Is t(14;16) an independent prognostic factor in patients with multiple myeloma?

Translocations of the immunoglobulin heavy-chain gene (IgH) locus at 14q32 are involved at early stages of multiple myeloma (MM) pathogenesis and occur in approximately 40% of cases. Different mutations confer different risk on prognosis: t(11;14), the most common lesion, is considered a standard-risk chromosomal abnormality (CA); while t(4;14), t(14;16), and t(14;20) have been historically associated with higher-risk disease.

Since the publication of the Revised International Staging System (R-ISS) in 2015 by Palumbo et al.¹, the t(14;16) was incorporated to the clinical practice as a CA associated with poor prognosis in patients newly diagnosed with MM (NDMM). However, multiple studies have been published questioning the direct impact of t(14;16) on the survival of these patients.

The main challenge when studying t(14;16) is that its incidence is relatively rare: it is only observed in 3–5% patients with MM. Therefore, all previous analyses included a limited number of patients with t(14;16) and were probably underpowered to define its prognostic value. To further elucidate the clinical effect of t(14;16) in a context where multiple new drugs have been incorporated to the MM therapeutic arsenal, Mina et al.² recently published one of the largest studies to date in Blood Cancer Journal, which included data from 123 patients with t(14;16) confirmed by centralized fluorescent in situ hybridization (FISH) at diagnosis.

The authors selected patients diagnosed between 2006–2017 with symptomatic MM and t(14;16)-positive FISH, registered in multiple databases from different European and American centers. When analyzing the patient characteristics at diagnosis (Table 1), one of the findings consistent with previous studies is that t(14;16) is rarely found as a single mutation (only in ten patients in this cohort). Interestingly, most patients presented concomitant CAs such as del(13q) (71%), amp(1q) (51%), and del(17p) (23%), all considered to be associated with a worse prognosis.

Table 1. Patient characteristics at diagnosis and first-line treatment²

After a median follow-up of 53 months (95% CI, 35–63), the median progression-free survival (PFS) was 19 months (95% CI, 16-30) and overall survival (OS) was 53 months (95% CI, 36-63) for the full cohort of patients with t(14;16). At 5 years, 39% were still alive. When analyzing the results according to cytogenetics, patients with additional CAs presented a significantly shorter PFS and shorter OS, compared to those without them (Table 2).

If the concomitant CA was del(13q), the risk of progression or death increased by 1.64-fold (p = 0.05), and OS was significantly shortened (HR, 1.96; p = 0.04). If the concomitant CA was del(17p), the risk of progression or death increased by 1.35-fold (p = 0.23) and this was 2.2-fold (p = 0.02) in patients with amp(1q). The significance of these comparisons, though, needs to be evaluated carefully since sample size of patients with no concomitant CAs was small.

Table 2. Outcomes based on CAs²

In addition to concomitant CAs, other characteristics negatively influenced the outcomes of patients with t(14;16) in the multivariate analysis. A shorter PFS was observed in patients classified as ISS-3, and hypercalcemia, elevated LDH, and again, ISS-3, were all correlated with a significantly shorter OS.

Lastly, in patients who were eligible for autologous stem cell transplantation (ASCT), the upfront transplant prolonged the median PFS compared to standard chemotherapy without ASCT, as did the use of maintenance therapy. Another factor associated with prolonged PFS was the achievement of complete response (CR), or better, as best response:

• ASCT vs no ASCT: 36 vs 17 months (HR, 0.5; p = 0.036)
• Maintenance vs no maintenance: 36 vs 19 months (HR, 0.59; p = 0.045)
• ≥ CR vs partial response (PR) or very good PR (HR, 0.29; p < 0.001)

In summary, according to this analysis, almost every patient with t(14;16) presented with at least one other high-risk characteristic at diagnosis, which are associated with poorer survival outcomes.

These results are in line with those reported recently by Goldman-Mazur et al.,³ in the only other study with an equally high sample size of patients with t(14;16) (N = 223). In this multicenter retrospective study, Goldman-Mazur et al. found that approximately a quarter of patients with t(14;16) initially present with renal failure. After a median follow-up of 4.1 years (95% CI, 3.7–18.7), the median PFS and OS were 2.1 years (95% CI, 1.5–2.4) and 4.1 years (95% CI, 3.3–5.5), respectively. However, the OS significantly decreased in older patients (age > 60 years) and patients with R-ISS 3 disease compared to the rest of the patients included in the study. It should be noted that in this study, as well as in Mina et al.,² results were not compared to a matched control group of patients without t(14;16).

The question remains then, whether it is possible to link this unfavorable prognosis solely to the presence of t(14;16) or not. Moreover, the decision to include t(14;16) in the R-ISS was based on the International Myeloma Working Group (IMWG) molecular classification,⁴ which initially used the data from only two small studies. Although its significance was validated later in larger cohorts, t(14;16) was always analyzed along with other CAs.

On the other hand, incorporating novel agents into first-line of therapy, and using some clinical protocols specifically for patients with a high-risk profile (i.e., double ASCT), it might be possible to improve the outcomes for patients with t(14;16), masking the previously described negative effect of this CA.

Taking everything into account, is it safe to say that there is a growing need for a revision of the Revised-ISS to address how to improve the evaluation of patients diagnosed with MM in the era of novel agents, according to their cytogenic profile.