Monoclonal Gammopathy of Undetermined Significance

-        Highlights: the findings of a recent study indicate that recommendations to routinely screen patients with autoimmune and autoinflammatory diseases for monoclonal gammopathy of undetermined significance (MGUS) may not be warranted.

A recent cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma [MM]), a prospective, population-based screening study of MGUS was published. 75,422 persons ≥ 40 years were screened. A total of 10,818 participants had an autoimmune disorder, of whom 599 (5.5%) had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A Poisson regression to estimate prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex, was carried out. A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). Included were patients with autoimmune diseases (systemic involvement, organ-specific, and seronegative) and autoinflammatory diseases [see Table 1 of original research]); this was determined by the presence of International Classification of Disease diagnosis codes for 42 autoimmune diseases at any time before or after the registered date of screening for MGUS. The study did not find an association between autoimmune disease and MGUS in a systematically screened population. The findings indicate that recommendations to routinely screen patients with autoimmune and autoinflammatory diseases for MGUS may not be warranted. However, the use of coded diagnoses has not been shown to be applicable to autoimmune/autoinflammatory disorders. The homogeneity of the Icelandic population may limit the generalizability of these results.

Multiple myeloma and minimal residual disease

-        Highlights: in patients with multiple myeloma (MM),minimal residual disease (MRD)-negativity at 12 months reduced the risk of progression; the treatment effect on MRD was correlated with the treatment effect on progression-free survival (PFS).

MRD-negativity in MM (determined by a validated bone marrow-based assay able to detect at least 1 myeloma cell in 100,000 tested cells [assay sensitivity of 10^-5]) is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with MM. A recent meta-analysis evaluated MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring the endpoint of MRD-negativity in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization.  Eight newly diagnosed MM(NDMM)studies evaluating 4,907 patients were included. The median follow-up for PFS was 29 months (interquartile range [IQR] 19-58), and the median follow-up for overall survival (OS) was 37 months (IQR 22-59). Trial-level associations between MRD-negativity and PFS were R²WLSiv (linear regression) (95% confidence interval [CI]) 0.67 (0.43-0.91) and R²copula (Copula bivariate) 0.84 (0.64->0.99) at the 12-month time point, as surrogacy models. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46).  The global odds ratio demonstrated strong individual-level associations between 12-month MRD-negativity and PFS, as well as between 12-month MRD-negativity and OS, for both the all-NDMM population (PFS: 4.72 [95% CI: 3.53-5.90], OS: 4.02 [95% CI: 2.57-5.46]).  For relapsed/refractory MM four studies were included comprising 1,835 patients in total. The median follow-up for the included studies was 37.7 months (22-54.2) for PFS and 38.7 months (IQR 26.3-43.8) for OS. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio of 7.67 (95% CI: 4.24-11.10). Trial-level correlations could not be estimated with only four studies. A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM.

Multiple myeloma and chimeric antigen receptor-T cell therapy

-        Highlight(s):In relapsed/refractory multiple myeloma (MM) patients, the maximum absolute lymphocyte count (ALCmax) in the first 15 days after B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR)-Tcell infusion is  associated with deeper response and occurrence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ALCmax <0.5 x10³/uL is predictive of non-responders, while that of >1.0 x10³/uL is an independent prognostic biomarker for sustained response.

BCMA-targeting CAR-Tcell expansion post-infusion has been shown to inform depth and duration of response, but measuring this process remains investigational. An interesting recent study describes the kinetics and prognostic impact of ALC in the first 15 days  after CAR-T cell infusion in 156 relapsed MM patients treated with the BCMA-targeting agents cilta-cel and ide-cel. Patients with higher ALCmax had better depth of response, progression-free survival (PFS), and duration of response (DoR). Patients with ALCmax >1.0 x10³/uL had a superior PFS (30.5 versus 6 months, p <0.001) compared to those ≤1.0x10³/uL, while patients with ALCmax ≤0.5 x10³/uL represent a high-risk group with early disease progression and short PFS (hazard ratio [HR] 3.4, 95% CI: 2.0-5.8, p<0.001). In multivariate analysis, ALCmax >1.0 x10³ /uL and non-paraskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for internationa staging system, age, CAR-T cell product, high-risk cytogenetics, and number of previous lines. They report for the first time the association of ALC after BCMA CAR-T cell infusion with clinical outcomes and its utility in predicting response in relapsed/refractory MM patients. ALCmax in the first 15 days after BCMA CAR-T cell infusion is associated with deeper response and occurrence of CRS and  ICANS. The presence of  CRS was associated with higher ALCmax for all patients, with an odds ratio (OR) of 5.16  (95% CI 1.4 – 18.7, p=0.018) and for those receiving cilta-cel (OR 12.6, 95% CI 1.7 –93.0 p=0.013). There was an association between ALCmax and presence of CRS in the ide-cel group which was not statistically significant (OR 1.38, 95% CI 0.77 – 1.7,p=0.1). Similarly, the presence of  ICANS was associated with higher ALCmax in the pooled cohorts (OR 6.6, 95% CI 1.8 – 24.5, p=0.005) and in both cilta-cel (OR 13, 95% CI 1.9– 90.1, p=0.009) and ide-cel (OR 1.57, 95% CI 1.03 - 2.03, p=0.03) groups. Interestingly, patients who developed late neurotoxicity had higher ALCmax compared to those who did not (4.3 vs. 1.1 x10³ /uL, p=0.02).

Relapsed/refractory large B‐cell lymphoma

-        Highlight(s): patients with relapsed/refractory large B‐cell lymphoma (R/R LBCL) who have very early progression after chimeric antigen receptor (CAR)-T cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and bispecific antibodies (BsAbs), can achieve prolonged survival after CAR-T cell therapy failure.

Recently published was a retrospective multicenter study that analyzed 387 R/R LBCL patients who progressed after CAR-T cell therapies (after third or later line treatment withaxicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel),with disease progression after CAR- Tcell therapy at a median of 2.6 months from infusion. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression: those who progressed within 2 months of the CAR-Tcell infusion had a significantly shorter median progression-free survival (2.7 months) in comparison to patients who progressed between 2 to 6 months (4.0 months [hazard ratio, HR 0.58, 95% CI: 0.4–0.8]) and later than 6 months (not reached [HR 0.25, 95% CI: 0.1–0.5]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall  response rates were 67% for polatuzumab–bendamustine–rituximab (POLA), 51% for BsAb, 45% for radiotherapy (RT), 33% for immune checkpoint inhibitors (ICIs), 25% for lenalidomide (LENA), and 25% for chemotherapy (CT).  In terms of survival, 12‐month progression‐free survival and OS were 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICIs, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT, respectively. Thirty‐two (14%) patients received an allogeneic hematopoietic cell transplantwith median OS not reached after a median follow‐up of 15.1 months.