐MM3.Methods:Pts who had achieved ≥partial response (PR) to induction therapy with a PI and/or immunomodulatory drug followed by single ASCT were randomized 3:2 to receive ixazomib (N = 395) or placebo (N = 261) on day 1, 8, and 15 of 28‐d cycles for up to 2 years or until progressive disease or unacceptable toxicity. Randomization was stratified by induction regimen, pre‐induction ISS stage, and post‐ASCT response (complete response [CR] or very good PR [VGPR] vs PR). Ixazomib dose was 3 mg in cycles 1–4 and 4 mg from cycle 5 if tolerated in cycles 1–4. Minimal residual disease (MRD) was assessed at screening by flow cytometry (10–5 sensitivity). The primary endpoint was PFS per independent review committee (IRC). Other endpoints included rate of response improvement in pts enrolled in VGPR or PR.Results:At study entry, 60 (15%), 213 (54%), and 89 (23%) pts in the ixazomib arm and 54 (21%), 152 (58%), and 35 (13%) in the placebo arm had CR, VGPR, and PR, respectively, by IRC. Deepening responses were seen in 139/302 (46%) ixazomib vs 60/187 (32%) placebo pts with VGPR/PR at enrollment (relative risk [RR] 1.41, 95% CI 1.1–1.8, p = 0.004), including 92/213 (43%) vs 48/152 (32%) VGPR to CR (RR 1.37, p = 0.025) and 47/89 (53%) vs 12/35 (34%) PR to VGPR/CR (RR 1.54, p = 0.063). On Kaplan‐Meier analysis of time to best deepened response in VGPR/PR pts (Figure), 24‐month rates of deepening response were 54.2% vs 41.4%, and there was a 38.4% improvement in the chance of deepening response over time with ixazomib vs placebo (HR 1.384, p = 0.034). A pooled analysis across arms among pts enrolled in VGPR/PR showed that deepening response vs no improvement was associated with prolonged PFS (median not reached vs 15.9 months; HR 0.245, 95% CI 0.184–0.325, p < 0.0001). Analysis by treatment arm showed that, in VGPR/PR pts with deepening response, 24‐month PFS rates were 77.4% vs 68.3% with ixazomib vs placebo (medians not reached; HR 0.875; 12.5% risk reduction; 95% CI 0.52–1.47; p = 0.615); in VGPR/PR pts without deepening response 24‐month PFS rates were 33.4% vs 23.6% (median 17.9 vs 14.1 months; HR 0.780; 22% risk reduction; 95% CI 0.59–1.03; p = 0.080). Baseline MRD status was a strong predictor of deepening response; deepening responses were seen in 63% (78/124) vs 32% (94/293) of MRD‐ vs MRD+ pts enrolled in VGPR/PR.Summary/Conclusion:Post‐ASCT maintenance with ixazomib resulted in a significantly higher rate of deepening response vs placebo; deepening response was associated with prolonged PFS. Ixazomib resulted in non‐significant PFS benefit vs placebo in VGPR/PR pts with and without deepening response; prolonged follow‐up would be needed to confirm these results.image

Background:Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL‐2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients.Aims: Primary objective: To describe the overall survival of myeloma patients with translocation t(11:14) Secondary objectives: To determine the response rates, progression free survival, time to progression, time to next treatment, duration of responses and overall survival with different regimens among patients with t(11;14), to determine the prognostic factors for overall survival among patients with t(11;14), and to identify the spectrum of co‐existing genetic abnormalities among patients with t(11;14)Methods:This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled.Results:The current analysis includes 848 patients; median age of 64.4 years; 60.0% male. The median follow‐up from diagnosis for the entire cohort was 46.5 months; 86.7% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.3%), Stage II (38.9%) and Stage III (25.8%). The distribution of FISH abnormalities included: del 13q (14.5%), 1q amp (12.1%), del 17p or monosomy 17 (6.1%). Initial therapy included different regimens: 23.3% had an IMiD, 43.3% had a PI, 20.0% had both and 13.3% had no novel agent. The drug classes by line of therapy are shown in Table 1. A stem cell transplant (SCT), defined as within 12 months of start of first line treatment, was used in 39.1% of patients. The median time to next treatment (TTNT) after initial treatment was 13.7 (95% CI: 11.3 to 16.5) months. The median overall survival (OS) from diagnosis for the entire cohort was 82.5 (95% CI: 73.5 to 95.8) months; 4‐year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 75.1% and 70.2%, respectively. Median OS by initial regimen is shown in Figure 1; those receiving an early SCT had median OS of 116.9 (95% CI: 85.6 to NA) months.Summary/Conclusion:This is the first study to examine the outcomes of a large group of myeloma patients with t(11;14) abnormality. Patients receiving a combination of a PI and an IMiD appear to have the best survival outcomes. Patients receiving an early SCT appear to have excellent survival with median OS approaching 10 years. Additional patients are being accrued to this study and additional analysis examining the variables affecting response duration and survival will be presented.image

AbstractThe treatment of myeloma is rapidly evolving. This article reviews the current diagnostic criteria, risk stratification, and approach to treatment of multiple myeloma. Treatment approach for both newly diagnosed and relapsed disease are discussed.