Georgia McCaughan

Cardiac amyloidosis is an under-recognised but treatable cause of heart failure, particularly in older adults. Early recognition of its clinical features can facilitate timely investigation and referral for treatment with disease-modifying therapies. This article provides a practical approach to recognition, investigation and referral.

Whilst the clearance of minimal residual disease (MRD) in the bone marrow is now an accepted therapeutic end-point in multiple myeloma (MM), less is known about the early clearance of circulating tumour cells (CTC). We assessed 41 MM patients receiving daratumumab, bortezomib and dexamethasone as second-line treatment and measured CTC using Euroflow next-generation flow cytometry prior to treatment, at day 8 and at day 21. Clearance of CTC on day 8 and day 21 was associated with improved PFS, with the most significant difference between persistent and cleared CTC observed on day 8 (median PFS 11.4 vs 32 months, p=0.0009). The association between pre-treatment CTC level and PFS did not reach statistical significance. In patients with standard risk genetics, CTC persistence was associated with worse outcomes, suggesting that this measure may identify clinically aggressive disease independent of genetics. This data raises the possibility of measuring CTC clearance very early in treatment to predict outcome, and identify patients suitable for prospective evaluation of response-adapted approaches.

Summary: SeaLAND (ALLG MM23, ACTRN12620000291987) was a randomized, open‐label phase III study evaluating low‐dose weekly selinexor (40 mg) plus lenalidomide (selinexor‐R) versus lenalidomide alone (R) as post‐transplant maintenance therapy for newly diagnosed, transplant‐eligible multiple myeloma. A total of 142 patients were enrolled (R = 64; selinexor‐R = 78); the trial closed early for futility. At best response, the complete response (≥CR) rate was numerically, but not significantly, higher with selinexor‐R than R (67% vs. 53%, p = 0.09). At 24 months median follow‐up, progression‐free survival (PFS) was not significantly different between selinexor‐R compared to R (hazard ratio [HR] = 1.22; 95% confidence interval [CI] 0.62–2.41; p = 0.56); 24‐month PFS rates were 73% (95% CI 57%–84%) for R and 70% (95% CI: 56%–81%) for selinexor‐R. The mean relative dose intensity (RDI) of R was lower in the selinexor‐R arm compared to R alone (68% vs. 81%, p = 0.002); the mean RDI of S was 55%. Grade ≥3 adverse events were more frequent with selinexor‐R (85% vs. 45%, p < 0.001). Common severe non‐haematological adverse events included infections (R: 6%, selinexor‐R: 19%, p < 0.01) and gastrointestinal disorders (R: 3%, selinexor‐R: 14%, p < 0.05). Selinexor‐R maintenance did not improve PFS and substantially increased toxicity. Selinexor‐R maintenance cannot be recommended for the general myeloma population; we did not observe a benefit among high‐risk disease.

Bispecific antibodies (bsAbs), such as teclistamab, elranatamab, linvoseltamab, and talquetamab, have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes IV and subcutaneous (SC) immunoglobulins, may lower these risks. In this viewpoint, we contrast primary IgRT prophylaxis (initiation regardless of IgG levels) with preemptive IgRT treatment (initiation only once IgG levels fall below a certain threshold) in this setting. We make evidence-based arguments for primary prophylaxis as a safer and simpler approach than preemptive IgG-guided IgRT. We also discuss strategies to improve the cost-effectiveness of IV and SC immunoglobulins across the world. Given the overwhelmingly favorable benefit-risk profile of IgRT, coupled with the limitations inherent to IgG measurements in MM, withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM who are receiving bsAb therapy.

The survival of newly diagnosed patients with multiple myeloma has improved significantly over the past 20 years with significant therapeutic advances. Despite this, high‐dose chemotherapy followed by autologous stem cell transplantation remains the standard of care in newly diagnosed patients who are considered transplant eligible. Here, we summarise the recommendations of the Medical and Scientific Advisory Group of Myeloma Australia for patients considered suitable for high‐dose chemotherapy and autologous stem cell transplantation as part of the initial therapy.

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real‐world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia‐Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow‐up time of 29.5 months (interquartile range 13.3–54.3 months) were included in the analysis – 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in‐situ hybridisation status, receive first‐line myeloma treatment with immunomodulatory drugs or anti‐CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow‐up (adjusted hazard ratio 0.72, 95% CI 0.46–1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

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