In this retrospective study of 591 NDMM patients diagnosed over two decades, we found a prevalence of t(11;14) (17.6%), consistent with other studies(5, 6, 8, 10, 18, 20, 22, 27, 30, 32). We also noted that this group of patients represents a subgroup of MM with unique biological and clinical characteristics, with outcomes similar to those of the SR group (except ISS-1 patients) but benefiting less from the introduction of novel agents in first line in terms of response and PFS.
Several studies have shown that primary cytogenetic abnormalities redefine MM as a compendium of neoplasms with different biological characteristics, clinical features, and responses to treatment(37). In the present study, we focused on one of these MM subtypes: the t(11;14). Some studies have attempted to analyze the prognostic significance of t(11;14) in terms of response and survival(5, 8, 24, 25, 32), but, to the best of our knowledge, this is the first to explore the value of t(11;14) as a predictor of response to new drugs or chemotherapy-containing regimens in first line as well as the prognostic value in the era of novel agents, in a representative and unique series, because almost half of the patients received chemo-schemes and the others received novel agents.
This study confirmed that patients with MM and t(11;14) make up a singular subtype of myeloma, as first described by Fonseca et al.(5). t(11;14) patients are characterized, in comparison to SR patients, by lower incidences of IgA, and of plasmacytomas, but a higher probability of having oligosecretory and non-secretory disease, higher PC bone marrow infiltration and levels of serum calcium. However, patients with t(11;14) had a less aggressive phenotype than those with HRCA that is typified by fewer plasmacytomas, a lower β2 level, and a higher hemoglobin level. Other characteristic features of t(11;14), such as being diagnosed at a young age (≤ 50 years)(38), and the presence of Bence Jones (7, 16), IgE (16) or IgD subtypes(20), were not disproportionally represented in our cohort. Lymphoplasmacytic morphology (13, 14, 20), the greater abundance of CD20(14, 20), the lesser abundance of CD56(20) in clonal PCs, and higher levels of circulating PCs(39) were not analyzed in the present study.
We hypothesize that MM t(11;14) patients have a higher degree of bone marrow PC infiltration because: 1) t(11;14)(q13;q32) results in upregulation of cyclin D1(40), and the overexpression of this favors cell cycle progression; 2) MM with t(11;14) could be a “genomically stable” variant of the disease, with a more indolent course(5); 3) the lymphoplasmacytic morphology results in less monoclonal component in the serum; and 4) there is a lower incidence of plasmacytomas at diagnosis. For these reasons, and because of its more indolent course, MM with t(11;14) might be diagnosed in advanced stages with higher BM PC infiltration.
The prognostic significance of t(11;14) is controversial. Some studies compared groups with and without t(11;14). The latter group included high-risk patients, which could have favored the group with t(11;14) and could explain why it was considered to have a good prognosis, especially in the pre-novel-agent era (6–8, 10). To avoid this, we considered three groups (t(11;14), high-risk, and all others considered to be standard risk) and analyzed the impact of chemo/novel-agent induction. In our series, when comparing these cytogenetics groups, patients of the t(11;14) group presented a similar PFS and OS to those of the SR group. However, MM t(11;14) showed better survival than the HRCA group. These results are supported by reports from several series(24, 31, 32). We found that, despite having the same prognosis as those with SR, ISS-1 patients with t(11;14) had a worse prognosis than ISS-1 patients with SR. However, the poor prognosis associated with t(11;14) was not observed in patients staged as ISS-2 and ISS-3. Lakshman et al(24) also demonstrated that ISS-1 and ISS-2 patients with t(11;14) had worse survival than SR MM patients. This lack of impact of t(11;14) in patients with high-risk features could be explained by the fact that typical biological markers associated with poor outcomes, like high levels of β2 microglobulin(41) or LDH(42), as well as additional chromosomal abnormalities, like del17p or 1q amplification(15, 27, 28), are stronger determinants than the presence of t(11;14).
Our results about the treatment response within the t(11;14) group are consistent with those previously published. Fonseca et al(7) and Kumar et al(28) obtained similar results of ORR with chemotherapy-containing induction in the t(11;14) population as we found in our cohort (73.6% vs. 76.0% and 80.0%, respectively). In our study, PR or better was achieved in almost 90% of patients with t(11;14) treated with novel agents, such as the ORR reported by Saini et al(26) (93.7%), although lower ORR were reported by other groups, like those of Lakshman et al(24) (73.6%), or Kumar et al(28) (79.0%). In addition, Takamatsu et al(15) evaluated the CR with novel agents in the t(11;14) subtype, obtaining a value of 38.0% that was slightly better than ours (23.4%). Unexpectedly, the introduction of new drugs did not improve the ORR or the percentage of CR in our series of t(11;14) patients. Conversely, an improvement was observed in the SR group. These findings are supported by the results of other authors who found that t(11;14) patients did not benefit as much from new treatments as did other myeloma subtypes(20, 24, 25, 33, 34).
The prognostic role of t(11;14) is evolving. In the pre-novel agent era, t(11;14) was considered a good prognostic factor, possibly because of its chemosensitivity, which was attributed to its lymphoplasmacytic morphology(6). Furthermore, the resistance to melphalan is not mediated by BCL-2 overexpression(43). Our study aimed to investigate the increased sensitivity to chemotherapy in t(11;14) by focusing on the “isolated” effect of melphalan in transplant-eligible patients, comparing responses immediately before transplant (after induction) with those achieved by day 100 after transplant, excluding patients who had achieved CR before transplantation since no minimal residual disease response was available for most subjects. The response of patients of the t(11;14) group did not improve after transplant any more than it did in the other cytogenetic groups. These results are consistent with those of Moreau et al(6) and Gao et al(31). Therefore, t(11;14) was not a predictive biomarker of response to chemotherapy in our cohort.
However, this abnormality was considered an intermediate prognosis translocation in the era of novel drugs (21, 22, 24–26). Suboptimal response to novel-agent inductions in t(11;14) patients was one of the foremost reasons for this conclusion. Kaufman et al(25) and Pirmohamed et al(33) undertook retrospective studies of patients homogenously treated with VRD, both showing that t(11;14) patients had a worse response to induction and, consequently, worse PFS than SR patients. In addition, a subanalysis conducted within the Spanish GEM2005MENOS65 and GEM2012 trials of transplant-eligible patients revealed similar responses and outcomes for patients with t(11;14) and SR when they received conventional chemotherapy. However, the efficacy was lower for patients with t(11;14) when treated with novel schemes, such as VTD or VRD (34).
Gasparetto et al recently published findings from the Connect MM registry (32), in which 24% of the cases were t(11;14) patients, and most were treated with novel agents in first line. Median PFS and OS of the t(11;14) group were 34.3 and 83.2 months, respectively. These results are consistent with our series, but no statistically significant differences in PFS or OS between t(11;14) and SR patients were noted, suggesting that, in the era of IMID/PI treatments, t(11;14) has a neutral prognosis. Another study, conducted by the IMWG, and which included more than 800 t(11;14) patients, showed that those who received a PI plus IMID combination had better outcomes than those treated with PI or IMID alone, and that upfront ASCT resulted in survival close to 10 years(28).
In our series, patients from the t(11;14) group treated with novel agents showed a trend towards better response and survival. However, the introduction of new drugs has not led to a significant improvement in the outcomes of these patients, as observed in the SR and HRCA groups, especially those who received two or more novel agents. Although the OS of patients with t(11;14) treated with novel agents is numerically longer, the difference was not statistically significant. The sample size of MM with t(11;14) treated with at least two drugs (N = 12) and the new treatments in the relapse setting, such as anti-CD38 monoclonal antibodies, bispecific monoclonal antibodies, and T lymphocytes with chimeric antigen receptors, could have influenced the results. Therefore, this translocation could be considered a marker of non-response to new treatments such as those with PIs or IMIDs. We suggest that the prognostic significance of this translocation is neutral, as the survival of patients with t(11;14) was comparable to that of the SR group, even though the new agents do not seem to improve their outcomes.
To explain why PIs and IMIDs are less effective in t(11;14) we can consider the expectations arising from the endoplasmic reticulum stress theory(44). This explains how compensatory pathways, such as the unfolded protein response, by activating the proteasome, are activated when PCs accumulate unfolded or misfolded proteins to eliminate them. However, clonal PCs that harbor t(11;14) have a lymphoplasmacytic morphology, with scant cytoplasm and less rough endoplasmic reticulum. For this reason, these PCs might be less likely to accumulate proteins and less able to activate the compensatory mechanism derived from endoplasmic reticulum stress, and thereby less susceptible to drugs that inhibit it directly (e.g., PIs(44)) or indirectly (e.g., IMIDs(45)).
The BCL-2 protein family is well known to play a critical role in the apoptosis of clonal PCs. Treatment with BCL-2 inhibitors, like venetoclax, is emerging as the first targeted therapy for MM, because it is more effective in cases of MM with a high level of expression of BCL-2 and a low level of MCL-1/BCL-XL expression, such as the t(11;14) profile(46–48). No targeted therapy has yet been approved for the treatment MM, because in the phase 3 BELLINI trial(49), relapsed/refractory MM patients randomized to the venetoclax arm exhibited higher mortality. Furthermore, the venetoclax group had a significantly better response and PFS in patients with t(11;14) and/or BCL-2 overexpression. Based on these promising results, ongoing trials are investigating the role of BCL-2 inhibitors in the t(11;14) group. Results are awaited for the phase 3 CANOVA study, which has recruited only MM patients with t(11;14) and randomized them to venetoclax-dexamethasone versus pomalidomide-dexamethasone(50). Based on these results and those of other studies, it is not clear whether the current treatment recommended for NDMM is optimal for patients with t(11;14). Although it is not feasible to conduct randomized clinical trials with conventional agents as the control arm, and since there are anti-BCL-2 agents that seem to be effective in t(11;14), once this is confirmed, it will be worth investigating the first line to define the optimal first line of therapy.
The present study has several limitations, most notably its retrospective nature and the heterogeneity of the induction schemes. In addition, our cohort included fewer patients with t(11;14) who received induction with at least two new drugs, for which reason the results associated with this variable should be interpreted with caution. However, as mentioned before, the study is of particular value because the inclusion of patients with MM diagnosed over 20 years makes this series unique.
In conclusion, MM with t(11;14) represents a subset of patients with unique clinical biological characteristics, with more bone marrow infiltration, less protein secretion and fewer plasmacytomas at diagnosis. The survival of patients with t(11;14) was not worse than that of the SR group, but better than that of the HRCA group. ISS-1 patients with t(11;14) showed poor survival compared to the SR group. The introduction of novel agents in first line did not benefit the t(11;14) group in terms of response, PFS, or OS compared with other cytogenetic subgroups, so this translocation may be considered a marker of non-response to IMIDs/PIs. Further studies with new treatments such as venetoclax are necessary if the outcome of t(11;14) patients is to be improved.