Goldman‐Mazur, Sarah

Abstract The treatment landscape for relapsed multiple myeloma (MM) has increased. In this study we aimed to characterize 2nd (n = 1439) and 3rd (n = 1104) line regimens and compare the results between subgroups based on the year of treatment initiation (2nd line: 2003–2008, 2009–2015, 2016–2021; 3rd line: 2004–2009, 2010–2015, and 2016–2021). In both 2nd and 3rd line we observed increasing use of novel agents (from 78–95% and from 77–95%, respectively) and triplet regimens (from 15–69% and from 21–71%, respectively). Most frequently used regimens in the last studied periods included lenalidomide-dexamethasone (RD; 14%), carfilzomib-RD (12%) and daratumumab-RD (10%) for 2nd line, and daratumumab-pomalidomide-dexamethasone (11%) and daratumumab-RD (10%) for 3rd line. Median time to next treatment from 2nd line therapy has improved from 10.4 months (95% CI 8.4–12.4) to 16.6 months (95% CI 13.3–20.3; p < 0.001). The median overall survival from 1st relapse increased from 30.9 months (95% CI 26.8–183.0) to 65.8 months (95% CI 50.7–72.8; p < 0.001). Over the last two decades more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and the survival after 1st relapse is continually improving.

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 Background Multiple Myeloma (MM) remains incurable with current approaches and eventually relapses in nearly all patients. At relapse, patients may present with increasing serum and/or urine monoclonal (M) protein or with clinical features suggestive of progression. The outcomes of different progression patterns need to be better understood to provide insight about the optimal time to intervene with salvage therapy. This study aimed to describe the prevalence and outcome of biochemical (BP) versus clinical progression (CP) in a real-world setting. Methods We retrospectively assessed 1347 relapsed MM patients seen at Mayo Clinic between February 2001 and December 2018. CP was defined as per IMWG criteria (increase ≥50% in size or new plasmacytomas/bone lesions, hypercalcemia ≥11.5 mg/dl, decrease in hemoglobin ≥2 g/dl or to ≤10 g/dl, rise in serum creatinine ≥2g/dl, hyperviscosity), while BP was defined as increase in serum or urine M protein leading to initiation of a new line of therapy without meeting criteria for CP. Aggressive relapse was defined as new extramedullary disease (EMD), plasma cell leukemia or hyperviscosity requiring plasmapheresis. The overall survival (OS) was defined as the time from 1 st relapse to last follow-up or death. Time to next treatment (TTNT) was defined as the time between initiation of 2 nd and 3 rd line therapy. Results Prevalence of different patterns of relapse is presented in Table 1. The majority of progressions were BP (60.4%); among the CP (39.6%), the most common presentation was a new bone lesion. Similar proportions of BP and CP patients were diagnosed before 2013 (70% and 73%; p=0.2). The median time from diagnosis to 1 st relapse was 22.8 months (range, 0.4-154.7) and was shorter in the CP group in comparison to BP (20.8 [range, 1.0-152.1] vs 23.7 [range, 0.4-154.7] months, p=0.001). With the exception of ISS stage, patients in the CP group had higher risk features at MM diagnosis including: high-risk (HR) FISH ([4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 29% vs 20%, p=0.01); elevated LDH (23% vs 17%, p=0.03); and EMD (19% vs 10%, p&lt;0.001). CP patients more often had non-secretory disease at baseline (6% vs 2%, p&lt;0.001). At 1 st line, patients with eventual CP were less likely to have received novel agents (78% vs 85%, p&lt;0.001), upfront autologous stem cell transplantation (ASCT, 43% vs 51%, p=0.004), and lenalidomide-based maintenance (11% vs 16%, p=0.01). While patients in the CP group were less likely to have achieved very good partial remission (VGPR) or better to the 1 st line therapy (53% vs 60%, p=0.01), the percentage of patients who achieved CR was similar between the groups (22% vs 24%, p=0.4). Relapse while on primary treatment/maintenance was more prevalent in the CP (46% vs 40%, p=0.04). On multivariable logistic regression model male sex, plasma cell labeling index (PCLI) ≥2% and EMD at diagnosis were associated with higher risk of CP, whereas achieving VGPR or better after 1 st line treatment was associated with decreased risk of CP. Patients with CP had shorter median TTNT from 2 nd line therapy compared to BP (9.6 vs 17.0 months, p&lt;0.001) as well as shorter median OS from 1 st relapse (26.2 vs 59.4 months, p&lt;0.001; Figure 1). Amongst patients with CP, those presenting with typical "aggressive" versus "CRAB" features at relapse had a significantly shorter median TTNT (6.0 vs 11.0 months, p&lt;0.001) and OS (17.2 vs 28.1 months, p&lt;0.001). Using a multivariable Cox proportional hazard model, CP (vs BP) was a predictor of shorter TTNT from 2 nd line therapy (HR 1.40, 95% CI 1.20-1.62, p&lt;0.001), along with ISS stage III, HR FISH at diagnosis and relapse while on primary treatment/maintenance, whereas the use of upfront ASCT was a predictor of longer TTNT from 2 nd line therapy. CP was also a predictor of shorter OS from 1 st relapse (HR 1.53, 95% CI 1.29-1.81, p&lt;0.001) along with age &gt;65 years, male sex, ISS stage III, HR FISH at diagnosis, EMD at diagnosis and relapse while on primary treatment/maintenance. Conclusions Patients with clinical features at relapse have a worse prognosis after 1 st relapse than patients who relapsed solely biochemically. Approximately half of CP presented while on active treatment, which suggests that even patients monitored closely may develop CRAB features at relapse. Factors that help predict the occurrence of CP include male sex, PCLI ≥2% and EMD at diagnosis. Patients with deeper response to 1 st line treatment are less likely to develop CP. Figure 1 Figure 1. Disclosures Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Alnylam: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dingli: Apellis: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Sanofi: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.

Abstract Background Multiple myeloma (MM) is an incurable disease, and its prognosis is largely influenced by clinicopathological features, response to therapy, and relapse characteristics. Despite novel agents and the attempts to individualize treatment strategies based on baseline risk stratification, significant variations in progression-free survivals (PFS) and overall survivals (OS) are observed between patients. We examined the outcomes of MM patients stratified according to timing of first relapse into early (&lt;2 years) and late (&gt;5 years). Methods We retrospectively assessed 1441 MM patients seen at Mayo Clinic between 2003 and 2018. Patients were 18 years or older and had at least one disease relapse that required an additional line of treatment. The study cohort was divided into three groups based on time of first relapse: early relapse (&lt;2 years from diagnosis), relapse between 2 to 5 years from diagnosis, and late relapse (&gt;5 years from diagnosis). The independent predictors of early/late relapse were identified using a forward stepwise multivariate logistic regression. Odds ratios in multivariate models were adjusted for age and sex. Results Early relapse has been recognized in 758 patients (52.6%), relapse between 2-5 years in 561 patients (38.9%), late relapse in 122 patients (8.5%). Six patients had a PFS &gt;10 years. In comparison to patients with late relapse, patients with early relapse were older (median 63 vs 61 years, p=0.04), more frequently ISS stage III (40% vs 20%, p&lt;0.001) had higher bone marrow plasma cell infiltration (median 60% vs 40%, p&lt;0.001), and were more likely to have high-risk (HR) FISH (defined as translocation t[4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 28% vs 11%, p&lt;0.001). At diagnosis, early relapse group more often presented with anemia (35% vs 21%, p=0.004), hypercalcemia (15% vs 5%, p&lt;0.001), renal insufficiency (19% vs 5%, p&lt;0.001) and higher serum beta-2-microglobulin (median 4.4 vs 3.4 mg/l, p&lt;0.001). In terms of first line treatment, novel agents use was higher in early relapse group in comparison to late relapse group (82% vs 72%, p=0.007). Early relapse patients more often received PI-based therapy (30% vs 10%, p&lt;0.001) or PI+IMID-based therapy (22% vs 12%, p=0.01), whereas late relapse patients received more often IMID-based therapy (63% vs 37%, p&lt;0.001). No differences in the maintenance therapy were observed. Early relapse patients were less frequently treated with upfront autologous stem cell transplantation (ASCT, 35% vs 60%, p&lt;0.001). Progression on active treatment/maintenance was observed more often in the early relapse group (55% vs 18%, p&lt;0.001). On multivariable logistic regression model early relapse (vs all remaining patients) was predicted by HR cytogenetic features (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.71-5.46, p&lt;0.001), non-IgG isotype disease (OR 2.17, 95% CI 1.33-3.54, p=0.02), a non-ASCT pathway (OR 2.78, 95% CI 1.71-4.52, p&lt;0.01), and by achieving less than a very good partial remission (VGPR; OR 3.23, 95% CI 1.96-5.35, p&lt;0.01). The only factor associated with decreased chances of late relapse (vs all remaining patients) on multivariate logistic regression model was the presence of HR FISH features (OR 0.18, 95% CI 0.04-0.82, p=0.03). Median PFS from first relapse for the whole population was 13.9 months (95% CI 12.9-15.1), median OS from first relapse - 44.6 months (95% CI 41.7-183.0). Early relapse group exhibited worse median PFS and OS from first relapse (median PFS 9.1 months; median OS 26.6 months) than patients who relapsed 2-5 years after diagnosis (median PFS 18.5 months; OS 71.9 months), or late relapse group (median PFS 31.6 months; median OS 87.8 months; p&lt;0.001) (Figure 1). Conclusions Early relapse (&lt;2 years) is an indicator for shorter duration of response to subsequent treatments, and worse OS. Treatment with upfront ASCT and achieving VGPR or better after first line therapy lower the risk of early relapse. The only parameter that is predictive for both early and late relapse is HR FISH features. Although factors that predict worse survival in MM are well defined, further studies are needed to identify predictors of a more indolent disease course so that future therapeutic approaches can be tailored to each individual. Figure 1 Figure 1. Disclosures Kapoor: AbbVie: Research Funding; Glaxo SmithKline: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Dingli: Alexion: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy; Apellis: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Abstract Background Recommendations for 2 nd line treatment for relapsed multiple myeloma (MM) patients have been changing over the past two decades, given the introduction of novel agents, different side-effect profiles, and attempts at more individualized treatment approaches. We designed this study to characterize how 2 nd line treatment strategies have evolved over the last two decades for MM patients. Methods Patients with MM with at least one relapse treated with a 2 nd line regimen, seen at Mayo Clinic between 2003-2021, were included. To visualize trends in treatment choices we divided the study period into 2-year intervals and for descriptive purpose the period was divided into three 6-year intervals. We used "100% stacked area" charts to show how the constituent parts of the whole have changed over time. The height of each colored stack represents the proportion of patients in that category at a given point in time. Results A total of 1439 patients were included. Patients were diagnosed between 2001 and 2018, the initiation of 2 nd line treatment occurred between June 2003 and February 2021. Median age at diagnosis was 62.7 years (interquartile range, 55.8-69.3), 60.0% were male. International Staging System stage I was present in 23.5% of patients, stage II in 32.9% and stage III in 28.8%. In the 1 st line therapy novel agents were used in 82.8% of cases, regimens based on proteasome inhibitors (PI) in 26.5%, immunomodulatory drugs (IMID) in 42.0% and combination of PI+IMID in 21.1%. Upfront autologous stem cell transplantation (ASCT) was performed in 50.1% of patients, and maintenance after 1 st line was used in 25.2%. For 2 nd line treatment, during 2003-2008 the majority were treated with doublets (70.5%), followed by triplets (14.8%) and salvage ASCT (7.7%) (Figure 1A). Patients were treated with IMID or PI-based therapy (50.7% and 21.8%, respectively); only 3.7% received PI+IMID and 20.1% of patients received alkylating agents/anthracyclines. The most frequently used regimens were lenalidomide-dexamethasone (RD, 32.2%) and bortezomib-dexamethasone (VD, 18.1%, Figure 1B). Between 2009-2014, the use of triplets in 2 nd line increased (43.0%), although doublets were still more common (50.9%). Like previous years, IMID-based therapy was most frequently used (37.3%), however, the use of PI-based therapy increased (36.0%). PI+IMID-based therapy was implemented in 17.9% of patient, and 27.3% received alkylating agents/anthracyclines. Most frequently used regimens included: RD (29.4%), bortezomib-cyclophosphamide-dexamethasone (CYBORD, 17.4%), bortezomib-lenalidomide-dexamethasone (VRD, 13.4%) and VD (13.3%). Finally, during 2015-2021, triplets were most common (68.9%), followed by doublets (23.0%). IMID- and PI+IMID-based therapies were most often implemented (34.2% and 31.1%, respectively), followed by PI-based therapy (26.8%). 28.1% of patients received monoclonal antibodies; only 15.9% received alkylating agents/anthracyclines. Most frequently used regimens include RD (13.8%), carfilzomib-RD (11.6%), daratumumab-RD (9.8%), CYBORD (9.3%), VRD (8.8%), daratumumab-pomalidomide-dexamethasone (5.9%) and daratumumab-VD (5.2%). Median time to next treatment (TTNT) from 2 nd line therapy has improved over the course of the three time periods (p&lt;0.01; Figure 1C): years 2003-2008, 10.4 months; years 2009-2014, 13.2 months; and years 2014-2021, 16.6 months. Similarly, the median overall survival from 1 st relapse has increased over the three intervals: 30.9 months, 48.4 months, and 65.8 months, respectively. Conclusions Over the past two decades, the effectiveness of 2 nd line treatment has improved, reflected by improved TTNT from 2 nd line therapy. With the introduction of new agents in 2012-2015 (carfilzomib, pomalidomide and daratumumab) and favorable results for triplets demonstrated in randomized trials, the triplet therapies started to be used more frequently. Over time, the landscape of 2 nd line therapies has become more diverse, which may reflect a more individualized approach to each patient. Moreover, the large variety of treatment strategies makes comparisons more and more challenging. Figure 1 Figure 1. Disclosures Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Sanofi: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy; GSK: Consultancy. Kumar: Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Carsgen: Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy.

AbstractThe median overall survival in multiple myeloma is rapidly approaching 10 years; however, in nearly a fifth of patients the prognosis remains poor. Therefore, the modern‐day management of myeloma patients should be individualized, with a more intense and continuous approach in these high‐risk patients. This includes first‐line treatment based on multi‐drug combinations employing the most effective drug combinations, upfront autologous stem cell transplantation (in eligible patients with tandem transplantation being a consideration), and maintenance based on proteasome inhibitor‐based combinations. This paper reviews the results of recent retrospective analyses and clinical trials, but also gives a glance into the future by presenting the ongoing trials.