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Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 + memory T cell progenitors that can become either functional stem-like T (T STEM ) cells or dysfunctional T progenitor exhausted (T PEX ) cells. To that end, we demonstrated that T STEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T STEM -like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4 + T cells during T STEM -like CAR-T cell production. Adoptive transfer of T STEM -like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T STEM -like CAR-T cells and an increased memory T cell pool. Last, T STEM -like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8 + CAR + T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.

All Supplementary Methods and associated references

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.Significance:CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983

Exposure-response relationship between CX-5461 levels and rDNA transcription rate in normal PBMCs

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Chimeric antigen receptor T-cell (CAR-T) therapy is a promising immunotherapy approved for hematological malignancies. Despite its effectiveness, clinically significant rates of toxicity, including immune effector cell associated neurotoxicity syndrome (ICANS), limit its widespread use. In certain contexts, ICANS may occur in up to one-third of patients using commercially available CAR-T therapies. The syndrome presents with a range of neurological signs and symptoms, as well as a variety of neuroimaging manifestations reported in the literature. A systematic review of the literature was performed. The systematic search strategy identified 24 studies discussing the neuroimaging appearances associated with ICANS. Imaging findings are more common in patients with higher grade neurotoxicity. The neuroimaging findings are heterogeneous, but can be grouped either anatomically (white matter, gray matter, brainstem, or leptomeninges) or pathologically (ischemic changes, hemorrhages, or cerebral edema). An understanding of the imaging manifestations of ICANS has the potential to impact the management of patients.

In the Phase III ICARIA-MM study (NCT02990338), the addition of the anti-CD38 monoclonal antibody isatuximab to pomalidomide and dexamethasone led to increased progression-free survival and improved response rates in patients with relapsed/refractory multiple myeloma. There is an unmet treatment need, particularly among patients with poor prognoses, including those with high-risk cytogenetics, those who have renal impairment, those who are elderly and those who are refractory to prior lines of treatment. In this review, the subgroup analyses from the ICARIA-MM study, representing subpopulations with poor prognostic factors, are discussed. Overall, the addition of isatuximab to pomalidomide and dexamethasone improved progression-free survival and disease response rates across different subgroups, regardless of prognostic factor.Lay abstract Currently, the majority of patients with multiple myeloma are not cured, and current treatments may not be helpful for patients with poor prognoses, including those with high-risk chromosomal changes, those who have impaired kidney function, those who are elderly and those who are refractory to prior treatments. In this review, we will discuss the benefits of the combination of isatuximab plus pomalidomide and dexamethasone in these difficult-to-treat patients.

The aims of this study were to investigate the effect of diabetes mellitus (DM) on patient-reported outcome measures (PROMs) and satisfaction after surgery for cubital tunnel syndrome (CuTS). Pre- and 1-year postoperative QuickDASH, normal hand, and satisfaction scores were prospectively collected from 107 patients over a 6-year period. Patients without DM reported a significant QuickDASH improvement after surgery (preoperative 34.1 versus postoperative 20.5; p Level of evidence: IV

Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population-based case-control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.

BACKGROUND: Real-world multiple myeloma (MM) data are scarce, with most data originating from clinical trials. The Myeloma and Related Diseases Registry (MRDR) is a prospective clinical-quality registry of newly diagnosed cases of plasma cell disorders established in 2012 and operating at 44 sites in Australia and New Zealand as of April 2020. METHODS: We reviewed all patients enrolled onto the MRDR between June 2012 and April 2020. Baseline characteristics, treatment, and outcome data were reviewed for MM patients with comparisons made by chi-square tests (categorical variables) and rank sum tests (continuous variables). Kaplan-Meier analysis was used to estimate progression-free survival and overall survival (OS). RESULTS: As of April 2020, a total of 2405 MM patients were enrolled (median age, 67 years, with 40% aged > 70 years). High-risk features were present in 13% to 31% of patients: fluorescence in-situ hybridization (FISH) ≥ 1 of t(4;14), t(14;16), or del(17p) 18%, International Staging System (ISS)-3 31%, and Revised ISS (R-ISS)-3 13%. Cytogenetic/FISH analyses were performed in 50% and 68% of patients, respectively, with an abnormal karyotype result in 34%. Bortezomib-containing therapy was the most common first-line therapy (79.3%, n = 1706). Patients not receiving bortezomib were older (median age, 76 vs 65 years, P < .001) with inferior performance status (Eastern Cooperative Oncology Group performance status ≥ 2, 41% vs 18%, P < .001). Median progression-free survival and OS were 30.8 and 65.8 months, respectively. Younger patients had superior OS (76.3 vs 46.7 months, P < .001, < 70 and ≥ 70 years, respectively). R-ISS score was available in 50.7% (n = 1220) of patients, and higher R-ISS was associated with inferior OS (R-ISS-1 vs R-ISS-2 vs R-ISS-3: not reached vs 68.1 months vs 33.2 months, respectively, P < .001). CONCLUSION: Clinical registries provide a more complete picture of MM diagnosis and treatment, and highlight the challenges of adhering to best practices in a real-world context.

Supported by clinical trial proven survival benefit, clinical guidelines recommend upfront autologous stem cell transplantation (ASCT) for eligible MM patients. However, reported real-world utilisation is lower than expected (40–60%). We reviewed ASCT utilisation, demographics and outcomes for MM patients (≤70 years, ≥12-month follow-up) enroled onto the Australian/New Zealand MRDR from June 2012 to May 2020. In 982 patients (

Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic., Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.

Multiple myeloma is the most common haematological malignancy accounting for ten percent of all haematological cancers. Treatment of myeloma has evolved in recent years leading to improved survival. Lesions related to myeloma are frequently observed within the oral cavity and jawbone. In addition, many of the therapeutic agents have side effects with implications for provision of dental treatment. This case series aims to highlight some of these presentations to remind dental practitioners to be vigilant. Observation of suspicious lesions within the oral cavity or jawbone may warrant further investigation.

A 63-year-old woman born in Vietnam was diagnosed with IgG Kappa Myeloma after presenting with severe back pain and pathological fracture of L5. Her medical history was notable for essential hypert...

CD3-engaging bispecific antibodies (BsAbs) have emerged as powerful therapeutic approaches by their ability to redirect T cells to eliminate tumor cells in a major histocompatibility complex–independent manner. However, how we can potentiate the efficacy of BsAbs remains largely unknown. To address this question, we investigated immunological mechanisms of action of a BsAb cotargeting CD3 and B-cell maturation antigen (BCMA) in syngeneic preclinical myeloma models. Treatment with the CD3/BCMA BsAb stimulated multiple CD3-expressing T-cell subsets and natural killer (NK) cells in the myeloma bone marrow (BM), highlighting its broad immunostimulatory effect. Notably, the BsAb-mediated immunostimulatory and antitumor effects were abrogated in mice lacking invariant NKT (iNKT) cells. Mechanistically, activation of iNKT cells and interleukin-12 production from dendritic cells (DCs) were crucial upstream events for triggering effective antitumor immunity by the BsAb. Myeloma progression was associated with a reduced number of BM iNKT cells. Importantly, the therapeutic efficacy of a single dose of CD3/BCMA BsAb was remarkably augmented by restoring iNKT cell activity, using adoptive transfer of α-galactosylceramide-loaded DCs. Together, these results reveal iNKT cells as critical players in the antitumor activity of CD3 engaging BsAbs and have important translational implications.

Australia and New Zealand have achieved excellent community control of COVID‐19 infection. In light of the imminent COVID‐19 vaccination roll out in both countries, representatives of all adult and paediatric allogeneic bone marrow transplant and cellular therapy (TCT) centres as well as representatives from autologous transplant only centres in Australia and New Zealand collaborated with infectious diseases specialists with expertise in TCT on this consensus position statement regarding COVID‐19 vaccination in TCT patients in Australia and New Zealand. It is our recommendation that TCT patients, should have expedited access to high‐efficacy COVID‐19 vaccines given that these patients are at high risk of morbidity and mortality from COVID‐19 infection. We also recommend prioritising vaccination of TCT healthcare workers and household members of TCT patients. Vaccination should not replace other public health measures in TCT patients given the effectiveness of COVID‐19 vaccination in TCT patients is unknown. Furthermore, given the limited available data, prospective collection of safety and efficacy data of COVID‐19 vaccination in this patient group is a priority.

We read with interest the study from Rampotas et al (1) where they evaluated 158 transplant-non-eligible newly diagnosed myeloma patients treated with bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) chemotherapy. They showed that fixed duration VCD led to an overall response rate (ORR) of 72% and was 'reasonably well tolerated'. They concluded that the comparatively poor event free survival (EFS) may be improved "with the use of higher cumulative bortezomib" doses.

Background Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous hematopoietic stem cell transplantation (autoHCT) patients. Methods A randomized, single-blind, controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomized 1:1 to high-dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or 2 SD vaccines (SD-SD arm) 4 weeks apart. Hemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2, and 6 months post–first dose. Evaluable primary outcomes were seroprotection (HI titer ≥40) and seroconversion (4-fold titer increase) rates and secondary outcomes were geometric mean titers (GMTs), GMT ratios (GMRs), adverse events, influenza-like illness (ILI), and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion. Results Sixty-eight patients were enrolled (34/arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentages of patients achieving seroprotection were 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all P > .05), and 78.8% and 97.1% for influenza-B/Yamagata (P = .03), respectively. Seroconversion rates, GMTs and GMRs, and number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR, 4.3; 95% CI, 1.2–14.9; P = .02). Conclusions High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either 2-dose vaccine schedules. Clinical Trials Registration Australian New Zealand Clinical Trials Registry: ACTRN12619000617167.

Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts as a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell-surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signaling pathways promoting cell proliferation and survival or apoptosis.This review focuses on the role of ER and csGRP78 in physiology and oncogenesis in multiple myeloma, addressing factors that shift the balance in GRP78 signaling from survival to apoptosis. The role of GRP78 as a potential prognostic biomarker is explored and current therapeutics in development aimed at targeting csGRP78 are addressed. We conducted a PubMed literature search using the keywords 'GRP78,' 'multiple myeloma' reviewing studies prior to 2020.Cell-surface GRP78 expression is a potential novel prognostic biomarker in myeloma and targeting of csGRP78 is promising and requires further investigation.

Multiple Myeloma (MM) accounts for 1-2% of all malignancies but is the second most common hematological malignancy. It is characterized by a proliferation of malignant plasma cells. The treatment paradigm of MM in Australia is traditionally hospital-based, complex, and costly. While MM comprises 1-2% of cancer diagnoses, it appears in the top 10 cancer diagnoses requiring hospital admission. The cumulative time spent receiving treatment is a significant burden for patients. The ability to receive treatment at home and maximize time away from hospital-based settings is a key preference for patients receiving anticancer therapies over a prolonged period of time.The Peter MacCallum Cancer Centre and Royal Melbourne Hospital's combined Clinical Hematology Unit has collaborated with their Hospital in the Home departments to develop several innovative programs to address this.We describe our current active programs and potential developments in home-based MM therapy.We have enabled large numbers of patients to receive complex therapies in their own home and the COVID-19 pandemic has increased the pace of the roll out without any compromise in safety. We anticipate that the next raft of immunotherapies will be able to transition into the @Home treatment setting in the coming years.

Background: Current therapies for multiple myeloma (MM) delay disease progression and prolong survival but most patients (pts) eventually relapse or become refractory (RR). Daratumumab (D), an anti-CD38 antibody (Ab), plus bortezomib (V), a proteasome inhibitor (PI) and dexamethasone (d), is approved for the treatment of MM in pts who have received ≥1 prior line of therapy. Venetoclax (Ven), a potent and selective oral BCL-2 inhibitor, demonstrated anti-myeloma activity in pts with t(11;14) RRMM. This 3-part Phase 1/2 study is investigating the combination therapy VenDd +/- V in pts with RRMM. Treatment of pts with t(11;14) RRMM using VenDd (part 1) and pts with RRMM (irrespective of t(11;14) status; part 2) with VenDVd demonstrated a tolerable safety profile and an overall response rate (ORR) of 95.8% and 91.7%, respectively (Bahlis N et al. J Clin Oncol 2021). Part 3 further evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM, with preliminary results presented here. Methods: Part 3 of this Phase 1/2, multicenter, dose-escalation and expansion study (NCT03314181) evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM. The study was expanded to further interpret the pt safety profile in light of the increased incidence of infections in pts in the Ven arm of the BELLINI study (Kumar SK et al. Lancet Oncol 2020). Pts were randomized 4:2:5 to receive VenDd at 400 (Ven400Dd) or 800 mg (Ven800Dd), or DVd. Randomization was not stratified due to small sample size. Eligible pts must have received ≥1 prior line of therapy, including an immunomodulatory agent (IMiD), and be non-refractory to PIs or anti-CD38 Ab. This interim analysis was conducted to evaluate the safety profile of pts in part 3 only. No statistical comparisons were conducted for safety or efficacy. Treatments in Part 3 were as follows: VenDd cycles (C) were 28-day: daily, oral Ven (400 mg or 800 mg) + D (1800 mg SC [Cycle, C1, 2: Days 1, 8, 15, 22; C3-6: Days 1, 15; C7+: Day 1]) + d (40 mg total weekly); DVd C1 - 8 were 21-day, C9+ were 28-day: D (1800 mg SC [C1 - 3: Days 1, 8, 15; C4 - 8: Day 1; C9+: Day 1]) + V (1.3mg/m 2 [C1 - 8: Days 1, 4, 8 and 11]) + d (20 mg [C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12 ,15; C4 - 8: Days 1, 2, 4, 5, 8, 9, 11,12; C9+: Day 1]). Results: As of 10 May 2021, 11, 7 and 16 pts were enrolled in the Ven400Dd, Ven800Dd and DVd arms, respectively. The median age (range) was Ven400Dd: 58.0 (42 - 75); Ven800Dd: 57 (53 - 82); and DVd: 68.5 (51 - 77). Median prior lines of therapy (range) were 1.0 (1 - 6) in Ven400Dd; 1.0 (1 - 3) in Ven800Dd; and 2.0 (1 - 3) in DVd. Pts with ISS I%/II%/III% disease were Ven400Dd: 54.5/9.1/0; Ven800Dd: 57.1/14.3/0; DVd: 25.0/25.0/31.3. All pts in the Ven400Dd and Ven800Dd arms had an ECOG performance status of ≤1. In the DVd arm, 87.5% and 12.5% of pts had a ECOG performance status of ≤1 and 2, respectively. Prior PI%/IMiD%/anti-CD38 Ab% exposure were Ven400Dd: 100/90.9/0; Ven800Dd: 100/100/0; DVd: 93.8/100/0. The most common adverse events (AEs) occurring in ≥5% of pts in ≥2 treatment groups included insomnia, fatigue, diarrhea, and nausea (Table). Grade 3/4 AEs (≥5% of pts in ≥2 treatment groups) were mainly hematologic toxicities (Table). There were no grade 3/4 infections occurring in ≥2 treatment groups. Serious AEs were observed in a total of 6 pts. In the Ven400Dd arm, 1 pt had a femur fracture and 1 pt had non-cardiac chest pain. In the Ven800Dd arm, 1 pt had febrile neutropenia and 1 pt had tonsil cancer. In the DVd arm, 1 pt had pyrexia and upper respiratory tract infection, and a second pt had hyperglycemia, autonomic neuropathy, distributive shock, disseminated cryptococcosis, and cytomegalovirus infection. No deaths were reported in part 3 of the study. The median treatment duration based on D exposure at the time of data cut was 6.5, 5.6, and 3.9 months for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The preliminary ORR was 72.7%, 100%, and 62.5% for the Ven400Dd, Ven800Dd, and DVd arms. The preliminary rate of very good partial response or better (≥VGPR) was 72.7%, 100%, and 31.3% for the Ven400Dd, Ven800Dd, and DVd arms. Follow-up is still immature, and responses may deepen with time. Conclusion: The preliminary results from part 3 of this novel randomized, phase 2 study of t(11;14)-selected RRMM pts treated with VenDd vs DVd demonstrate a tolerable safety profile. Updated analyses, including response rates with longer follow-up and minimal residual disease status, will be included at presentation. Figure 1 Figure 1. Disclosures Kaufman: Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; Sutro, Takeda: Research Funding; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Quach: Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baz: GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy; Merck: Research Funding; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding. Harrison: Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Celgene/ Juno/ BMS: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Plesner: Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding; Genmab, Genentech, Roche: Research Funding. Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Sehgal: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kang: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks 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. Lash-Fleming: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Bahlis: Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a potent and selective oral BCL-2 inhibitor being investigated in the treatment of relapsed/refractory multiple myeloma.

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that is currently being evaluated as a targeted therapy for the treatment of t(11;14) relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown promising efficacy with a tolerable safety profile in the phase 1/2 study (NCT03314181). VenDd is hypothesized to have increased anti-myeloma activity based upon complementary mechanisms of pro-apoptotic effects on tumor cells as well as potentially enhanced T-cell activation and clonal expansion, which has been shown to be associated with achieving deep sustained response to D-based therapy in MM. Results presented herein describe the immunomodulatory effects observed upon VenDd treatment in t(11;14) RRMM patients, including effects on the T-cell repertoire. Methods: Peripheral blood samples from t(11;14) RRMM patients (n=18) treated with VenDd (NCT03314181) were collected at day 1 of cycles 1-5 to characterize effects on B-, T-, and NK-cell populations by multicolor flow cytometry. TCRβ sequencing (ImmunoSEQ, Adaptive Biotechnologies) was also conducted on peripheral blood samples collected from t(11;14) RRMM patients (n=31) treated with VenDd at day 1 of cycles 1, 3, 5, and 9 to assess changes in T-cell clonality, defined as the extent of mono- or oligoclonal expansion by Simpson clonality index, and T-cell richness, defined as the number of clones with unique TCRβ rearrangements after computationally down-sampling to a common number of T-cells. Results: Consistent with previous findings with Ven, rapid and sustained depletion of B-cells (CD19+/CD5-) was observed in patients treated with VenDd (median absolute count: 115 cells/ml at baseline vs 13 cells/ml at C2D1 (89% decrease), p Conclusions: Treatment of t(11;14) RRMM patients with VenDd resulted in selective depletion of B-cells, NK-cells, and immunosuppressive regulatory T-cells, but not CD8+ T-cell subsets. Increased T-cell clonality indicates focusing of the T-cell repertoire and generation of an adaptive anti-myeloma immune response upon treatment with VenDd. The study is continuing with a randomized, open-label expansion that will further evaluate the safety and efficacy of VenDd in patients with t(11;14) RRMM, including correlative studies between the observed immune modifications and patient outcome. Figure 1 Figure 1. Disclosures Bahlis: Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman: Fortis Therapeutics: Research Funding; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy. Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: 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; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Genmab, Genentech, Roche: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mantis: AbbVie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Harrison: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: 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; Eusa: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that is being investigated as therapy for the treatment of relapsed/refractory multiple myeloma.

Patients with refractory relapsed multiple myeloma (RRMM) respond to Elotuzumab (Elo) and lenalidomide (Len) combination treatment. The mechanisms underlying this observation are not fully understood. Furthermore, predictive biomarkers of response have not been revealed to date. To address these issues, we used a humanized myeloma mouse model and adoptive transfer of human NK cells to show that Elo and Len treatment controlled myeloma growth, and this was mediated through CD16 on NK cells. In co-culture studies, we showed that PBMCs from a subset of RRMM patients were effective killers of OPM2 myeloma cells when treated with Elo and Len, and this was associated with significantly increased expression of CD54 expression on OPM2 cells. Furthermore, Elo and Len induced OPM2 cell killing and increased OPM2 CD54 expression was dependent on both monocytes and NK cells, and was not mediated by soluble factors alone. At the transcript level, Elo and Len treatment significantly increased OPM2 myeloma cell expression of genes for trafficking and adhesion molecules, NK cell activation ligands and antigen presentation molecules. In conclusion, our findings suggest that MM patients require Elo and Len-mediated upregulation of CD54 on the autologous myeloma cells, in combination with NK cells and monocytes to mediate an effective anti-tumour response. Further, our data suggest that increased myeloma cell CD54 expression levels could be a powerful predictive biomarker for response to Elo and Len treatment.

Simple Summary Myeloma is a common cancer involving the bone marrow. Some of the medications used in the treatment of myeloma, including those that reduce the risk of bone fractures, can increase the chance of side effects occurring in the jawbone. The most serious complication in the jawbone is called medication-related osteonecrosis, meaning part of the jawbone dies. The aim of this review is to highlight some of the medications that are implicated and other risk factors that can contribute to osteonecrosis. Suggestions to prevent this complication from occurring are described. Conventional methods of treating established medication-related osteonecrosis of the jawbone are outlined as well as emerging new treatments. Abstract Myeloma is a common haematological malignancy in which adverse skeletal related events are frequently seen. Over recent years, treatment for myeloma has evolved leading to improved survival. Antiresorptive therapy is an important adjunct therapy to reduce the risk of bone fractures and to improve the quality of life for myeloma patients; however, this has the potential for unwanted side effects in the oral cavity and maxillofacial region. Osteonecrosis of the jaw related to antiresorptive medications and other myeloma therapies is not uncommon. This review serves to highlight the risk of osteonecrosis of the jaw for myeloma patients, with some suggestions for prevention and management.

Background Although responsible for significant mortality and morbidity, our knowledge of modifiable causes of multiple myeloma (MM) remains limited. This analysis of an Australian population-based case-control family study investigated associations between smoking and alcohol consumption and MM risk. Methods Incident cases (n = 789) of MM were recruited mainly via cancer registries in Victoria and NSW. The controls included in the analysis (n = 1,113) were either family members of cases (n = 696) or recruited as part of a similarly designed case-control family study of renal cancer (n = 417). Unconditional multivariable logistic regression was used to estimate ORs, 95% CIs and p-values for associations between alcohol- and tobacco-related exposures and risk of MM. Results Heavy drinkers of alcohol had lower MM risk compared with non-drinkers (OR = 0.68, 95% CI = 0.50 – 0.93), and there was an inverse dose-response relationship for alcohol intake (OR per 10g ethanol per day = 0.92, 95% CI: 0.86 – 0.99); there was no evidence of interaction with sex (p = 0.27). There was no evidence of association between smoking-related exposures and MM risk. Conclusions These findings extend the knowledge of MM risk factor epidemiology. Further research into the causality of the association of alcohol with MM risk and potential underlying mechanisms is recommended. Key messages We found alcohol consumption to be inversely associated with risk of multiple myeloma.