The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies.

Treatment outcomes in multiple myeloma (MM) have improved dramatically over the past 10 years. However, patients with high-risk disease such as those with Stage III disease by the Revised International Staging System, the presence of adverse cytogenetics, or who are refractory to proteosome inhibitors, immunomodulatory drugs and monoclonal antibodies may have dismal outcomes. These patients represent an urgent ongoing need in MM. One of the hallmarks of MM is immune dysfunction and a tumour-permissive immune microenvironment. Ameliorating the immune-paresis could lead to improved outcomes. The role of immunotherapies has been growing at an exponential pace with numerous agents under development in clinical trials. In the present review, we provide an overview of immunotherapies in MM, focussing on bispecific antibodies (BsAbs). We review efficacy outcomes from the published clinical trials and consider the important safety aspects of these therapies, in particular the risk of cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome, and how these compare with patients receiving chimeric antigen receptor T cells. We discuss the MM epitopes being targeted by BsAbs, either in clinical or preclinical stages, and we consider where these therapies might best fit within the future ever-changing paradigm of MM treatment.

VEXAS syndrome: A dermatological perspective.

VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a genetically defined disorder identified in 2020, describing patients with inflammatory syndromes associated with haematological dysfunction. It is a severe, treatment-resistant condition, with estimated mortality between 40% and 63%. A wide range of cutaneous manifestations have been described. Here, we report on two patients with treatment-resistant neutrophilic dermatosis and myelodysplastic syndrome, who were subsequently diagnosed with VEXAS syndrome. Our cases highlight the need for dermatologists' awareness of this novel condition and to initiate early referral to haematologists for appropriate multidisciplinary care.

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Autologous stem cell transplantation in elderly multiple myeloma patients aged ≥65 years: a two-centre Australian experience.

There are currently limited Australian data on the outcomes of autologous stem cell transplantation (ASCT) in elderly multiple myeloma (MM) patients. We present the largest cohort of elderly MM patients aged ≥65 years undergoing ASCT in Australia and report their outcomes based on our two-centre experience. Our study affirms that ASCT is well tolerated, safe and effective in elderly MM patients aged ≥65 years and should be considered an important component of treatment in patients who are fit enough for the procedure.

Consensus guidelines for improving patients' understanding of invasive fungal disease and related risk prevention in the haematology/oncology setting, 2021.

Patients with invasive fungal disease (IFD) are at significant risk of morbidity and mortality. A productive partnership between patients, their carers/families, and the multidisciplinary team managing the infection and any underlying conditions, is essential. Sharing information and addressing knowledge gaps are required to ensure those at risk of IFD avoid infection, while those with suspected or confirmed infection optimise their therapy and avoid toxicities. This new addition to the Australian and New Zealand consensus guidelines for the management of IFD and antifungal use in the haematology/oncology setting outlines the key information needs of patients and their carers/families. It specifically addresses risk factor reduction, antifungal agents and adherence, and the risks and benefits of complementary and alternative therapies. Knowledge gaps are also identified to help inform the future research agenda.

Recent advances in therapy of chronic lymphocytic leukaemia.

The last 5 to 10 years have been marked by considerable advances in both our understanding of the biology and treatment of chronic lymphocytic leukaemia (CLL). Fludarabine-based immuno-chemotherapy is the current standard of care for first line therapy in younger fit patients and although this can be highly effective its use in older co-morbid patients is limited by toxicity, and the prognosis for patients with high risk or fludarabine-refractory disease is poor. The introduction of new antibodies has however, facilitated the use of immuno-chemotherapy in co-morbid patients. Beyond this, the recognition that CLL cells are critically dependent on B-cell receptor (BCR) signalling and interactions with the cellular micro-environment for proliferation and survival has led to the investigation of BCR inhibitors in CLL treatment. These have been shown to be highly effective although a number of questions remain about how they should be optimally used in clinical practice.

The prognostic impact of t(11;14) in multiple myeloma: A real-world analysis from the Australian Lymphoma Leukaemia Group (ALLG) and the Australian Myeloma and Related Diseases Registry (MRDR).

The prognostic impact of t(11;14) in multiple myeloma (MM) needs to be better understood to inform future treatment decisions. The Australian Lymphoma Leukaemia Group embarked on a retrospective, observational cohort study using real-world data to interrogate treatment patterns and outcomes in 74 MM patients with t(11;14) [t(11;14)-MM] diagnosed over 10 years. This was compared to 159 and 111 MM patients with high-risk IgH translocations (IgH HR-MM) and hyperdiploidy (Hyperdiploid-MM), respectively, from the Australian Myeloma and Related Diseases Registry. No appreciable differences in age, gender, ISS, LDH levels, 1q21 or del(17p) status, or treatment patterns were observed between groups. Median PFS-1 was not different between groups but both t(11;14)-MM and IgH HR-MM had an inferior PFS-2 vs. Hyperdiploid-MM: median PFS-2 8.2 months, 10.0 months, and 19.8 months (p = 0.002), respectively. The 3-year OS were 69%, 71%, and 82% (p = 0.026), respectively. In the t(11;14)-MM group, gain or amplification of 1q21 at diagnosis predicted for poorer OS (HR 3.46, p = 0.002). Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.

Outcomes Following Extracorporeal Photopheresis for Chronic Lung Allograft Dysfunction Following Lung Transplantation: A Single-Center Experience.

INTRODUCTION: Survival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD. METHODS: A retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV1) within 6 weeks of commencing therapy. RESULTS: Mean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP. CONCLUSION: Rescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.

The development of a home-based therapeutic platform for multiple myeloma.

BACKGROUND: 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. METHODS: 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. RESULTS: We describe our current active programs and potential developments in home-based MM therapy. CONCLUSION: 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.