For how long has this problem been there?

One of the most frequent questions asked by patients with monoclonal gammopathies is “Doctor, how long has this problem been there?” To this question, answers vary: Sometimes scavenging medical records will reveal the presence of a gammopathy years before; other times the doctor will simply state that this process usually takes a long time to develop. In this issue of Blood, using whole-genome sequencing and advanced analyses, Samur et al¹ provide new context to the current knowledge of monoclonal gammopathies initiation and progression.

Hyperdiploidy is considered an initiating event in multiple myeloma. In newly diagnosed hyperdiploid multiple myeloma cases, the authors analyzed the number of mutations acquired before and after the chromosomal gains to assess the mutational rate pre- and postgain, and to estimate the time window of acquisition of each trisomy. Furthermore, by subsetting mutations only belonging to clock-like signatures---that is, those created by processes that have stable activity over time---they were able to estimate the patient age at the time of acquisition of the first and last chromosomal gain. The results show that not all chromosomal gains are acquired at the same time, with trisomies of chromosomes 9, 15, and 19 being acquired earlier, on average. Initiation of hyperdiploidy occurs at a much earlier age than expected, that is, on average by the first 3 decades of life and takes about 8 years to complete. The subsequent evolution to a clinically overt diagnosis of myeloma does not occur for decades. During this time, the clonal plasma cells continue acquiring mutations at an even higher rate than beforehand, through activation of aberrant mutagenic processes that were not present previously, enhancing their growth potential.

These results confirm previously published findings obtained by similar analyses in unrelated data sets,^2,3 and complement recently presented evidence that even hyperdiploidy itself can be preceded by other clonal aneuploidies,⁴ challenging its status of “initiating” event. This new body of evidence opens a new field of investigation in the preclinical evolution of clonal plasma cell neoplasia. Traditionally, we would time the initiation of a plasma cell dyscrasia with the appearance of a monoclonal gammopathy using serum protein electrophoresis. This work by Samur et al, along with others, suggests that the presence of clonal plasma cells likely precedes the clinical detection of a monoclonal protein by decades, providing an unexpected, more informed answer to the patient’s question presented above.

However, there are more questions raised than answers given by these novel findings. One is related to the actual prevalence of clonal plasma cell conditions in the overall population. This point has been experimentally addressed by several other investigators using population-wide screening in the iStopMM trial,⁵ or through more sensitive methods in the high-risk population of the PROMISE study.⁶ The former approach revealed a previously unexpected prevalence of smoldering myeloma of 0.53% in individuals ≥40 years of age. The latter study showed that 43% of individuals ≥50 years of age had evidence of a monoclonal protein by mass spectrometry of serum proteins. Altogether, this body of evidence implies that clonal plasma cells should exist in healthy people at a stage when a monoclonal protein is not detectable by any means, and that the actual prevalence of plasma cell clonality is higher than expected by several orders of magnitude than what would be found using standard methods (see figure). Once hard to believe, this model should be less surprising today thanks to recent works demonstrating the near universal age-dependent loss of clonal diversity in the hematopoietic⁷ and other tissues of healthy individuals.

Taken to its extreme consequences, the concept that most (all?) human beings harbor a multitude of small clones in their tissues as they age brings us to another relevant question: If loss of clonal diversity is a pervasive feature of human aging, where do we draw a line between the presence of clonal cells and a clinically relevant neoplastic condition? In other words, although this new evidence provided by Samur et al is extremely intriguing from a biological point of view, will this also be clinically meaningful for patients? Indeed, most people with clonal plasma cells will likely not ever progress to development of a monoclonal protein in serum. However, knowing the actual prevalence of plasma cell dyscrasias and their mode of development over time may provide us with opportunities to screen and possibly intercept the rare cases that have the potential to evolve into a clinically aggressive neoplasia. This would require that the genomic findings are first validated through ultrasensitive detection of clonal plasma cells in samples of healthy people. Furthermore, cell-intrinsic and cell-extrinsic determinants of progression need to be well characterized at this early stage if they are to be used as prognostic markers for clinical purposes. Samur et al report on the differential activity of mutational processes before and after the acquisition of clonality, suggesting that analysis of mutational signatures may have prognostic value in this respect, as suggested in other studies.^3,8,9 This and other opportunities provided by genomic and single-cell research are likely to help predict the risk of evolution of asymptomatic gammopathies by moving from surrogates of disease burden in favor of actual biological determinants of disease progression.¹⁰ 

Conflict-of-interest disclosure: N.B. served on the advisory board for Takeda, Pfizer, and Johnson & Johnson and on the speakers bureau for Amgen, GlaxoSmithKline, Johnson & Johnson, Jazz, Pfizer, Oncopeptides, Sanofi, and Takeda. and received unrestricted research funding from Johnson & Johnson. M.C.D.V. served on the advisory board for Takeda, Pfizer, Menarini-Stemline, Amgen, and Johnson & Johnson, and on the speakers bureau for Johnson & Johnson, Sanofi, and GlaxoSmithKline, and received unrestricted research funding from Pfizer.