Ludwig, Heinz

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

ABSTRACT Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN‐related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m 2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30–59, 15–29, and < 15 mL/min/1.73 m 2 , respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard‐risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.

Introduction: Acute kidney injury (AKI) due to cast nephropathy is a medical emergency that leads to a diagnosis of myeloma in less than 3% of cases, but up to 30% of patients develop kidney impairment during the course of their disease. Currently, studies aiming to identify parameters that correlate with kidney function recovery and response to myeloma are limited due to small sample size or single center reports. We have therefore initiated an international collaboration and collected a large number patients (pts) from 16 participating centers. Objectives: To assess the impact of pts and disease characteristics and treatment-specific factors on renal outcome and overall survival and to validate the IMWG criteria for renal response in pts with cast nephropathy and newly diagnosed MM. Patients and Methods: Three-hundred forty-three pts (median age: 65.5 range 35-93 yrs) with newly diagnosed MM and an eGFR &lt;40ml/min/1.73m2 have been selected from 704 pts that had been enrolled in the database hosted by RedCap. Eligibility criteria were a diagnosis of AKI due to cast nephropathy diagnosed either by kidney biopsy (n=119) or on clinical criteria (AKI in the setting of involved free light chain concentration of ≥500 mg/L), newly diagnosed multiple myeloma, &gt;2 cycles of therapy, time and type of therapy, best eGFR and best myeloma response available. Results: Median follow up was 36.9 months. Myeloma therapy resulted in renal CR, and PR as defined by the IMWG criteria in 131 (38.2%) and 57 (16.6%) pts, respectively, 54 (15.7%) and 82 (23.9%) pts had minor response or no response, respectively. Nineteen (5.5%) pts were not classifiable by the IMWG response criteria (pts with eGFR 15-&lt;30, with increase to eGFR to ≥30-&lt;40). An eGFR of &gt;60, ≥30-&lt;60, ≥15-&lt;30, and &lt;15ml/min was achieved by 131 (38.2%), 112 (32.7%), 67 (19.5%), and 33 (9.6%) pts respectively. Myeloma response (≥VGPR) correlated significantly with renal response (≥PRrenal) (OR 1.64, CI 1.05-2.56, p=0.03) and with OS compared to no myeloma response (median 89.7 vs. 39.7 months, HR 2.12, CI 1.55-2.89, p&lt;0.0001). A &gt;50% reduction in FLCs from baseline to treatment cycle 2 (OR 5.92, CI 2.15-19.23, p=0.001) and cycle 3 (OR 5.25, CI 2.15-19.25, p=0.006) were strongly associated with renal response Median OS was 69.6 months (CI 55.4-89.7). Forty-three pts died within the first 12 months of treatment and additional 146 during further FU. Pts with a best GFR of &gt;15ml/min had a significantly longer OS compared to those with GFR &lt;15ml/min (median: 77.9 vs 31.9 months, HR 1.85, CI 1.16-2.94, p=0.01). The comparison of survival of pts with different renal response groups and with the best eGFR showed no statistically significant difference (log rank p=0.1, long rank p=0.057, respectively). Other factors that correlated with longer OS were bortezomib-based therapy (77.9 vs. 44.0 months, HR 1.59, CI 1.05-2.38, p=0.03), M-protein isotype with κ as compared to l light chain type (84.9 vs. 51.4 months, HR 1.47, CI 1.09-2.00, p=0.013), and higher hemoglobin (HR 1.16, CI 1.06-1.26, p=0.001). In contrast, hypercalcemia which was noted in 101 (29.4%) pts (HR 1.10, CI 1.03-1.18, p=0.005), ISS stage III vs. I-II (57.8 vs. 126.2 months, HR 2.26, CI 1.22-4.17, p=0.009), and ECOG status 3+4 vs. 2 vs. 0+1 (24.4 vs. 44.6 vs. 103 months, HR 2.83, CI 2.15-3.74, p&lt;0.0001) were associated with shorter OS. Hypercalcemia, correlated with renal response (OR 1.27, CI 1.12-1.44, p=0.0002), and best eGFR ≥46.4 ml/min (median dichotomized) (OR 1.28, CI 1.14-1.46, p&lt;0.0001). 119 (34.7%) pts required initial dialysis, OS was significantly longer in those who achieved best eGFR levels of &gt;15ml/min. (77.6 vs 31.9 months, HR 0.54, CI 0.34-0.86, p=0.01); 64 (53%) pts discontinued dialysis. Conclusion: Myeloma response correlated with renal response as defined by IMWG criteria. A &gt;50% reduction in FLCs from baseline to treatment cycle ≥2 was strongly associated with renal response. OS was longer in pts with renal response, in pts receiving bortezomib-based therapy, and in pts with kappa light chain M-proteins. Hypercalcemia was frequent (29.4%), and associated with higher renal response rate and best eGFR, but shorter OS. Pts on dialysis who achieved eGFR &gt;15ml/min had better survival. Fast diagnostic work up, rapid treatment initiation and achieving significant myeloma response (≥VGPR) is essential to prevent irreversible kidney damage. Including novel immunotherapies may further improve outcome.

AbstractInfections are a major cause of morbidity and mortality in multiple myeloma. The increased risk for bacterial and viral infections results mainly from the disease‐inherent and treatment‐induced immunosuppression. Additional risk factors are older age with immune senescence, T cell depletion, polymorbidity, and male gender. Hence, every effort should be taken to reduce the risk for infections by identifying patients at higher risk for these complications and by implementing prophylactic measures, including chemoprophylaxis and immunization against various relevant pathogens. Here, we review the available evidence and provide recommendations for medical prophylaxis and vaccination in clinical practice.

Abstract Background: Initial studies with venetoclax, a BCL-2 inhibitor, alone or in combination with either dexamethasone or bortezomib and dexamethasone has shown considerable anti-tumor activity in t(11;14) MM with relapsed disease. Based on preclinical studies suggesting synergy when combined with bortezomib and phase 1 data showing efficacy for venetoclax, this combination was compared with bortezomib and dexamethasone (BortDex) in relapsed MM. While the BELLINI (NCT02755597) trial did demonstrate improved PFS with the combination, there were limited number of patients with t(11;14) treated with BortDex. The objective of this study was to assess real-world effectiveness of BortDex in patients with t(11;14) positive relapsed/refractory MM. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving BortDex in ≥2 nd and ≤4 th line were initially selected. The cohort was further limited to patients with no evidence of allogeneic SCT within 16 weeks or autologous SCT within 12 weeks prior to BortDex initiation. Finally, patients non-refractory to prior PI regimen and not receiving BortDex regimen as part of a clinical trial were included in the study. Patient demographic and clinical characteristics along with real-world effectiveness outcomes including best response, overall survival (OS), and time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) were assessed. All analyses were descriptive in nature and were conducted using the SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Overall, 144 patients who met the inclusion criteria were analyzed. Median age was 62.5 years, 62% were male. Patients had a median of 1 prior line (range 1-3) at start of BortDex, at a median of 18.4 months (range, 1-100) from diagnosis; 29% had a prior transplant. A PR or better was observed in 53% of patients with BortDex. The median TTNT for this cohort was 8.4 months and median OS was 46.1 months. Conclusions: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone as well as combinations using the -BortDex backbone. Disclosures Emechebe: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Pharmaceutical/Biotech Companies: Current holder of stock options in a privately-held company. Kumar: Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Goldschmidt: Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: 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; AbbVie: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Kim: Janssen, BMS: Research Funding. Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. Handa: Kyowa Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Janssen: Honoraria; BMS: Honoraria; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Takeda: Honoraria, Research Funding. Fernandez de Larrea: Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy. Reece: Amgen: Consultancy, Honoraria; GSK: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

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 (&lt;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.

Abstract Frailty is most prevalent among elderly multiple myeloma (MM) patients, and frail patients have a higher risk of poor outcomes due to reduced performance status or comorbidities. This post hoc analysis assessed efficacy and safety of carfilzomib combinations in frail patients with relapsed and/or refractory MM from the phase 3 ASPIRE (carfilzomib [27 mg/m2]-lenalidomide-dexamethasone [KRd27] vs lenalidomide-dexamethasone [Rd]), ENDEAVOR (carfilzomib [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), and ARROW (once-weekly carfilzomib [70 mg/m2]-dexamethasone [Kd70] vs carfilzomib [27 mg/m2]-dexamethasone [Kd27]) studies. A frailty algorithm incorporating age, Charlson comorbidity index, and performance status classified patients as fit, intermediate, or frail. Results are presented for frail patients (ASPIRE, n = 196; ENDEAVOR, n = 330; ARROW, n = 141). In ASPIRE, median progression-free survival (PFS) (hazard ratio; 95% confidence interval) was 24.1 (KRd27) vs 15.9 months (Rd) (0.78; 0.54-1.12); median overall survival (OS) was 36.4 vs 26.2 months (0.79; 0.57-1.08). In ENDEAVOR, median PFS was 18.7 (Kd56) vs 6.6 months (Vd) (0.50; 0.36-0.68); median OS was 33.6 vs 21.8 months (0.75; 0.56-1.00). In ARROW, median PFS was 10.3 (once-weekly Kd70) vs 6.6 months (twice-weekly Kd27) (0.76; 0.49-1.16). In all 3 studies, rates of grade ≥3 treatment-emergent adverse events were consistent with those observed in the primary studies. The ASPIRE, ENDEAVOR, and ARROW primary analyses demonstrated favorable benefit-risk profiles with carfilzomib-containing regimens compared with controls. Across clinically relevant subgroups, including those by frailty status, consistent efficacy and safety were observed with KRd27, Kd56, and weekly Kd70, and treatment with these regimens should not be restricted by frailty status.

Abstract MM has a median age at presentation of 65–68 years, rarely occurring in pts before age 40. Here, we present clinical, laboratory and survival data in the largest ever-analyzed cohort of young pts compared with pts aged ≥ 40 years. 259 pts aged &lt; 40 and 8,296 aged ≥ 40 years were enrolled. These 8.555 pts were part of the cohort analyzed for the ISS staging project. Previously untreated pts entered into randomized trials with standard (SDT) or high dose treatment (HDT). Clinical data were available for all pts, 526 pts had karyotypic analysis and 454 pts testing for Del 13 testing by FISH. The Chi-Square test was used to identify significant prognostic factors. A maximum likelihood model was used to estimate relative excess risk (RER) for younger versus older pts treated with SDT or HDT. Observed survival was adjusted by life expectancy depending on age, gender, and nationality. Young pts had significantly lower ISS stage I than older pts (stage I; 39% vs. 28%, stage II: 28 vs. 39%, stage III 33% vs. 33%, p&lt;. 001, p&lt;001, p=0.863, respectively) due primarily to a lower prevalence of high ß2m levels and low albumin levels in the younger age group. Paradoxically, the younger pts more frequently presented with higher M-component levels and Durie Salmon stage III (65% vs. 54%, p&lt;0.001). Prevalence of other important prognostic parameters like Hb, platelet count, creatinine, calcium, CRP, LDH and bone marrow PC infiltration was similar in both groups. Younger pts had more frequently good ECOG performance status (PS) (0–2), (87% vs. 81%, p&lt;0.01). Karyotypic abnormalities and Del 13 were similarly distributed between both cohorts. Median OS was significantly longer in young pts (median: 4.8 years vs. 3.7 years; hazard ratio (HR): 1.46; 95%, CI (1.27, 1.68); p=&lt;0.001). Better outcome in the younger cohort was seen in all three ISS stages, independent of gender. Median OS survival was significantly longer after SDT in the young cohort (median: 49 months (mos) vs. 39 mos; HR 1.49; CI (1.27, 1.75); p&lt;0.001). Median survival: 86 mos in young and 68 mos in older pts on HDT; this did not translate into a statistical difference (HR 1.8; CI (0.81,1.44); p=0.6). Risk estimates in a maximum likelihood analysis revealed that, apart from ISS Stage, young age followed by female sex was statistical significant for a good outcome for pts treated with SDT (Age RER: 1.43, CI (1.20, 1.70), p&lt;0.001; Sex RER: 1.07, CI (1.02, 1.14); p &lt; 0.013). For pts treated with HDT, only ISS Stage was found to be a risk factor, but not age or gender. Conclusions: Patients &lt; 40 have better prognosis and survival than older patients. The most important features of young patients are low SßM, normal S. Alb, and good performance status.

8027 Background: A.R.R.O.W. demonstrated superior progression-free survival (PFS) with once-weekly K (70 mg/m2)-dexamethasone (Kd70) vs twice-weekly K (27 mg/m2)-dexamethasone (Kd27) in relapsed and refractory multiple myeloma (RRMM) pts, regardless of age. Weekly Kd70 is US-approved for relapsed or refractory MM (1–3 prior therapy lines). For a comprehensive fitness measure, frailty scales were developed incorporating age, comorbidities, and functional status. (Palumbo Blood 2015; Facon Blood 2015). Here we assessed post hoc pt outcomes by frailty status. Methods: PFS and safety were assessed by treatment arm and a frailty algorithm incorporating age, medical history–derived Charlson Comorbidity Index, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate (int), or frail, respectively. PFS was assessed with the Kaplan-Meier method. Safety was assessed in pts who received ≥1 treatment dose. Results: Pt distribution by frailty status was generally balanced between arms (Table). Once-weekly Kd70 vs twice-weekly Kd27 resulted in median PFS for fit, int, and frail pts of 15.7 vs 5.7 (mos; HR 0.53 [95% CI, 0.33–0.86]), 11.1 vs 7.7 mos (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 mos (HR 0.76 [95% CI, 0.49–1.16]), respectively. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once-weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy (PN); grade ≥3 cardiac failure rates were ≤4%. Conclusions: Once-weekly Kd70 resulted in PFS benefits vs twice-weekly Kd27 with a favorable benefit/risk profile regardless of frailty score as defined. These results support weekly Kd70 as a treatment option for both fit and frail RRMM pts. Clinical trial information: NCT02412878. [Table: see text]

8015 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 chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in approx. 15% of patients (pts) with MM, is considered a standard risk abnormality, but recent data suggest that the prognosis may be inferior to what had been expected. This is of particular relevance as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be effective in t(11;14) pts. Methods: This was a multicenter study designed and conducted by the IMWG, to identify the outcomes of pts with t(11;14) using a retrospective cohort of pts. Pts with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months (mos) of diagnosis, and with treatment details available and if alive, a minimum of 12 mos of follow up, were enrolled. Results: The current analysis includes 848 pts with a median age of 64.4 years; 60.0% are male. The median follow-up from diagnosis for the entire cohort was 45.7 mos; 84.7% of the pts were alive at the last follow up. ISS stage distribution included: Stage 1 (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%). Pts received initial therapy with different regimens: IMiD-24.3%, PI-41.0%, both-20.8% and 13.8% had no novel agent. The drug classes by line of therapy are shown in table. An early stem cell transplant (SCT) was used in 40.8% of pts. The median time to next treatment (TTNT) after initial treatment was 15.0 (95% CI: 12.2 to 17.7) mos. The median overall survival from diagnosis for the entire cohort was 82.5 (95% CI: 73.5 to 95.8) mos. Conclusions: This is the first study to examine the outcomes of a large group of myeloma pts with t(11;14) abnormality. Pts receiving a combination if a PI and an IMiD appear to have the best survival outcomes and thse receiving an early SCT appear to have excellent survival with median OS approaching 10 years. Additional pts are being accrued to this study and additional analysis examining the variables affecting response duration and survival will be presented. [Table: see text]