FormalPara Key Summary Points

Monoclonal gammopathy of undetermined significance is an asymptomatic plasma cell disorder characterised by a serum M protein level below 3 g/dL, percentage of bone marrow clonal plasma cells below 10%, absence of end-organ damage and absence of any other disease known to produce M protein

Monoclonal gammopathy of undetermined significance may progress to myeloproliferative disorders or multiple myeloma, but very little is known about any modifiable risk factors or any preventative treatment that might delay this progression

Metformin has begun to be discussed as a potentially useful agent in monoclonal gammopathy of undetermined significance as it has been demonstrated that it may be beneficial in patients with leukaemia, lymphomas and multiple myeloma

Although dedicated studies are currently very limited, it would appear that there may be hope for reducing progression of monoclonal gammopathy of undetermined significance to multiple myeloma with metformin in type 2 diabetes mellitus

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder characterised by a serum M protein level below 3 g/dL, percentage of bone marrow clonal plasma cells below 10%, absence of end-organ damage (hypercalcaemia, renal insufficiency, anaemia, bone lesions) and absence of any other disease known to produce M protein [1]. MGUS is encountered in 1.11% of Chinese, 3.2% of Caucasian and 3.7% of African-American adults at least 50 years old and may progress to myeloproliferative disorders or multiple myeloma [1, 2]. Importantly, very little is known about any modifiable risk factors or any preventative treatment that might delay progression [2, 3].

In this context, metformin has begun to be discussed as a potentially useful agent. Its postulated actions may be manifold. Indeed, on the basis of epidemiological and preclinical research, this agent may be beneficial in patients with leukaemia, lymphomas and multiple myeloma [4, 5]. Metformin might reduce pro-inflammatory soluble mediators (e.g. interleukin-6 and insulin-like growth factor 1 (IGF1) [6]. Moreover, it may improve T cell and immune suppressor cell function, increasing anti-tumour activity [7]. Of note, reduction of insulin and IGF1 production with increased insulin sensitivity due to metformin are considered to reduce progression of MGUS to multiple myeloma [8, 9]. Finally, metformin activates the adenosine monophosphate-activated protein kinase signalling pathway, which induces apoptosis of myeloma cells and contributes to suppression of bone resorption [10].

Metformin studies dedicated to MGUS are currently very limited. We performed an electronic search in PubMed, Google Scholar and SCOPUS databases until February 2022 using combinations of the following keywords: MGUS; metformin; monoclonal gammopathy of undetermined significance; multiple myeloma; progression; type 2 diabetes mellitus. Only publications in English were considered.

Chang et al. [11] retrospectively studied 3287 US veterans with MGUS and type 2 diabetes mellitus (T2DM). Metformin users exhibited a lower risk of progression to multiple myeloma than non-users. In their sensitivity analyses, in which they explored metformin use 2–6 years after T2DM diagnosis, the following hazard ratio (HR) and 95% confidence interval (CI) were identified, depending on years of metformin therapy: HR 0.76, 95% CI 0.48–1.12 for 2-year use; HR 0.63, 95% CI 0.38–1.05 for 3-year use; HR 0.50, 95% CI 0.23–1.06 for 5-year use; HR 0.58, 95% CI 0.24–1.40 for 6-year use [11]. In metformin users, significantly reduced incidence of multiple myeloma (3% vs. 5%) and significantly increased median time of progression to multiple myeloma (71 vs. 47 months) were seen [11].

Two case–control studies have looked at the utility of metformin [12, 13]. Boursi et al. [12] identified 124 MGUS cases progressing to multiple myeloma. Subjects with T2DM but without antidiabetic therapy exhibited no increased risk of developing multiple myeloma (odds ratio [OR] 0.96, 95% CI 0.38–2.38). In contrast, metformin-treated subjects with T2DM had a non-significant reduction of this risk (OR 0.39, 95% CI 0.14–1.13) [12]. The same held true for other antidiabetic agents (sulfonylureas, thiazolidinediones and insulin) without metformin (OR 0.17, 95% CI 0.02–1.28). Thus, metformin appeared protective, but wide confidence intervals precluded significance and this applied also to other antidiabetic agents [12]. Similarly, another study of 2363 patients with MGUS and 9193 controls showed a borderline significant reduction (OR 0.77, 95% CI 0.56–1.05) in the risk of progression to multiple myeloma among metformin-treated subjects with T2DM vs. those without diabetes [13].

It would appear that there may be hope for reducing progression of MGUS to multiple myeloma with metformin in T2DM. This prospect is nowadays beginning to be discussed more vividly [14]. However, more data is needed, until we reach a clearer view of what is to be gained with metformin in this setting. Interestingly, a phase 2, double-blind, randomised placebo-controlled trial is now being carried out (NCT04850846) [15]. It is recruiting patients with higher-risk MGUS and low-risk smouldering multiple myeloma not previously diagnosed with diabetes mellitus, aiming to investigate the efficacy of metformin in reducing clinical indicators of disease progression [15]. Studies with enough cases and adequate follow-up will be required, so as to ascertain whether any such protective effect of metformin in T2DM is consistent and significant. We will also need to look at the effect of tight glycaemic control per se, as well as at any patient characteristics that might increase the protection offered by metformin. A better understanding of underlying mechanisms will be appreciated as well.

In conclusion, it is being discussed that metformin may contribute to reduced progression of MGUS to multiple myeloma in subjects with T2DM. However, data is very limited for the moment and we need to know a lot more before we reach a definitive answer. Should this beneficial effect be confirmed, it would enrich the widespread appreciation of this agent’s variegated pleiotropic actions, from anti-tumour [5, 16] to anti-depressive [17].

This article is based on previously conducted studies and does not contain any novel data from studies with human participants or animals performed by any of the authors.