In total, 1630 individuals were screened for MBL and MGUS; 1151 (70.6%) were negative for both, 275 (16.9%) identified to have MBL only, 147 (9.0%) identified to have MGUS only, and 57 (3.5%) identified to have both MBL and MGUS (Table 1). Individuals with MBL only were, on average, older than those without MBL/MGUS (median 70 vs. 63 years of age, respectively, p < 0.001) and were more likely to be male (54.5% vs. 41.0%, respectively, p < 0.001). CLL-like MBL was the most common MBL subtype (87.3%), followed by non-CLL-like (8.4%), and atypical MBL (4.4%). Individuals with MGUS only were also older than those without MBL/MGUS (median 68 vs. 63 years of age, respectively, p < 0.001); however, there was no significant difference in sex (p = 0.13). Non-IgM (86.0%), and particularly IgG MGUS (63.5%), were the most common MGUS isotypes.

Among the 57 individuals with both MGUS and MBL, 49.1% were male and median age was 72 years (Table 1). The frequency of MBL and MGUS coexisting was 3.5%, which is higher than the 0.4% reported previously [13]. This discrepancy is likely due to the higher sensitivity of MGUS detection used in the current study [15]. When restricted to the detection metrics of M-spike >0.2 g/dl, the frequency of those with MBL and MGUS was similar to the prior report (0.8%), although the prior publication was unclear of their M-spike threshold.

A subset of 918 individuals were sequenced for CH, of whom 249 (27.1%) had CH detected. Genes DNMT3A, TET2, and ASXL1 (DTA-CH) made up 65.1% of the CH carriers (Table 1).

Although CH screening was not available on the entire cohort, it was complete for those with both MBL and MGUS (Table 1), allowing for accurate estimates of all three conditions. In total, 17 (1.0%) individuals concurrently had all three premalignant conditions. These individuals were 47% male with a median age of 78 years. CLL-like MBL was the most common MBL subtype (47.1%) and non-IgM MGUS were the most common MGUS isotypes (73.7%).

Further, CH screening was available on all but 2 individuals with MBL from the full cohort, allowing for accurate estimate of the prevalence of CH and MBL. In total, 92 (5.6%) out of the1,630 individuals concurrently had MBL and CH. We did not have sequencing completed on all MGUS in the full sample and thus were unable to estimate their co-occurrence.

The associations among these premalignant conditions are shown in Fig. 1. There was an elevated OR for the association of MGUS overall with MBL (OR = 1.29, 95% CI: 0.91–1.81, p = 0.15) which did not reach statistical significance. The OR was highest for IgA MGUS 1.59 (95% CI: 0.70–3.42), but small sample sizes limited power for subtype specific associations.

DTA CH: DNMT3A, TET2, or ASXL1 somatic mutation carrier.

When we subset to individuals with CLL-like MBL, there was no evidence of an association between MGUS overall and CLL-like MBL (OR = 1.10, 95% CI: 0.75–1.60, p = 0.62, Fig. 1). Similarly, there was no evidence of an association between CLL-like MBL and non-IgM MGUS or any of the MGUS isotypes, although power was limited for these MGUS isotype analyses. Moreover, there was no statistical evidence of an association between CH and MBL overall or with CLL-like MBL (ORs 1.03 and 0.87, respectively). There was also no evidence of an association between DTA-CH and MBL overall or CLL-like MBL (ORs 0.96 and 0.85, respectively). When investigating the relationship between CH and MGUS, we found no statistical evidence of an association, although there may be an inverse relationship between CH and MGUS (Fig. 1), like the nonsignificant association in Da Via et al. [14]. The results were similar when analysis was limited to individuals with CH who had a VAF > 2% (Supplementary Table 2) [2].

Lastly, there are 19 genes in our CH gene list (Supplementary Table 1) that are also recurrently mutated in lymphoid malignancies. Because MBL and MGUS are precursors to lymphoid malignancies, we restricted our CH definition to exclude these 19 genes and found similar results to our overall analysis (Supplementary Table 2).

In summary, this study of 1630 individuals found no statistical evidence of a relationship among risk of common hematological premalignant conditions. Particularly, we found no evidence of associations between MGUS with CLL-like MBL or between CH with CLL-like MBL. However, further studies are needed to evaluate associations among the rare subtype conditions due to limited sample size herein. Overall, these results suggest these premalignant conditions do not appear to cluster together. Future studies are needed to investigate whether those with two or more of these conditions have increased clinical phenotypes (e.g., cytopenias, cancers, infections) or mortality compared to those with only one or no premalignant condition.