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MEDI2228 is an antibody drug conjugate (ADC) comprised of a fully human B-cell maturation antigen (BCMA) antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer. This phase 1 trial evaluated MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma (MM), who received prior treatment with approved agents from 3 classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies). Primary endpoint was safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. A total of 107 patients were treated and the maximum tolerated dose (MTD) was 0.14 mg/kg Q3W. Two patients had dose-limiting toxicities (DLTs; thrombocytopenia; 0.20 mg/kg Q3W). The most frequent treatment-related adverse events were photophobia (43.9%), rash (29.0%), and thrombocytopenia (19.6%). In MTD cohort A ( n  = 41), the objective response rate (ORR) was 56.1%, with 1 stringent complete response, 9 very good partial responses, and 13 partial responses. ORR was 53.3% in triple refractory patients. In cohort B ( n =25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug.

Considerable healthcare resource utilization and financial burden have been associated with the treatment of WM; however, the impact of health insurance status on outcomes has not been previously reported. We conducted a National Cancer Database analysis of newly diagnosed cases of active WM between 2004 and 2017 to evaluate the impact of insurance status on outcomes. For patients <65 years old ( n  = 1249, male sex: 62.4%, median age: 58 years), significant insurance-based survival differences were observed on multivariable analysis; patients who were uninsured [ n  = 63; HR 3.11 (95%CI, 1.77-5.45), p  < 0.001], on Medicaid [ n  = 87; HR 1.88 (95% CI, 1.01-3.48), p  = 0.045], or on Medicare [ n  = 122; HR 2.78 (95%CI, 1.76-4.38), p  < 0.001], had inferior survival compared to patients with private insurance ( n  = 977; reference). In patients ≥65 years, no insurance-based survival differences were found ( p  = 0.10). Overall, significant insurance-based outcome disparities exist in WM. Further work is desperately needed to systematically uncover and address these disparities.

Waldenstrom macroglobulinemia (WM) has an annual incidence of 3-3.2 cases per million-person/year. National Cancer Data Base was used to identify newly diagnosed WM cases requiring initiation of therapy and their annual facility volume was used to divide the treatment facilities into four quartiles (Qs). Cox regression was used to analyze the association between facility volume and survival, adjusted by demographics, socioeconomic, geographic, comorbidity factors and year of diagnosis. A total of 3064 patients treated in 795 facilities were included. The unadjusted median overall survival (OS) by facility volume was: Q1:6.5 years (5-year OS 55%), Q2:7 years (5-year OS 60%), Q3:8 years (5-year OS 64%), and Q4: NR (5-year OS 71%), p  < 0.0001. Our results demonstrated that a volume-outcome relationship exists in WM and is an independent predictor of overall survival in addition to the established risk factors as age and disease severity.

Lack of head-to-head trials highlights a need for comparative real-world evidence of proteasome inhibitors plus Rd. Methods : In this retrospective, US population-representative EHR study of RRMM patients initiating IRd, KRd, or VRd in line of therapy (LOT) ≥2 between 1/2014 and 9/30/2018, 664 patients were treated in LOT ≥2 with: IRd, n = 168; KRd, n = 208; VRd, n = 357. Median age was 71/65/71 years; 67%/70%/75% had a frailty modified  score of intermediate/frail; 20%/28%/13% had high cytogenetic risk in I-/K-/V-Rd groups. Risk of PI-triplet discontinuation was lower for I- vs. K-Rd (HR: 0.71) and I- vs. V-Rd (HR: 0.85); unadjusted, median TTNTs (months): 12.7/8.6/14.2 (LOT ≥2) and 16.8/9.5/14.6 (LOT 2-3) (I-/K-/V-Rd). Adjusted TTNT was comparable between I-/K-/V-Rd in LOT ≥2 with a TTNT benefit among intermediate/frail patients for I- (HR: 0.70; P=0.04) and V- (HR: 0.73; P<0.05) vs. K-Rd. I/K/V-Rd triplets were comparable in TTNT overall, but IRd and VRd were associated with longer TTNT in intermediate/frail patients than KRd. The results suggest a trial-efficacy/real-world-effectiveness gap, especially for KRd, underlining the limited generalizability of trial results where >50% of patients are excluded. Individualized treatment based on patient characteristics, such as frailty status, is especially pertinent in an elderly RRMM population.

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies ( N  = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.

Background: We assessed the economic value of carfilzomib 56 mg/m 2 and dexamethasone (Kd56) vs. bortezomib and dexamethasone (Vd) for relapsed/refractory multiple myeloma (R/RMM) using ENDEAVOR trial results., Methods: Cost-effectiveness of Kd56 vs. Vd was assessed using a partitioned survival model by estimating progression-free survival, overall survival, and direct costs over a lifetime horizon. Surveillance Epidemiology and End Results (SEER) survival data were extrapolated after matching registry and ENDEAVOR patients. Utilities were sourced from the literature and mapped from patient-reported quality of life in ENDEAVOR to estimate quality-adjusted life-years (QALYs) from life-years (LYs)., Results: The model predicted an average gain of 1.66 LYs and 1.50 QALYs with Kd56 vs. Vd, and lifetime additional costs of $182,699, resulting in an incremental cost-effectiveness ratio (ICER) of $121,828/QALY gained. The ICER was $114,793/QALY in patients with 1 prior treatment; $99,263/QALY in those not transplanted, and <$150,000/QALY up to an 85% discount in bortezomib price., Conclusions: Kd56 is cost-effective for patients with R/RMM at a willingness-to-pay threshold of $150,000/QALY. Trial data in the model may limit generalizability; however, SEER registry data mitigates this challenge. Kd56 provides additional value in key subgroups, and remains cost-effective after steep comparator discounts.

Understanding the biology of Waldenström macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-IgM) with κ-light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenström macroglobulinemia.

Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical response was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.

Novel agents have demonstrated enhanced efficacy when combined with other antimyeloma agents especially dexamethasone. The steroid doses employed in myeloma regimens are often poorly tolerated. Therefore, in a phase II clinical trial we investigated the efficacy of a steroid-free combination including bortezomib, pegylated liposomal doxorubicin and thalidomide (VDT regimen). Twenty-three patients with relapsed or refractory myeloma or other plasma cell cancers were treated with the VDT regimen. Patient had a median of five prior therapies and 65.2% were refractory to their last regimen. The overall response rates were 55.5% and 22%, respectively. The median progression free survival was 10.9 months (95% CI: 7.3-15.8) and the median overall survival was 15.7 months (95% CI: 9.1-not reached). Fatigue and sensory neuropathy were the most common side effects noted. We observe that VDT is an effective steroid-free regimen with ability to induce durable remission even in patients with refractory myeloma.