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Summary: Multiple myeloma (MM) and anti‐MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID‐19) and other infections. We investigated anti‐severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) antibodies longitudinally in ultra‐high‐risk patients with MM receiving risk‐adapted, intensive anti‐CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross‐reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID‐19, even with intensive anti‐CD38 therapy for high‐risk MM. [ABSTRACT FROM AUTHOR]

Summary: Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1–21 of each 28‐day cycle), or in combination with vorinostat (300 mg/day on day 1–7 and 15–21 of each 28‐day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression‐free survival between those receiving lenalidomide‐vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96–1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76–1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide‐vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end‐point, there was no benefit from the addition of vorinostat to lenalidomide maintenance. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty‐one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression. [ABSTRACT FROM AUTHOR]

Summary: Second‐generation immunomodulatory agents, such as lenalidomide, have a more favourable side‐effect profile than the first‐generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant‐ineligible myeloma (ND‐TNE‐MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND‐TNE‐MM. CRDa deepened response but did not improve progression‐free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND‐TNE‐MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual. [ABSTRACT FROM AUTHOR]

Summary: The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re‐induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high‐risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow‐up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16–26) vs. 11 months (9–12), hazard ratio [HR]: 0·40, 95% CI: 0·29–0·56, P < 0·001), on which the presence of any single high‐risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59‐not reached) vs. 55 months (44–67), HR: 0·64, 95% CI: 0·42–0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty‐one (24·7%) cyclophosphamide patients received an ASCT post‐trial, median OS was not reached (95% CI: 39‐not reached) for these participants compared to 31 months (22–39), in those who did not receive a post‐trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high‐risk patients, highlighting the need for targeted study in this patient group. [ABSTRACT FROM AUTHOR]

IgM myeloma is a very rare and poorly defined entity. In a detailed assessment of 10 cases, it was demonstrated that 70% had an aberrant phenotype based on the expression of CD19, CD45, CD27 and Cyclin D1 but all cases lacked CD56 and CD117. Interphase fluorescence in situ hybridization demonstrated deletion 13 in 50% while 5/8 cases assessed had a t(11;14). Despite the high incidence of the t(11;14), CD20 was only expressed in one of nine cases. We conclude that IgM myeloma is a distinctive subset characterized by a CD20−CD56−CD117− phenotype and the t(11;14). [ABSTRACT FROM AUTHOR]

Plateau phase has been achieved in 64% of all newly diagnosed patients with multiple myeloma treated with the ABCM (adriamycin, BiCNU, cyclophosphamide and melphalan) regimen in the Medical Research Council (MRC) trials; this stable clinical stage of the disease is associated with no more than minimal symptoms. Several studies have found that α-interferon (α-IFN) maintenance therapy increases the duration of plateau phase, but it is less clear if this translates into prolonged survival. We report the effect of α-IFN on the duration of plateau phase and overall survival in a trial with 284 patients who were randomized to receive α2b-IFN (Intron-A) or no maintenance therapy during first plateau phase. The minimum follow-up after randomization was 21 months. There was no significant difference in the overall survival between the two treatment groups (χ2 = 0.32, P = 0.57). There was a trend towards longer relapse-free survival in the patients allocated α-IFN, but this trend to longer plateau phase was not statistically significant (χ2 = 1.62, P = 0.2). Disease progression at relapse on α-IFN appears to be more severe with greater elevations from plateau levels of serum paraprotein (P = 0.06) and β2-microglobulin (P = 0.03) levels. Physicians tended to start chemotherapy sooner after diagnosis of relapse when patients had received α-IFN (P = 0.16). Although, in common with most other studies, there is a trend for patients treated with α-IFN to have a longer plateau phase, this is counteracted by morbidity attributable to the treatment and a somewhat shortened survival post relapse. Meta-analysis of interferon trials is required to assess whether the minor trend for longer survival in patients maintained on α-IFN found in some studies is significant and, if so, the extent of this advantage. [ABSTRACT FROM AUTHOR]

IgM myeloma is a very rare and poorly defined entity. In a detailed assessment of 10 cases, it was demonstrated that 70% had an aberrant phenotype based on the expression of CD19, CD45, CD27 and Cyclin D1 but all cases lacked CD56 and CD117. Interphase fluorescence in situ hybridization demonstrated deletion 13 in 50% while 5/8 cases assessed had a t(11;14). Despite the high incidence of the t(11;14), CD20 was only expressed in one of nine cases. We conclude that IgM myeloma is a distinctive subset characterized by a CD20-CD56-CD117- phenotype and the t(11;14).