Citations

Abstract The immediate postautologous stem cell transplant (ASCT) period in multiple myeloma represents a unique opportunity for long-term disease control because many patients have eradicated most of their disease but also a challenge because it is characterized by the increase of immune subsets detrimental to tumor immunosurveillance. The impact of the tumor immune microenvironment (iTME) in post-ASCT outcomes is not known. In this study, we included 58 patients undergoing upfront ASCT and evaluated their cellular and humoral iTME with cytometry by time of flight (CyTOF) and luminex, respectively, at day +60 to 100 post-ASCT. We identified 2 cellular iTME patterns. Group 1 was enriched in T-cell subsets at the opposite ends of the spectrum of T-cell differentiation compared with the rest of the patients, that is, cells already terminally differentiated (immune senescent or exhausted) and naive T cells. This group had worse hematologic responses post-ASCT, inferior survival, and shorter time to hematologic progression independent of established risk factors. No differences in the humoral iTME were noted between the 2 groups. In addition, no differences in the cellular/humoral iTME were noted according to high-risk fluorescence in situ hybridization status, early or late relapse. Finally, males had higher levels of natural killer cells negative for CD16, a key receptor mediating antibody-dependent cell cytotoxicity, a major mechanism of antitumor efficacy by therapeutic antibodies such as elotuzumab. Our findings suggest that T-cell iTME dysfunction post-ASCT, some of which could be reversible (exhaustion), correlates with worse outcomes. These results could be used to guide rational selection of post-ASCT maintenance/consolidation approaches in these patients.

Abstract Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.

AbstractSurrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event‐defined endpoints in 91 studies (60.3%) and response‐based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re‐analysis.

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.

Abstract Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged.

Abstract The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.

Background: Here we describe an online network of patients with cancer, clinicians and researchers, layered on top of a comprehensive real world database of treatments and outcomes, continuously updated in near real time, and initially focused on multiple myeloma. Methods: Patients with multiple myeloma register at www.all4cure.com and sign HIPAA release forms to provide access to all of their medical records from all of the institutions from which they have received care. From the medical records, a structured dataset of treatments and lab results is extracted by a myeloma-dedicated team for display on each patient's de-identified, personalized dashboard. A discussion panel allows more than 1200 participating patients, clinicians and researchers to post comments or questions regarding each patient's specific circumstances. For each patient, lines of therapy and responses are determined according to IMWG and published criteria (Blood [2015] 126: 921-922). Here we report initial results from the treatments and responses among patients with multiple myeloma and plasma cell leukemia. Results: A total of 493 patients includes 26 with monoclonal gammopathy of undetermined significance (MGUS), 51 with smoldering myeloma, 408 with multiple myeloma, and 8 with primary plasma cell leukemia. Among patients with multiple myeloma, 42 (10.3%) had antecedent MGUS and/or smoldering myeloma. The average age is 65.6 (+/- 9.7). 50.9% are male and 49.1% are female. 42 states in the U.S. and 8 other countries are represented. Two patients with multiple myeloma had not started treatment by the time of this report. The remaining 414 patients with multiple myeloma or plasma cell leukemia received 1 to 16 lines of therapy. Among the 414 patients that received at least one line of therapy, a remarkable 89 distinct first line therapies were administered. The most common first line therapies were lenalidomide, bortezomib, dexamethasone (n=92), cyclophosphamide, bortezomib, dexamethasone (n=50), lenalidomide, bortezomib, dexamethasone + autologous stem cell transplant + lenalidomide maintenance (n=41), lenalidomide and dexamethasone (n=29), and bortezomib and dexamethasone (n=22). 62 patients received a first line therapy that was not received by any other patient in our database. This variation was attributable to participation in clinical trials, variation in the availability of drugs over time and different geographic locations, and the very large number of distinct combinations associated with multi-agent regimens. Seventy six percent of patients with multiple myeloma or plasma cell leukemia received a second line of therapy, 52% received a third line of therapy, 34% received a fourth line of therapy, 23% received a fifth line of therapy, and 18% received a sixth line of therapy. We observed a trend toward a decline in favorable responses with successive lines of therapy (Table 1) consistent with previous reports, with a correlation coefficient between the line of therapy and overall response rate of -0.74. Among the 76 patients who received 6 or more lines of therapy (247 lines of therapy in total), only 7 achieved stringent complete responses (sCRs), of which 5 were associated with a CAR-T therapy. Table 1 also shows a trend toward more rapid changes in treatment associated with later lines of therapy. 57 of 493 patients (12%) are deceased. Conclusions: Our findings reveal remarkable variation in the treatment of myeloma and provide a potentially valuable resource of up to date and current clinical features, prognosis, treatments, side effects, and outcomes of patients with myeloma in the real world. Table 1. Summary of lines of therapy and outcomes across 414 patients with multiple myeloma and plasma cell leukemia. The percentages of patients achieving sCR, ≥ PR (overall response rate - ORR), and ≥MR (clinical benefit rate - CBR) are shown for each line of therapy. Also depicted is the interval mortality and the mean and median number of days between the beginning of a line therapy and the beginning of the next line of therapy. Table Disclosures Richter: Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy; X4 pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive biotechnologies: Consultancy; Secura bio: Consultancy; Astra Zeneca: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy. Chhun:All4Cure: Current Employment. Zheng:All4Cure: Current Employment. Piboonvaranggoon:All4Cure: Current Employment. Mallick:All4Cure: Current Employment. Wren:All4Cure: Current Employment. Nam:All4Cure: Current Employment. Lopez Barquilla:All4Cure: Current equity holder in private company. Blau:All4Cure: Current equity holder in private company. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Other; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees. Blau:All4Cure: Current Employment, Current equity holder in private company.