Cytogenetic aberrations (CAs) are vital markers for risk stratification of multiple myeloma (MM). The prognostic significance of the aberration, t(11;14)(q13;q32), in MM has remained controversial over recent years. In addition, studies on the heterogeneity of t(11;14) MM and the impact of additional CAs are rare. We therefore conducted a retrospective study on relevant data collected at our center in order to further analyze the characteristics of Chinese patients with t(11;14) MM and elaborate on heterogeneity in their genetic profile.
All newly-diagnosed patients with MM (NDMM) treated at Peking University People's Hospital from January 2009 to December 2019 with fluorescence in-situ hybridization (FISH) proven t(11;14)(q13;q32) were enrolled in the study group. Patients were excluded if they had been diagnosed with primary plasma cell (PC) leukemia or had been followed-up for < 1 year. All interphase FISH before 2015 were performed without CD138 sorting. From January 2015, the specimens were purified using CD138 microbeads magnetic cell sorting (Miltenyi Biotec, Bergisch Gladbach, Germany). High risk (HR) CA included t(4;14)(p16;q32), t(14;16)(q32;q23), deletion (del) (17p13), and gain/amplification (amp) of 1q21. Standard risk (SR) CA was based on FISH without any of the above HR aberrations. The study group consisted of 109 t(11;14) positive NDMM patients while the control group included 109 control cases who were selected randomly from 1046 non-t(11;14) NDMM patients at a ratio of 1:1 using the time of diagnosis as the matching variable. The case-control matching was based on the year of diagnosis. The median follow-up period was 5.18 years. All the statistical analyses were performed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA). The study was approved by the Peking University People's Hospital Institutional Review Board (ID: 2021PHB299–001).
A total of 109 patients in the t(11;14) group, the median age was 59.4 years (range 38–81 years), with 75 being male. Twenty cases (18.3%) had renal impairment (serum creatinine >2.0 mg/dL). The number of patients classified as international staging system (ISS) stage I, II, and III were 25, 44, and 40, respectively. As shown in Supplementary Table 1, https://links.lww.com/CM9/B69, there were no statistical differences in median age and sex distribution at diagnosis between the t(11;14) and non-t(11;14) groups. The distribution of ISS stage was also similar in the two groups. In the t(11;14) group, the free light chain subtype of M protein was present in 33.9% (37/109) of patients compared to 20.2% (22/109) in the non-t(11;14) group (P = 0.019). Fewer gain/amp of 1q21 was found in the t(11;14) group than that in the non-t(11;14) group (45.9% [50/109] vs. 60.6% [66/109], respectively, P = 0.026). The positive rate of CD20 in the t(11;14) group which was significantly higher than that in the non-t(11;14) group (31.7% [33/104] vs. 13.9% [14/101], respectively, P = 0.002). There was no statistical difference in treatment patterns between the two groups. In the study group, the patients received different induction regimens: 67 (61.5%) a proteasome inhibitor (PI)-based regimen; 16 (14.7%) an immunomodulator (IMiD)-based regimen; 25 (22.9%) bortezomib combined with thalidomide or lenalidomide; and one patient who received conventional chemotherapy. After induction therapy, 24 (22.0%) patients received first-line autologous stem cell transplantation (ASCT) as consolidation. In the non-t (11;14) control group, the treatments included a PI-based regimen in 78 patients (71.6%), an IMiD-based regimen in 15 (13.8%), a PI+IMiD-based regimen in 13 (11.9%), and conventional therapy in 3 (2.8%). The treatment response for myeloma was based on the International Myeloma Working Group response criteria. As shown in Supplementary Table 1, https://links.lww.com/CM9/B69, after induction therapy the overall and very good partial response (VGPR) + complete response responses were similar in the t(11;14) and non-t(11;14) groups. Median progression free survival (PFS) was 2.48 (95% confidence interval [CI], 1.99–2.97) years and 1.87 (95% CI, 1.17–2.57) years for patients in the t(11;14) and non-t(11;14) groups, respectively (P = 0.342). There was a trend towards a longer median overall survival (OS) in the t(11;14) group in comparison with that observed in the non-t(11;14) group (7.25 years [no CI] vs. 4.75 [95%CI,3.62–5.89], respectively, P = 0.074). All 218 patients were subdivided into four groups: t(11;14) without HR CA, t(11;14) with at least one HR CA, non-t(11;14) with at least one HR CA, and non-t(11;14) without HR CA. As shown in Figure 1, we compared the PFS and OS in these four groups, with the results showing that patients with t (11;14) +non-HR CA had comparable outcomes to that of the non-t(11;14) + non-HR CA patients, whereas patients with HR CA had inferior outcomes independent of whether or not they possessed t(11;14). These findings suggested that the outcome of patients relied mainly on whether HR CA existed and that t(11;14) did not confer any benefits or inflict any harm on clinical outcomes.
We next analyzed the t(11;14) positive study group separately by subdividing the t(11;14)+ group into gain/ amp of 1q21 positive and negative groups. There was no significant difference in gender, age, ISS stage, renal function damage, lactate dehydrogenase (LDH) level, platelet count, free light chain M-protein ratio, the proportion of PCs, G-banding abnormalities in the BM samples, and the incidence of extramedullary infiltration (P > 0.050) between the 1q21 positive and negative groups [Supplementary Tables 2, https://links.lww.com/CM9/B69 and 3, https://links.lww.com/CM9/B69]. Compared with the 1q21 negative group, the positive group had a lower lymphocyte-monocyte ratio (LMR) (median, 3.48 vs. 4.61; P = 0.022) and higher neutrophil-lympho-cyte ratio (NLR) (median, 3.14 vs. 2.14; P = 0.002). There were no significant differences between the two groups in the patterns of different treatments. There was also no difference in overall response (ORR) and ≥VGPR between the gain/amp of 1q21 positive and negative groups. The median PFS was 3.49 years in the 1q21 negative group and 1.65 years in the 1q21 positive group (P = 0.003). However, there was a trend towards a shorter median OS in the 1q21 positive group compared to that observed in the 1q21-group (5.41 years vs. not reached; P = 0.091). Multivariate analysis showed that the gain/amp of 1q21 was an independent factor for PFS (P = 0.030, HR = 2.350, 95% CI: 1.343–4.112) and OS (P = 0.004, HR = 5.660, 95% CI: 1.725–18.575) in the t(11;14) positive NDMM. In the gain/amp of 1q21 positive patients, no further significant differentiation was observed for the various gain/amp ratios of 1q21 (5%, 10%, 20%, 30%, 40%, and 50%, respectively).
Our study showed that patients harboring t(11;14) without HR CA had comparable survival to that of t(11;14) negative patients without any HR CA. Similar conclusions have been reported in the literature. Saini et al, using the same 1:1 propensity score matching method as used in our study, compared outcomes and showed no significant differences between PFS and OS in the t(11;14) and control SR groups. Gao et al analyzed one ASCT cohort and showed that patients with t(11;14) alone had outcomes similar to those of patients with a SR. However, Lakshman et al from the Mayo Clinic investigated 365 patients with t(11;14) and 730 matched control NDMM patients, and found that both PFS and OS in the t(11;14) patients were significantly shorter than those in the patients with no translocation. One possible explanation for this discrepancy was the FISH examination spectrum and the question as to whether cytoplasmic immunoglobulin FISH (cIg FISH) or CD138 magnetic bead sorting FISH was used. For instance, FISH detection carried out at the Mayo Clinic used cIg FISH with the spectrum including trisomy (ie, chromosomes 3, 7, 9, and 15), and the partner chromosome of 14q32 including t (4;14), t(8;14), t(6;14), t(14;20), and t(14;16), which was considerably more complex than those used in other studies and had the potential to improve identification of more “high risk” indicators.
Our study showed that gain/amp of 1q21 was an independent prognostic risk factor for PFS and OS in t (11;14) NDMM. Only a small number of studies have analyzed 1q21 in the t(11;14) population alone. Pawlyn et al analyzed 847 patients in a clinical trial in which all patients received thalidomide-based or traditional chemotherapy. In the 127 patients with t(11;14), it was found that the concurrent del (17p) or gain/amp of 1q21 was an independent risk factor for OS (38.1 months vs. 51.2 months, P = 0.050) and that there was a trend towards a difference in PFS (24.2 months vs. 19.7months, P = 0.108). In contrast to these findings on the gain/amp of 1q21, Gao et al analyzed 455 MM patients who all received ASCT, including 55 patients with t(11;14). Their results showed that in the t(11;14) MM subgroup, gain/amp of 1q21 accounted for 38.9% and had no impact on median PFS or OS. In our study, we were able to observe the prognostic significance of the gain/amp of 1q21 in the patient group treated with either a PI or IMiD, whereas in patients receiving ASCT, the adverse effect of gain/amp of 1q21 was offset. This result indicated that the inconsistency probably resulted from a different spectrum of treatment. Although the number of patients receiving transplantation was small, our study showed that in the 1q21+ group, the patients who received ASCT had a trend towards a better OS (P = 0.076, data not shown) compared with those who did not receive ASCT. This suggests that ASCT was very important for this MM subtype.
The above results raise the question as to why additional gain/amp of 1q21 confers inferior significance in NDMM with t(11;14)(q13;q32). Analysis of clinical and laboratory indices showed no significant difference in ISS stage, LDH level, extramedullary plasmacytoma, or proportion of peripheral PCs between the 1q21 positive and negative patients. There was also no significant difference in the effect on ORR or at least VGPR. On the other hand, there is evidence that co-occurrence of 1q21+ is likely to be associated with a worse prognosis in not only t(11;14) MM but also other subgroups of NDMM. Our results showed that the adverse effect of 1q21+ on prognosis may not occur by reducing the induced remission rate, but rather through an increase in the early recurrence rate. A similar viewpoint was reported by Schmidt TM. It is therefore very important to closely monitor disease status after treatment, especially during the consolidation/maintenance phase. We observed a lower LMR and higher NLR in the 1q21+ group, and this finding may reflect a possible immune dysfunction mechanism for the adverse significance of 1q21.
Our study had several limitations including its retrospective design, heterogeneous treatment population, and a relatively small number of patients. However, our study was based on data pertaining to a Chinese population, and using this data we explored the impact of additional CA in t(11;14) MM.
In conclusion, this single-center, retrospective study showed that patients harboring t(11;14) had comparable survival to patients without any high-risk cytogenetics. Gain/amp of 1q21 was an adverse prognostic risk factor for patients with t(11;14) myeloma, a finding that provides a better understanding of this particular type of myeloma.
This research was supported partly by Capital's Funds for Health Improvement and Research (No. 2020–2–4082), Peking University People's Hospital Scientific Research Development Funds (No. RDY2019–33), and National Natural Science Foundation of China (No. 82170196).
1. Lakshman A, Moustafa MA, Rajkumar SV, Dispenzieri A, Gertz MA, Buadi FK, et al. Natural history of t(11;14) multiple myeloma. Leukemia 2018;32:131–138. doi: 10.1038/leu.2017.204.
2. Saini N, Ma J, Milton DR, Patel R, Varma A, Bashir Q, et al. Impact of autologous transplantation in patients with multiple myeloma with t (11;14): a propensity-score matched analysis. Clin Cancer Res 2019;25:6781–6787. doi: 10.1158/1078-0432.CCR-19-0706.
3. Gao W, Du J, Liu J, Zhou H, Zhang Z, Jian Y, et al. What multiple myeloma with t(11;14) should be classified into in novel agent era: standard or intermediate risk? Front Oncol 2020;10:538126. doi: 10.3389/fonc.2020.538126.
4. Pawlyn C, Melchor L, Murison A, Wardell CP, Brioli A, Boyle EM, et al. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood 2015;125:831–840. doi: 10.1182/blood-2014-07-584268.
5. Schmidt TM, Barwick BG, Joseph N, Heffner LT, Hofmeister CC, Bernal L, et al. Gain of chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J 2019;9:94. doi: 10.1038/s41408-019-0254-0.