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B-Cell maturation antigen (BCMA) is a cell membrane receptor expressed on mature B lymphocytes, with elevated serum levels found among patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL). Serum BCMA (sBCMA) levels were measured in 331 untreated, newly diagnosed CLL patients using an enzyme-linked immunosorbent assay with a polyclonal anti-BCMA antibody. Elevated sBCMA levels were found among patients with CLL compared with age- and sex-matched healthy controls and those with more active CLL based on prognostic factors. The relationships between sBCMA, time to first treatment (TTFT), overall survival (OS) and multiple prognostic factors were compared using Mann-Whitney and Kruskal-Wallis tests. The median sBCMA level in the CLL cohort (48.6 ng/mL) was significantly higher (p0.001) compared with those of age- and sex-matched healthy subjects (n = 100; 37.8 ng/mL). Serum BCMA correlated with TTFT (hazard ratio [HR] = 2.9, 95% confidence interval 2.0-4.2, p0.001) and OS (HR = 2.5, 95% confidence interval: 1.5-4.0, p0.001). Multiple models were used to test the predictive effects of sBCMA, sex, CLL International Prognostic Index (CLL-IPI) and International Prognostic Score for early-stage CLL (IPS-E) on TTFT and OS. The addition of sBCMA to CLL-IPI and IPS-E improved their prognostic ability to predict TTFT and OS. Thus, sBCMA is a new promising prognostic biomarker for CLL.

Evaluation of AKT signaling pathway in primary MM cells treated with a TRAF6dn inhibitory peptide.

Cloning of the pLenti6.2-hTRAF6dn vector. The TRAF6dn cDNA was cloned into PCRII TOPO vector to produce a 167-amino acid peptide and then sub-cloned into a pLenti6.2 expression vector (pLenti6.2-hTRAF6dn).

TRAF6dn FITC-labeled peptide cultured with MM cell lines for 72 hours and monitored FITC positive MM cells using immunofluorescent microscopy (20X).

TNF receptor–associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant–negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti–multiple myeloma effects and also decreased TLR/TRAF6/NF-κB–related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14+ monocytes, induced with RANKL and mCSF, and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti–multiple myeloma effects and reduces bone loss.Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598–609. ©2017 AACR.

Purpose:Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry.Patients and Methods:A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1–21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR).Results:Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%).Conclusions:This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

Supplementary Tables and Figure

Purpose SARS-CoV-2 RNA has been detected in ocular tissues, but their susceptibility to SARS-CoV-2 infection is unclear. Here, we tested whether SARS-CoV-2 can infect human conjunctival epithelial cells (hCECs) and induce innate immune response. Methods Conjunctival tissue from COVID-19 donors was used to detect SARS-CoV-2 spike and envelope proteins. Primary hCECs isolated from cadaver eyes were infected with the parental SARS-CoV-2 and its beta variant of concern (VOC). Viral genome copy number, and expression of viral entry receptors, TLRs, interferons, and innate immune response genes were determined by qPCR. Viral entry receptors were examined in hCECs and tissue sections by immunostaining. Spike protein was detected in the cell culture supernatant by dot blot. Results Spike and envelope proteins were found in conjunctiva from COVID-19 patients. SARS-CoV-2 infected hCECs showed high viral copy numbers at 24–72h post-infection; spike protein levels were the highest at 24hpi. Viral entry receptors ACE2, TMPRSS2, CD147, Axl, and NRP1 were detected in conjunctival tissue and hCECs. SARS-CoV-2 infection-induced receptor gene expression peaked at early time points post-infection, but gene expression of most TLRs peaked at 48 or 72hpi. SARS-CoV-2 infected hCECs showed higher expression of genes regulating antiviral response, RIG-I, interferons (α, β, & λ), ISG15 & OAS2, cytokines (IL6, IL1β, TNFα), and chemokines (CXCL10, CCL5). Compared to the parental strain, beta VOC induced increased viral copy number and innate response in hCECs. Conclusions Conjunctival epithelial cells are susceptible to SARS-CoV-2 infection. Beta VOC is more infectious than the parental strain and evokes a higher antiviral and inflammatory response.

High-risk multiple myeloma (MM) continues to have a poor prognosis and remains a therapeutic challenge. This phase 2 study evaluated the efficacy and safety of elotuzumab in combination with pomalidomide, carfilzomib, and low-dose dexamethasone for patients with high-risk relapsed/refractory (RR)MM (NCT03104270). Of 13 enrolled patients, 11 were evaluable for efficacy. Overall response rate and clinical benefit rate were 45.4% and 54.5%, respectively. Deep responses were observed including two complete responses. The novel quadruplet combination was overall well-tolerated, with clinically manageable adverse events. Common adverse events of ≥ grade 3 included lymphopenia (15%), anemia (15%), sepsis (15%), pneumonia (15%), and hypophosphatemia (15%). The novel combination showed promising efficacy and was well tolerated in this heavily pretreated MM population. Even though the study was terminated early prior to completion of enrollment, the results indicate that this may be a promising therapeutic approach for high-risk RRMM patients, which warrants further study.

Multiple myeloma (MM) patients are at higher risk for severe COVID-19. Their mRNA vaccination response against SARS-CoV-2 is unknown. Thus, we analyzed responses to mRNA vaccination against COVID-19 among these patients. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined serum antibody levels prior to immunization and 12–21 and 14–21 days following the first and second vaccinations, respectively, with mRNA-1273 (Moderna) or BNT162b2 (Pfizer/BioNTech) among 103 MM patients (96 and 7 with active and smoldering disease, respectively). We stratified patients into clinically relevant responders (>250 IU/mL), partial responders (50–250 IU/mL, which was above pre-COVID-19 background), and nonresponders ( second line of treatment, and among those not in complete remission. Patients who received mRNA-1273 vaccine had higher anti-spike antibody levels than those who were vaccinated with BNT162b2. Thus, most MM patients have impaired responses to mRNA vaccination against COVID-19, and specific clinical and myeloma-related characteristics predict vaccine responsiveness.

Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.

The purpose of this single-center retrospective study was to determine the incidence of decreased blood phosphorus levels and hypophosphatemia among multiple myeloma (MM) patients treated with elotuzumab. Hypophosphatemia, which is defined as a serum phosphorus concentration

Identifying effective combination regimens is a high priority in multiple myeloma (MM), as most patients eventually become refractory to their current treatments. In this study, we investigated whether the proteasome inhibitor (PI) ixazomib could delay disease progression among patients who failed regimens containing another PI, bortezomib or carfilzomib. This phase 1/2, multicenter, open-label, nonrandomized study enrolled patients who were refractory to a previous regimen containing bortezomib or carfilzomib. Patients continued the other anti-MM drugs in the regimen at the same doses and frequencies. Patients with combination regimens with unknown maximum tolerated dose (MTD) of ixazomib were enrolled in phase 1, with ixazomib starting at 3 mg and then dose escalated to 4 mg. Patients on regimens with a known ixazomib MTD were enrolled in phase 2. Primary endpoints were overall response rate (ORR), clinical benefit rate (CBR), adverse events (AEs), and determination of maximum tolerated dose (MTD). Of the 46 patients enrolled, 39 were evaluable for efficacy. ORR and CBR were 12.8% and 17.9%, respectively. Ixazomib appeared to be well tolerated as a replacement for carfilzomib and bortezomib, with 23.9% of patients experiencing at least one grade ≥3 serious adverse event (SAE) and 37.0% experiencing at least one grade ≥3 AE. The most common grade ≥3 AEs were hyponatremia (8.7%), anemia (8.7%), dyspnea (8.7%), thrombocytopenia (6.5%), dehydration (4.3%), and pneumonia (4.3%). The results indicate that ixazomib is not an effective replacement for bortezomib or carfilzomib for patients with MM who have previously relapsed on other bortezomib/carfilzomib-containing regimens.

A 52-year-old African-American woman with a prior history of monoclonal gammopathy of undetermined significance (MGUS) developed infiltrating ductal carcinoma of the left breast. Following a mastectomy, she underwent reconstruction with a silicone gel breast implant. Three years later, her MGUS had progressed to active multiple myeloma (MM). She had a minimal response after two different regimens of bortezomib-based treatments and monthly zoledronic acid, and was placed on maintenance therapy with bortezomib, intravenous dexamethasone, and oral methylprednisolone, as well as ongoing monthly zoledronic acid. After 1 year of this maintenance therapy, during which her myeloma markers remained unchanged, she had her silicone implant replaced with saline. Despite no change in her myeloma treatment, her laboratory values began to steadily improve following removal of the silicone implant. Her M-protein decreased from 2.14 to 0.83 g/dL and her IgG levels from 3,330 to 1,210 mg/dL following replacement of her silicone implant with saline. To our knowledge, this is the first report in which removal of silicone implants improved the clinical status of a patient with MM following a year of maintenance therapy during which the patient’s myeloma laboratory values remained unchanged. Further studies are warranted to determine if silicone breast implant removal can, in fact, improve MM patients’ disease status.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (

Previous retrospective studies have shown that serum B-cell maturation antigen (sBCMA) levels predict outcomes among patients with multiple myeloma (MM) undergoing new treatments. Specifically, baseline levels and changes during treatment of this protein predict both progression free survival (PFS) and overall survival. However, prospective studies are lacking evaluating sBCMA for determining outcomes among MM patients undergoing new treatments. Thus, we evaluated whether its baseline levels and changes during treatment in the amount of this serum marker predict outcomes among 38 relapsed/refractory MM patients treated with ruxolitinib, lenalidomide and methylprednisolone in a phase 1 trial. Patients with baseline sBCMA levels in the lowest three quartiles had longer PFS (median PFS 136 vs. 28 days; p 0.0001). This was also shown for patients with baseline levels below the median (median PFS 140 vs. 77 days; p = 0.0225). PFS was shorter for patients whose sBCMA levels increased ≥25% through their first cycle (median PFS: 50 vs. 134 days, p = 0.0022), second cycle (median PFS: 50 vs. 141 days, p = 0.0273), and during the first three cycles of study treatment (median PFS: 50 vs. 220 days, p 0.0001). No patient whose sBCMA increased ≥25% during cycle 1 responded whereas the majority (58%) of patients whose level increased25% responded. This is the first prospective study to determine whether sBCMA levels predict outcomes for MM patients undergoing a non-BCMA directed treatment regimen and demonstrates that baseline levels and its changes during treatment predict PFS and the likelihood of responding to their treatment. These results add to the growing literature suggesting that this serum marker will be useful for determining outcomes for patients undergoing treatment for MM.

B-cell maturation antigen (BCMA) is expressed on malignant plasma cells from patients with multiple myeloma (MM). These patients have higher levels of serum (s)BCMA than healthy subjects, and levels correlate with disease status. The half-life of sBCMA is only 24–36 h, and levels are independent of renal function. We determined whether baseline sBCMA values, a ≥ 25% increase, and a ≥ 50% decrease during treatment predicted progression-free survival (PFS) and overall survival (OS) among 81 patients with relapsed/refractory MM (RRMM) starting new treatments. Serum was obtained on day 22 of each patient’s 28-day cycle of new therapy. Kaplan–Meier survival analysis and log-rank comparison tests were used to determine the effect of baseline sBCMA. The effect of percentage change in sBCMA was investigated using time-dependent Cox proportional hazard models. Patients with baseline sBCMA levels above the median had a shorter PFS (p = 0.0077), and those in the highest quartile had a shorter PFS (p = 0.0012) and OS (p = 0.0022). A ≥ 25% increase at week 4, week 8, and anytime through week 12 predicted a shorter PFS (p = 0.0011, p = 0.0005, and p < 0.0001, respectively). A ≥ 50% decrease at week 4, week 8, and anytime through week 12 predicted a longer PFS (p = 0.0045, p = 0.029, p = 0.0055, respectively). A ≥ 25% increase in sBCMA occurred before progression according to International Myeloma Working Group criteria in 67.5% of patients. Our results indicate the potential for the use of sBCMA as a new biomarker for monitoring patients with RRMM.

Background Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. Methods A receiver operating characteristic curve was used to establish a definition for high risk baseline sBCMA. Mantel Byar analysis was used to examine if high risk sBCMA was correlated with shorter time to transformation, and a time dependent cox proportional hazard was used to determine if it is independent of other risk factors. A z-test for proportions was used to compare the percentage of patients that progressed among high risk versus low risk sBCMA patients. Results A baseline sBCMA level ≥ 137.5 ng/mL was found to be the optimal cut off between high and low risk SMM patients. Patients with high risk sBCMA levels had a shorter time to transformation (p = 0.000332). sBCMA was also higher at the time of transformation than baseline levels (p = 0.0116). sBCMA was the only variable found to be significantly predictive of time to transformation, and additionally was found to be independent of other risk factors. Conclusions In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.

The purpose of this single-center retrospective study was to determine the incidence of decreased blood phosphorus levels and hypophosphatemia among multiple myeloma (MM) patients treated with elotuzumab. Hypophosphatemia, which is defined as a serum phosphorus concentration 2.5 mg/dL, leads to complications ranging from muscle weakness and disorientation to seizures and heart failure. A total of 23 MM patients receiving care in a clinic specializing in treatment of MM from July 2018 to March 2020 and treated with an elotuzumab-containing therapy were evaluated, and 9 were investigated for this study. Elotuzumab was given at 10 mg/kg weekly for the first two treatment cycles (28 days/cycle), followed by 10 mg/kg every other week for all subsequent cycles. Four different elotuzumab combination therapies were administered: 1) elotuzumab and dexamethasone 2) elotuzumab, lenalidomide and dexamethasone 3) elotuzumab, pomalidomide and dexamethasone and 4) elotuzumab, carfilzomib, pomalidomide, and dexamethasone. Phosphorous levels were determined at a median of every 13 days at intervals ranging from once weekly to once monthly until a phosphate supplement was prescribed to the patient or when elotuzumab treatment was discontinued. We found that regardless of elotuzumab combination therapy, all patients treated showed decreased phosphorus levels after initiating elotuzumab treatment with reductions ranging from 12.5% to 44.1% below baseline. Six participants (67%) demonstrated an average serum phosphorus at or below 2.5 mg/dL after starting elotuzumab therapy. This retrospective study suggests that hypophosphatemia commonly occurs among MM patients receiving elotuzumab-containing therapies.

The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance, downregulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical benefit rate (CBR) and overall response rate (ORR) were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. We evaluated whether the combination of RUX and steroids without LEN was active for treating similar patients through treatment of a cohort within the current trial using this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, ORR and CBR. Results As of July 15, 2021, 27 patients were enrolled. The median age was 64 years (range, 46-85), and 17 (63%) were male. Patients received a median of 4 (range, 3-11) prior treatments including LEN and steroid-containing regimens to which they were all refractory. Twenty-six patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The ORR and CBR were 35% (n=9) and 39% (n=10), respectively. Notably, all 10 responding patients were refractory to LEN (i.e., progressed while on or within 8 weeks of last dosage). The remaining patients showed stable disease (n=12) or PD (n=4). The median follow-up was 13 months. The median progression-free survival was 4 months (range, 1-21). The median duration of response was 11 months (range, 1-20). Of 13 patients who progressed on the two-drug combination and had LEN added to their regimen, 6 patients responded (3 MR and 3 PR). Nine patients experienced SAEs including sepsis (12%), sepsis with neutropenic fever (4%), thrombocytopenia (4%), hyperglycemia (4%), neutropenia (4%), anemia (4%), acute heart failure (4%), rotator cuff tear (4%), osteomyelitis (4%), aspiration pneumonia (4%), pneumonia and pneumothorax (4%), and deep venous thrombosis (4%). Two patients died (one each from pneumonia and PD). Conclusions This ongoing Phase 1 trial is the first study demonstrating clinical activity of the two-drug combination of the JAK inhibitor RUX with steroids for MM patients. The treatment was well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being investigated off-label to determine if it shows anti-myeloma activity in combination with steroids for relapsed/refractory myeloma patients.

TNF receptor–associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant–negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti–multiple myeloma effects and also decreased TLR/TRAF6/NF-κB–related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14+ monocytes, induced with RANKL and mCSF, and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti–multiple myeloma effects and reduces bone loss. Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598–609. ©2017 AACR.

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P

New classes of drugs including the proteasome inhibitors (PI) bortezomib and, more recently, carfilzomib and the immunomodulatory agent lenalidomide have shown improved outcomes for multiple myeloma (MM) patients during the past decade. However, most of the studies reporting outcomes for patients receiving these drugs have relied on older data sets derived from large institutions that included patients not receiving their treatment at those facilities and represented only those eligible for clinical trials or were from sites where treatment options were limited. We have analyzed data from 258 MM patients who have received treatment with at least one of three agents: bortezomib, carfilzomib, and lenalidomide in a single clinic specializing in MM with respect to their responses and other outcomes to treatment regimens including these agents. Response rates were similar between these three drugs when used for the first time and again during subsequent treatment regimens. As expected, the clinical benefit rates (CBRs) were better for patients receiving their first treatment when compared to their use in subsequent treatment regimens. The CBRs were similar during their 2nd, 3rd, and 4th treatments containing these agents. Many patients refractory to these agents showed responses to regimens containing these same drugs when used in different combinations. In addition, patients refractory to one PI often responded to the other PI. The results of this study demonstrate that novel agents can be used repeatedly in novel combinations with significant clinical benefit for patients with MM.

Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients’ quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (

Objective To evaluate the efficacy and safety of elotuzumab and dexamethasone (Ed) for relapsed or refractory multiple myeloma (RRMM) patients. Method This retrospective study evaluated the efficacy and safety of (Ed) treatment for 21 RRMM patients, 11 of whom were considered lenalidomide-refractory, and all of whom had progressed on at least 1 prior steroid-containing regimen. We also evaluated the efficacy of adding lenalidomide to a subset of patients following progression from Ed. Results The overall response rate (ORR) and clinical benefit rate (CBR) of Ed were 10% and 19%, respectively. An additional 52% of patients demonstrated stable disease as their best response. The median PFS was 1.8 months on Ed for all patients. Fifteen patients received ERd following progression on Ed, and 60% of these patients were lenalidomide-refractory. The ORR and CBR were 20% and 33%, respectively, and the median PFS was 3.4 months. Conclusion Our results suggest that some patients can benefit from Ed without an accompanying immunomodulatory agent and that efficacy can be achieved with the addition of lenalidomide at the time of progression. No new safety signals were detected, except for thrombocytopenia in 1 patient on Ed. This article is protected by copyright. All rights reserved.

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of MM. Many newer drugs have been evaluated together and in combination with older agents. However, even in combination with other active MM agents, the responses are transient, and; thus, therapeutic approaches to help overcome resistance to these drugs are necessary. Recently, the Janus kinase (JAK) family of tyrosine kinases, including JAK1 and JAK2, has been shown to play a role in the pathogenesis of MM. Preclinical studies have demonstrated that the JAK1/2 inhibitor ruxolitinib, in combination with lenalidomide and dexamethasone, reduces proliferation of the MM cell lines and primary tumor cells derived from MM patients, and this inhibition is greater when these drugs are combined than with single agents. Clinically, early results from the oral treatment regimen of ruxolitinib, corticosteroids (methylprednisolone), and lenalidomide for patients with relapsed/refractory disease are encouraging in terms of safety and efficacy, and additional studies will provide further support for this promising new therapeutic approach for patients with MM.

Chronic lymphocytic leukemia (CLL) is a malignancy of late B cells. In another late B-cell malignancy (multiple myeloma), levels of solubilized B-cell maturation antigen (sBCMA) are elevated and predict outcomes.We sought to evaluate sBCMA as a possible prognostic factor and monitoring tool for patients with CLL.Using an enzyme-linked immunosorbent assay (ELISA), we assessed plasma (p) levels of BCMA in 171 CLL patients and compared them with levels in healthy individuals.pBCMA levels were significantly higher among patients with CLL than those from healthy donors (p 0.0001). Among patients with aggressive disease, pBCMA was elevated compared with patients with indolent disease (p 0.001). Those with an initial pBCMA level in the highest quartile had a shorter time to first treatment compared with CLL patients with pBCMA levels in the lowest three quartiles (p 0.0001). Among those in the highest quartile (pBCMA 110.9 ng/mL), overall survival was shorter than those in the lowest three quartiles (p = 0.0007). Finally, among those patients who underwent serial pBCMA testing, changes in these levels correlated with changes in their clinical status.Together, our findings show that pBCMA is a promising new prognostic and predictive indicator for patients with CLL.

Purpose: Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry. Patients and Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1–21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR). Results: Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%). Conclusions: This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance and down-regulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical and overall response rates were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. To further evaluate whether RUX and steroids without LEN demonstrate clinical activity and its tolerability in the same patient population, an ongoing Phase I trial was expanded to also include a cohort of patients treated with this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of July 25, 2020, 16 of the planned 29 patients have been enrolled, and 15 patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The median age was 64 years (range, 46-77), and 9 (60%) were male. Patients received a median of 4 (range, 3-10) prior treatments including LEN and steroids to which they were all refractory. Of the 15 evaluable patients treated with RUX and steroids, the CBR and ORR were 53% (n=8) and 33% (n=5), respectively. With a median follow-up of 4.7 months, the median duration of response was 3.5 months (range, 1-11+). Five and 2 patients showed stable disease and progressive disease, respectively. Notably, all 8 responding patients were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). Of 6 patients who had progressed on the two-drug combination and had LEN added to their regimen, 3 patients responded (2 MR and 1 PR). Four patients experienced SAEs including sepsis (7%), group B strep sepsis with neutropenic fever and nausea (7%), pneumonia and pneumothorax (7%), thrombocytopenia (7%), and hyperglycemia (7%). Two patients died (one each from pneumonia and progressive disease). Conclusions This ongoing phase 1 trial is the first study reporting clinical activity of the JAK inhibitor RUX with steroids for MM. These results demonstrate that RUX with only steroids is also well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Berenson: Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Patents & Royalties: OncoTracker, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Swift:Jassen: Consultancy, Honoraria, Speakers Bureau; bristol myers squibb: Consultancy, Honoraria, Speakers Bureau; Amgent: Consultancy, Honoraria, Speakers Bureau. Boccia:Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Rigel: Consultancy, Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Ruxolitinib and steroids only for treatment patients with Multiple Myeloma

Immunosuppressed patients are known to have an increased incidence of skin cancer. Patients with multiple myeloma (MM) show impaired immune function. In the past, because of poor survival, the incidence of specific secondary primary malignancies such as skin cancer among these patients was difficult to establish. With more effective MM therapies that have emerged in recent years, these patients are living markedly longer, and therefore, it becomes of increasing importance to determine whether their risk of developing other medical problems such as skin cancer is increased. We performed a retrospective cohort study of 205 myeloma patients and 193 age-, race-, and gender-matched control subjects to assess the incidence of skin cancers among patients with MM and determine the specific types of and risk factors for skin cancer. We found that there is an increased occurrence of skin cancer among patients with MM compared to control subjects (26.8% vs. 16.1% in controls; P = 0.009). Among specific types of skin cancer, the proportion of patients with squamous cell carcinoma (SCC) was higher than controls (P = 0.016). In addition to MM diagnosis, older age and Caucasian ethnicity were predictors of skin cancer of any type. Furthermore, older age was also a predictor of SCC.

Since the early 1990s, the generation and subsequent use of small molecule inhibitors targeting the ubiquitin proteasome pathway have transformed the treatment and improved the outcomes for patient...

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 (Mucin 1) is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 patients. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of March 1, 2019, 43 patients were enrolled, and 40 were evaluable for efficacy. The median age was 65 years (range, 46-81), and 25 (58%) were male. Patients received a median of 6 prior treatments including LEN and steroids to which they were all refractory. No DLTs occurred, and DL+3 was expanded. Among all 40 evaluable patients, the CBR and ORR were 47% and 37%, respectively (1 CR, 4 VGPR, 10 PR and 4 MR), and 16 and 5 patients showed SD and PD. Notably, all 19 patients achieving > MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 4 months. G3/4 AEs included anemia (16%), sepsis (14%), lymphocytopenia (14%), pneumonia (12%), neutropenia (12%) and hypokalaemia (12%). Most common SAEs included sepsis (14%) and pneumonia (12%). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to expansion of the current clinical trial to 78 patients, and represent a potential novel therapeutic approach for treating MM. Disclosures Berenson: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; OncoTracker: Equity Ownership, Other: Officer; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding; Incyte Corporation.: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Eades:Celgene: Other: Stock. Boccia:Genentech: Speakers Bureau; DSI: Speakers Bureau; AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory multiple myeloma patients.

Introduction: B-cell maturation antigen (BCMA) is a protein that is expressed on malignant plasma cells from patients (pts) with multiple myeloma (MM). Our group has previously shown that MM pts have higher levels of serum (s) BCMA than healthy subjects and that sBCMA levels can be used to monitor the disease course of MM pts. Notably, we have shown that the half-life of soluble BCMA is only 24-36 hours which is much shorter than sM-protein, and its levels are independent of renal function. With the expanding therapeutic options for the treatment (Tx) of MM, there is a need for more rapid and accurate ways to assess the efficacy of new therapies. In this study, we analyzed the relationship between progression free survival (PFS) and changes in weekly levels of sBCMA, sM-protein and serum free light chain (sFLC) during the first cycle of a new treatment among relapsed/refractory (RR)MM patients. Methods: Serum was obtained weekly during each pt's first cycle of a new therapy (C1) and the first day of their second cycle (C2D1) from all RRMM pts (n = 122) at a single clinic from August 2016 to December 2018. sM-protein and sFLC levels were measured, and sBCMA levels were determined using an enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Percentage changes in sBCMA, sM-protein and sFLC (difference between involved and uninvolved FLCs) throughout Tx were determined relative to levels measured at the start of treatment (C1D1). Kaplan-Meier analysis was used to assess differences in PFS based on the percentage changes from baseline in these levels at cycle 1 day 8 (C1D8), day 15 (C1D15), day 22 (C1D22), and day 29 (C2D1). All pt samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: The analysis involved 122 Tx in 75 RRMM pts undergoing new treatment (IgG [n = 33], IgA [n= 15], IgM [n = 1], and light chain only [n = 26]). All pts were evaluable by sBCMA (above the lower limit of detection of the assay [16 ng/mL]). Pts whose baseline sBCMA was higher than the median (217.6 ng/mL) had a significantly shorter PFS (n = 61, median PFS = 2.5 mo) than those below the median (n = 61, median = 7.3 mo, p = 0.0003). When baseline sBCMA levels were quartiled, there was an inverse relationship between sBCMA and PFS (Q1: n = 30, median = 8.0 mo; Q2: n = 31, median = 7.2 mo; Q3: n = 31, median = 3.2 mo; Q4: n = 30, median = 1.9 mo; p = 0.0002). Pts whose sBCMA increased ≥ 25% on C1D8 (n = 8) had a shorter PFS (median = 1.6 mo) than those that did not (n = 114, median = 3.9 mo, p = 0.0042). Those whose sBCMA increased ≥ 25% at any time during C1 (n = 31) also had a shorter PFS (median = 1.6 mo) than those that did not (n = 91, median = 5.2 mo, p < 0.0001). sM-protein was only evaluable by IMWG criteria (> 1.0 g/dL) in 45 (37%) of the pts and only 2 and 5 pts showed an increase of > 25% on C1D8 and anytime during cycle 1, respectively. In the remaining 77 pts who were not evaluable by sM-protein, 51 (68%) were evaluable by sFLC using IMWG criteria (> 100 mg/L difference between the involved and uninvolved FLC) and only 13 showed a > 25% increase during the first cycle. Next, we determined if changes in sBCMA could be used for pts who were not evaluable by either sM-protein or sFLC. Among pts that could not be followed by sM-protein, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 18, median = 2.2 mo) had a significantly shorter PFS than those who did not (n = 59; median = 4.4 mo; p = 0.0218). Among pts that could not be followed by sFLC, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 12) had a significantly shorter PFS (median = 1.6 mo) than those who did not (n = 30; median PFS = 8.7 mo; p = 0.0072). Among pts that could not be followed by either sFLC or sM-protein, a > 25% in sBCMA at any point in C1 (n = 8) showed a shorter PFS (median = 1.6 mo) than those who did not (n = 17; median = 19.3 mo; p = 0.0154). Notably, among pts whose sFLC or sM-protein were below evaluable levels, ≥ 25% increases in sFLC or sM-protein did not predict PFS. Conclusions: We have shown that serum BCMA was evaluable in all RRMM pts at the start of new therapy in contrast to the standard sM-protein and sFLC biomarkers. Baseline levels of sBCMA predict PFS in RRMM pts undergoing new therapy. Additionally, increases of sBCMA > 25% during the first cycle occur in more pts than sM-protein or sFLC, and predict for a shorter PFS. These results suggest that baseline sBCMA and monitoring its levels weekly during the first cycle of a new treatment can help improve predicting outcomes for RRMM pts. Disclosures Chen: Oncotraker Inc: Equity Ownership. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Berenson:Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; OncoTracker: Equity Ownership, Other: Officer; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding.

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation in bone marrow of terminally differentiated plasma cells. MM is a slowly growing, heterogeneous disease with no known cure. Patients with MM have a median survival of approximately 5 years, during which they may experience significant morbidity. More reliable and rapid determination of changes in the clinical status of patients with MM is becoming increasingly important because of the increasing number of available treatments for these patients. Currently available tests for monitoring patients with MM most often include assessments of monoclonal paraprotein and serum free light chain levels, but the tests have several limitations. Measurement of serum B-cell maturation antigen level may overcome these limitations and improve outcomes for patients with MM. Newer radiologic procedures such as positron emission tomography/computed tomography are superior to plain radiographs, but are costly and inconvenient. Bone marrow examination directly identifies malignant cells, but the heterogeneous nature of the disease makes it problematic to use routinely to follow patients with MM. The development of new markers and approaches to more accurately and quickly assess changes in tumor burden in patients with MM should result in better outcomes for these patients.

Summary Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3–29·0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.

Although selective binding of 53BP1 to dimethylated histone H4 lysine 20 (H4K20me2) at DNA double-strand breaks (DSBs) is a necessary and pivotal determinant of nonhomologous end joining (NHEJ)-directed repair, the enzymes that generate H4K20me2 at DSBs were unclear. Here, we determined that the PR-Set7 monomethyltransferase (H4K20me1) regulates de novo H4K20 methylation at DSBs. Rapid recruitment of PR-Set7 to DSBs was dependent on the NHEJ Ku70 protein and necessary for NHEJ-directed repair. PR-Set7 monomethyltransferase activity was required, but insufficient, for H4K20me2 and 53BP1 nucleation at DSBs. We determined that PR-Set7-mediated H4K20me1 facilitates Suv4-20 methyltransferase recruitment and catalysis to generate H4K20me2 necessary for 53BP1 binding. The orchestrated and concerted activities of PR-Set7 and Suv4-20 were required for proficient 53BP1 nucleation and DSB repair. This report identifies PR-Set7 as an essential component of NHEJ and implicates PR-Set7 as a central determinant of NHEJ-directed repair early in mammalian DSB repair pathway choice. © 2014 The Authors.