Choosing the Right Therapy for Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease- and Treatment-Related Factors

Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.

Symptomatic relapse and long-term sequelae of COVID-19 in a previously healthy 30-year-old man

Much has been reported on the clinical course of severe COVID-19, but less is known about the natural history and sequalae of mildly symptomatic cases and the prospects of reinfection or recurrence of symptoms. We report a case of a patient with mildly symptomatic PCR-confirmed COVID-19 who, after being symptom-free for 2 weeks, redeveloped symptoms and was found to be PCR-positive again >4 weeks from original testing. Surprisingly, IgG and IgM antibody testing was negative 2 months after reinfection. Although no negative testing was performed between the two symptomatic bouts, this case raises the possibility of reinfection after controlling the virus and highlights the long period with which a patient can shed virus and experience symptoms after initial infection. Characterising variations in clinical symptoms and length of viral shedding after improvement is essential for informing recommendations on patients safely resuming contact with others.

Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma (GEAC).

e15579 Background: Although commonly performed, evidence supporting routine surveillance testing (SvT) in patients (pts) with resected GEAC is lacking. We evaluated patterns of relapse, frequency of salvage therapy and outcomes among pts with resected GEAC who underwent surveillance. Methods: Between 2011 and 2016, 210 consecutive pts with GEAC followed at Princess Margaret Cancer Center after resection were reviewed. SvT was any investigation performed in the absence of pt-reported symptoms, abnormal physical exam findings, or bloodwork. Relapse patterns were classified as locoregional (LRR; surgical anastomosis/gastroesophageal lumen/regional nodes) or distant (DR; beyond locoregional). Time-to-relapse (TTR) and overall survival (OS) were calculated from initial diagnosis, post recurrence survival (PRS) from initial relapse. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%), surgery plus perioperative chemotherapy (26%) or surgery plus chemoradiation (45%). SvT included imaging (71%), endoscopy (19%), tumor markers (6%), and clinical visits alone (9%). After median follow-up of 38.3 months (mo) (range 5.6-122.3), 3- and 5-year OS rates were 68% (95% confidence interval (CI) 62-75%) and 56% (95% CI 49-64%) respectively. Among 97 relapses (46%), 51 were detected by SvT, 45 by symptoms. Relapse patterns included LRR alone (4%), DR alone (86%) and both (10%). The majority of relapses (93%) occurred within 3 years. Pts with SvT-detected relapse had similar median TTR (16.2 vs 13.3 mo, p = 0.40) but longer PRS (16.5 vs 4.6 mo, p < 0.001) and OS (36.2 vs 23.7 mo, p = 0.004) than pts with symptomatic relapse. Salvage therapy in 4 pts (2%) resulted in post recurrence disease-free survival ≥2 years. Duration of palliative chemotherapy was similar between 28 pts with SvT-detected relapse and 18 pts with symptomatic relapses (3.9 vs 3.3 mo, p = 0.64). Conclusions: Following curative resection, 96% of relapses were distant. Routine SvT rarely enabled successful salvage therapy and did not extend duration of palliative chemotherapy. Longer OS in SvT-detected relapses was not due to earlier disease detection. These findings do not support routine SvT in pts with resected GEAC.

Subgroup Analysis of Patients with Biochemical or Symptomatic Relapse at the Time of Enrollment in the Endeavor Study

Introduction: The randomized phase 3 ENDEAVOR trial demonstrated superior progression-free survival (PFS), overall survival (OS), and health-related quality of life in patients with relapsed or refractory multiple myeloma (RRMM) for patients treated with carfilzomib (56 mg/m2) and dexamethasone (Kd56) compared with bortezomib and dexamethasone (Vd). In patients with relapsed MM, the time of therapy initiation might impact treatment outcome. Prior studies have demonstrated a median of 5 months between the presence of biochemical and symptomatic relapse (Lopez. Leuk Res Rep. 2015;4:64-69). Herein, we report a post hoc subgroup analysis from the ENDEAVOR study to evaluate the impact of initiating Kd56 therapy upon biochemical relapse. Methods: Adults with RRMM who previously received 1-3 lines of therapy and had measurable disease were eligible to participate in the ENDEAVOR trial. Symptomatic disease was not required for eligibility. Kd56 patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 as a 30-minute intravenous infusion and dexamethasone (20 mg) on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Vd patients received bortezomib (1.3 mg/m2; intravenous bolus or subcutaneous injection) on days 1, 4, 8 and 11 and dexamethasone (20 mg) on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Treatment continued until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or death. This post hoc subgroup analysis evaluated PFS, OS, and safety in subgroups defined according to the presence of symptoms at the time of enrollment. Patients with RRMM who experienced biochemical progression without CRAB symptoms (hypercalcemia, renal impairment, anemia, or bone lesions) upon relapse were considered asymptomatic, whereas symptomatic patients were those who had CRAB symptoms upon relapse. In each subgroup, PFS and OS were compared between treatment arms using an unstratified Cox proportional hazards model. Results: Of the 929 patients enrolled and randomized in ENDEAVOR, 117 (12.6%) were asymptomatic (Kd56, n=60; Vd, n=57) and 812 (87.4%) were symptomatic (Kd56, n=404; Vd, n=408). In the asymptomatic group, the median PFS was not estimable (NE) for Kd56 vs 13.7 months for Vd (hazard ratio [HR]: 0.462; 95% confidence interval [CI]: 0.232-0.922), and the median OS was NE for either treatment arm (HR: 0.768; 95% CI: 0.350-1.683) (Table). In the symptomatic group, median PFS was 17.7 months for Kd56 vs 8.8 months for Vd (HR: 0.539; 95% CI: 0.439-0.662), and median OS was 44.0 months for Kd56 vs. 36.8 months for Vd (HR: 0.801; 95% CI: 0.653-0.982) (Table). Kaplan-Meier PFS and OS curves are shown in the Figure. The rate of grade ≥3 treatment-emergent adverse events (Kd56 vs Vd) was 78.3% vs 58.9% in the asymptomatic group and 81.9% vs 72.8% in the symptomatic group (Table). Conclusions: Kd56 demonstrated superior survival outcomes compared with Vd in patients with RRMM, regardless of presence of CRAB symptoms at study randomization. As expected, outcomes were improved when Kd56 was initiated early in the disease course, before CRAB symptoms occurred. The small size of the subgroups in this study is a limitation. However, the findings warrant further investigation. The safety profile of Kd56 in both subgroups was consistent with that in the overall population as previously reported (Dimopoulos. Lancet Oncol. 2016;17:27-38; Siegel, Clin Lymphoma Myeloma Leuk. 2017;17:e142). Overall, Kd56 had a favorable benefit-risk profile in both patients with biochemical and symptomatic relapse. Disclosures Moreau: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Goldschmidt:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding. Niesvizky:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Bringhen:Takeda: Consultancy; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Orlowski:Spectrum Pharma: Research Funding; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Sanofi-Aventis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy. Blaedel:Amgen: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Dimopoulos:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria.

Contemporary multi-modal management of colorectal cancer: Evolving patterns of care in an Irish cohort.

827 Background: The last 15 years have seen significant improvements in the outcomes of patients (pts) with CRC. More effective systemic therapy (Rx) and wider use of surgery (Sx) in stage IV disease (Dx) are key drivers of this. We evaluated the impact of intense surveillance in concert with greater use of metastasectomy and improved systemic Rx on CRC outcomes. Methods: This is a retrospective review of the clinical, radiologic and histological records for consecutive pts with CRC who were referred to the multi-disciplinary CRC team from 2003-2016. Pts with stage I/II Dx were included when referred for adjuvant Rx for high-risk features. We recorded pt characteristics, Rx received and outcomes. Survival was assessed using Kaplan-Meier analysis. Results: We identified 600 pts. Median age was 65 (22-97 years). 71.2% (n=427) of pts had left sided CRC and 25.7% (n=154) had right sided Dx. 211 pts (35.2%) had de novo metastatic Dx. 163 of 389 pts (41.9%) with stage II/III disease relapsed. Median Dx-free interval was 16 months. Of 163 relapses, 121 (74%) were detected by radiologic surveillance and 14 (9%) by rise in CEA. Symptomatic relapse occurred in 20 pts (12%). Median overall survival (OS) was significantly improved in pts with relapse detected by CT, PET/CT or CEA rise (54, 53 and 54 months respectively) vs pts with symptomatic relapse (4 months, p<0.001). Metastasectomy rates were higher in pts with image-detected relapse ( p=0.017). Median OS for pts with stage IV CRC who received any Rx was 27 months. Pts with right sided Dx had shorter median OS vs pts with left sided Dx (24 months vs 40 months, p=0.002). 195 pts (52.8%) underwent metastasectomy; median OS was 71 months vs 16 months in those who did not undergo Sx. 84 pts (14%) with stage IV CRC are currently Dx-free after Sx. Median OS was improved with increasing lines of Rx. Survival in pts receiving best supportive care was 5 months vs 17, 25, 34, 38 and 42 months for pts receiving 2, 3, 4 and 5 lines of Rx respectively ( p<0.001). Conclusions: CRC outcomes are improving with effective multi-disciplinary care, close surveillance, sequencing of systemic Rx and judicious use of salvage Sx following relapse. Our findings support long-term benefit for surgical metatastectomy in stage IV CRC.

Patterns of Relapse Among Myeloma Patients Post-Autologous Stem Cell Transplant

Introduction: In younger patients that are transplant-eligible, autologous stem cell transplant (ASCT) prolongs overall survival based on several prospective randomized control trials. Nevertheless, ASCT is not a curative approach and majority of the patient's relapse, requiring further salvage therapeutic options. However, in the face of an ongoing paradigm shift in myeloma therapeutics, there is a significant knowledge gap regarding how patients relapse following ASCT. We analyzed the patterns of relapse among myeloma patients after ASCT. Methodology: We have evaluated a total of 975 patients that underwent ASCT during the period January 2008 through June 2014 from our myeloma database. 273 patients had documented evidence of first relapse post-ASCT on the laboratory parameters, radiologic or pathologic findings based on IMWG criteria for relapse. We categorized the relapses as biochemical vs symptomatic, and described their frequencies and characteristics. Median time of follow up from diagnosis is 68 months and from ASCT is 54 months. We used IBM SPSS version 23.0 to generate the survival statistics. Results: Median time from ASCT to relapse is 20 months. A total of 182 (66.7%) patients (105M, 77F) experienced biochemical relapse, while 91 (33.3%) patients (50M, 41F) had symptomatic relapse. More IgA patients (30.8% vs 23.1%, p=0.06) relapsed as symptomatic myeloma. While characterizing relapses, we did not find any differences in symptomatic relapses by the risk group [high risk (31.3%) vs standard risk (31.9%), p=0.193, ISS stage I (29.3%) vs II (32.9%) vs III (32.8%), p=0.807] or by maintenance [yes (30.7%) vs no (38.1%), p=0.211]. Among the patients that had a symptomatic relapse, presence of new bone lesions (52%) and anemia (42%) are the most common forms of relapse seen. Only 4% presented as hypercalcemia and 1% presented as renal failure illustrating the benefits of closer follow up. Overall survival is similar among patients that relapsed as biochemical or symptomatic relapse (log rank, p=0.105). More importantly, impressive median OS of 145 months from the ASCT among this entire cohort (at median follow up 54 months, figure 1). Conclusions: Two-thirds of the patients relapse as a biochemical relapse post-ASCT. The patterns of biochemical vs symptomatic relapses were similar among patients by maintenance, by risk status and also by the ISS stage. The significant improvement in OS among the entire cohort emphasizes the power of the new therapeutic salvage strategies aimed at gaining the survival advantage even among this selected group of patients undergoing early relapses. Disclosures Kaufman: Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Pharmacyclics: Consultancy. Lonial:Novartis: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Onyx: Consultancy; Merck: Consultancy; Janssen: Consultancy; BMS: Consultancy; BMS: Consultancy; Millenium: Consultancy; Celgene: Consultancy. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy.