Edited by: Alessandro Gozzetti, University of Siena, Italy
Reviewed by: Shaji Kumar, Mayo Clinic, United States; Francesca Patriarca, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Italy
*Correspondence: Weijun Fu,
†These authors share first authorship
This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology
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To investigate the prognostic value of t(11;14) for
A total of 455 patients with fluorescence
A total of 152 patients were in the HR group. Of patients without HR cytogenetics, 55 were in the t(11;14) group, and 248 were in the standard risk (SR) group without t(11;14). Gain in 1q21 was observed in 38.9% patients with t(11;14). There were no differences in median progression free survival (PFS) and overall survival (OS), respectively, between patients in the t(11;14) group and those in the SR group. Patients in the t(11;14) group had the longer median PFS and OS, respectively, compared with those in the HR group. Regardless of coexisting with 1q21 gain or not, patients in the t(11;14) group still had similar median PFS and OS compared to those in the SR group. Finally, multivariate analysis indicated that including 1q21 gain and bone marrow plasma cell with CD20 expression, no variables were found to predict the outcome of the t(11;14) group in our cohort.
These results confirm that outcomes of t(11;14) MM are similar to standard risk patients when they receive novel agent induction therapy consolidated by ASCT. Gain of 1q21 coexists with t(11;14) frequently. In addition, both bone marrow plasma cell with CD20 expression and 1q21 gain have no impact on median PFS or OS for patients with t(11;14).
Multiple myeloma (MM) is still incurable. But overall survival for these patients has been improved significantly with novel agents in combination with autologous stem cell transplantation (ASCT). With the rapid changes of treatment pattern, the role of prognostic factors for MM has to be reevaluated accordingly. Among MM patients, about 16–24% can be detected with translocation t(11;14)(q13;q32), which ranks with the most common chromosomal translocation (
In this context, we retrospectively reviewed patients from three Chinese hospitals to assess the survival outcomes of 455 MM patients under treatment of novel agents in combination with ASCT. Among them, 55 patients were detected with t(11;14).
Between March 2003 and January 2018, 455 patients with newly diagnosed symptomatic myeloma had received fluorescence
Among the patients enrolled in this study, some had already participated in clinical trials under local hospital routine practice. Data were obtained from the three hospital databases, respectively, which were created and maintained prospectively. All MM diagnosis and treatment responses were based on the International Myeloma Working Group (IMWG) criteria (
FISH screening was performed using DNA probes (Abbott Molecular) targeting at least one of the following chromosomal abnormalities: 17p13 deletion, t(11;14), t(4;14), t(14;16), and 1q21 gain. A total of 200 interphase nuclei were analyzed. The cutoff values were as follows: 20% for 17p13 deletion and 1q21 gain; 10% for t(11;14), t(4;14), and t(14;16) (
We summarized categorical variables as proportions and continuous variables as median (range). X^{2}-test was used to compare categorical variables among different groups with Fisher’s exact test when appropriate. Non-parametric Kruskal–Wallis test was used to compare continuous variables. Progression free survival (PFS) was defined as the duration from initiation of therapy to first evidence of disease progression or death. Patients without evidence of progressive disease were censored at the date of last follow-up. OS was calculated from the date of treatment initiation until the date of death or date of last follow-up. PFS and OS were estimated with the method of Kaplan and Meier and compared among groups using log rank test. For multivariate analysis, factors associated with PFS and OS were introduced into a Cox proportional hazards model.
To identify predictors of outcome for patients in the t(11;14) group, univariate analysis was performed with age ≧̸50 vs. <50 years; hemoglobin ≧̸10 vs. <10 g/dl; bone marrow plasma cell (BMPC)≧̸30% vs. <30%; bone marrow plasma cell with vs. without CD20 expression and with vs. without 1q gain; light chain myeloma vs. others; ISS (International Staging System) I vs. II/III stage; less than vs. at least VGPR before ASCT, and less than vs. at least VGPR at three months after ASCT as independent variables to confirm their association with median PFS and OS. Variables with a P-value <0.166 (For PFS) or P-value <0.4 (For OS) on univariate analysis and bone marrow plasma cell with vs. without CD20 expression were analyzed as predictor variables in multivariate Cox proportional hazards model.
IBM SPSS v21 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
The baseline characteristics of the three groups are summarized in
The Baseline Clinical Characteristics of the Study Populations at Diagnosis (n=455).
Characteristic | All patients | t(11;14) group | Standard risk | High risk | P |
---|---|---|---|---|---|
(n=455) | 55 | 248 | 152 | ||
Male, n(%) | 272 (59.8) | 35 (63.6) | 146 (58.9) | 91 (59.9) | 0.823 |
Age, y(median/range) | 53 (23-69) | 50 (30-65) | 54 (23-66) | 53 (25-69) | 0.062 |
M-protein isotype | |||||
IgG, n (%) | 240 (52.7) | 22 (40) | 128 (51.6) | 90 (59.2) | 0.044 |
IgA, n (%) | 94 (20.7) | 5 (9.1) | 55 (22.2) | 34 (22.4) | 0.066 |
IgD, n (%) | 18 (4.0) | 5 (9.1) | 7 (2.8) | 6 (3.9) | 0.098 |
Light chain, n (%) | 89 (19.6) | 20 (36.3) | 51 (21.4) | 18 (11.9) | <0.001 |
Others, n (%) | 14 (3.1) | 4 (7.3) | 6 (2.4) | 4 (2.6) | 0.150 |
ISS I/II, n (%) | 288 (63.3) | 41 (74.5) | 152 (61.3) | 95 (62.5) | 0.175 |
ISS-III, n (%) | 167 (36.7) | 14 (25.5) | 95 (38.3) | 57 (37.5) | 0.190 |
LDH, median (range) (n=413) | 161 (67-732) | 162 (82-704) | 161 (84-615) | 160 (67-732) | 0.63 |
Hb, g/L, median (range) | 97 (44-159) | 105 (57-159) | 95 (44-151) | 94.5 (51-150) | 0.111 |
Platelets, 10^{9}/L, median (range) | 196 (28-485) | 200 (85-325) | 205 (31-841) | 178 (28-386) | 0.032 |
Creatine, umol/L, median (range) | 77.9 (30-881) | 78.3 (36.3-404) | 78 (31-777) | 76 (30-881) | 0.997 |
Calcium, mmol/L, median (range) | 2.38 (1.65-5.08) | 2.46 (2.03-4.29) | 2.35 (1.8-5.09) | 2.35 (1.65-4.11) | 0.082 |
BMPC, %, median (range) | 31 (0.5-96.5) | 35 (10-89) | 29.3 (1-96.5) | 32.5 (0.5-94) | 0.090 |
Novel agents containing regimens during induction, n (%) | |||||
PI based, n (%) | 403 (88.6) | 50 (90.9) | 221 (89.1) | 132(86.8) | 0.708 |
IMiDs based, n (%) | 2 (0.4) | 0 | 2 (0.8) | 0 | |
PI + IMiDs based, n (%) | 5 (1.1) | 0 | 3 (1.2) | 2 (1.3) | |
Conventional therapy, n(%) | 45 (9.9) | 5 (9.1) | 22 (8.9) | 18 (11.8) | 0.640 |
Conditioning regimens | |||||
Melphalan alone, n(%) | 224 (49.2) | 30 (54.5) | 126 (50.8) | 68 (44.7) | 0.125 |
Other regimens, n(%) | 231 (50.8) | 25 (45.5) | 122 (49.2) | 81 (55.3) | 0.125 |
t(11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p; Standard risk, defined as the absence of del17p, t(4;14), t(14;16), and t(11;14); High risk, defined as the presence of any of del17p, t(4;14), and/or t(14;16). P-value for Kruskal-Wallis test for continuous variables and Fisher’s exact test for categorical variables.
ISS, International Staging System; LDH, lactate dehydrogenase; Hb, Hemoglobin; BMPC, Bone Marrow Plasma Cell; PI, Proteasome inhibitors; IMiDs, Immunomodulatory drugs.
Cytogenetic Proﬁles of Patients Based on Interphase Fluorescent in Situ Hybridization (n=455)
Cytogenetic abnormality | t(11;14) group | Standard risk | High risk | p |
---|---|---|---|---|
(n=55) | (n=248) | (n=152) | ||
t(11;14), n (%) | 55 (100) | 0 | 10 (6.6) | |
t(4;14), n (%) | 0 | 0 | 84 (55.3) | |
t(14;16), n (%) | 0 | 0 | 15 (9.9) | |
Del 17p, n (%) | 0 | 0 | 70 (46.1) | |
1q21 gain, n (%) | 21 (38.9) |
80 (32.8) | 76 (51.4) | 0.001 |
t (11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p; Standard risk, defined as the absence of del17p, t(4;14), t(14;16), and t(11;14); High risk, defined as the presence of any of del17p, t(4;14), and/or t(14;16).
Among the t(11;14) group, one patient had missing data for 1q21 gain; among the standard risk group, 4 patients had missing data for 1q21 gain; among the high risk group, 4 patients had missing data for 1q21 gain.
The induction regimens for the three groups of patients are shown in
Response to induction was assessed in the t(11;14) group, the SR group, and the HR group, respectively. The proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), at least VGPR, partial response (PR), minimal response (MR), stable disease (SD), and progressive disease (PD) as best response to induction or ASCT are shown in
The Response of the Study Populations at Diagnosis (n=455).
Characteristic | All patients | t(11;14) group | Standard risk | High risk | P |
---|---|---|---|---|---|
(n=455) | 55 | 248 | 152 | ||
Pre-ASCT response, n (%) | |||||
sCR | 37 (8.1) | 4 (7.3) | 24 (9.7) | 9 (5.9) | 0.431 |
CR | 111 (24.4) | 11 (20) | 64 (25.8) | 36 (23.7) | 0.692 |
VGPR | 183 (40.2) | 16 (29.1) | 95 (38.3) | 72 (47.4) | 0.042 |
At least VGPR | 331 (72.7) | 31 (56.4) | 183 (73.8) | 117 (76.9) | 0.014 |
PR | 96 (21.1) | 15 (27.3) | 52 (21) | 29 (19.1) | 0.430 |
MR | 11 (2.4) | 3 (5.5) | 6 (2.4) | 2 (1.3) | 0.211 |
SD | 10 (2.2) | 6 (10.9) | 4 (1.6) | 0 | |
PD | 4 (0.9) | 0 | 2 (0.8) | 2 (1.3) | |
Unknown | 3 (0.7) | 0 | 1 (0.4) | 2 (1.3) | |
The response at three months after ASCT, n (%) | |||||
sCR | 53 (11.6) | 3 (5.5) | 34 (13.7) | 16 (10.5) | 0.21 |
CR | 156 (34.3) | 17 (30.9) | 93 (37.5) | 46 (30.3) | 0.299 |
VGPR | 133 (29.3) | 16 (29.1) | 69 (27.8) | 48 (31.5) | 0.712 |
At least VGPR | 342 (75.2) | 36 (65.5) | 196 (79) | 110 (76.9) | 0.069 |
PR | 58 (12.7) | 11 (20) | 28 (11.3) | 19 (12.5) | 0.214 |
MR | 7 (1.5) | 1 (1.8) | 6 (2.4) | 0 | |
SD | 5 (1.1) | 3 (5.5) | 1 (0.4) | 1 (0.7) | |
PD | 10 (2.2) | 1 (1.8) | 6 (2.4) | 3 (2.0) | |
Unknown | 33 (7.3) | 3 (5.5) | 11 (4.4) | 19 (12.5) | 0.012 |
t(11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p; Standard risk, defined as the absence of del17p, t(4;14), t(14;16), and t(11;14); High risk, defined as the presence of any of del17p, t(4;14), and/or t(14;16).
ASCT, Autologous stem cell transplantation; sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimum response; SD, stable disease; PD, progression of disease.
There were no differences in median progression free survival (PFS) (52 [95% CI, 26–78] vs 63 [95% CI, 44–82] months, P=.935) and overall survival (OS) (86 vs 100 months, P=.836) respectively between patients in the t(11;14) group (n=55) and those in the SR group (n=248) (
Impact on PFS and OS with t(11;14) group (n=55), standard risk group (n=248), and high risk group (n=152).
Impact on PFS and OS with t(11;14) group and standard risk group without or with 1q21 gain.
The results of analysis showed that there were no variables to predict median OS. The presence of 1q gain was associated with reduced median PFS in univariate but not in multivariate analysis (
Effect of baseline characteristics and response on PFS in the t(11;14) group (n=55).
Variables | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
HR | 95%CI | p | HR | 95%CI | p | |
Age ≧̸50 vs <50 years (30 vs 25) | 1.952 | 0.767-4.970 | 0.161 | 0.635 | 0.115-3.507 | 0.602 |
Hb ≧̸10 vs <10 g/dl (34 vs 21) | 0.946 | 0.372-2.405 | 0.907 | |||
BMPC ≧̸30% vs <30% (29 vs 26) | 0.345 | 0.122-0.979 | 0.045 | 0.206 | 0.024-1.759 | 0.149 |
BMPC with vs without CD20 expression (18 vs37) | 0.467 | 0.105-2.072 | 0.316 | 2.652 | 0.122-5.782 | 0.534 |
with vs without 1q gain (21 vs 33) | 0.297 | 0.110-0.803 | 0.017 | 0.274 | 0.030-2.482 | 0.250 |
Light chain myeloma vs others (20 vs 35) | 0.990 | 0.374-2.619 | 0.984 | |||
ISS I vs II/III stage (19 vs36) | 2.065 | 0.740-5.761 | 0.166 | |||
Less than vs at least VGPR before ASCT (19 vs 36) | 1.646 | 0.333-2.056 | 0.683 | |||
Less than vs at least VGPR at three months after ASCT (19 vs 36) | 1.646 | 0.660-4.103 | 0.285 |
t(11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p.
Hb, Hemoglobin; BMPC, Bone marrow plasma cells; ISS, International Staging System; LDH, lactate dehydrogenase; VGPR, very good partial remission; ASCT, autologous stem cell transplantation.
Effect of baseline characteristics and response on OS in the t(11;14) group (n=55).
Variables | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
HR | 95%CI | p | HR | 95%CI | p | |
Age ≧̸50 vs <50 years (30 vs 25) | 2.181 | 0.484-9.829 | 0.310 | 1.206 | 0.217-6.716 | 0.831 |
Hb ≧̸10 vs <10 g/dl (34 vs 21) | 0.546 | 0.106-2.820 | 0.470 | |||
BMPC ≧̸30 vs <30% (29 vs 26) | 0.409 | 0.079-2.126 | 0.288 | 0.821 | 0.122-5.546 | 0.840 |
With vs without CD20 expression (18 vs37) | 0.667 | 0.078-5.709 | 0.711 | |||
with vs without 1q gain (21 vs 33) | 0.314 | 0.057-1.725 | 0.183 | 0.355 | 0.056-2.255 | 0.272 |
Light chain myeloma vs others (20 vs 35) | 1.018 | 0.196-5.280 | 0.983 | |||
ISS I vs II/III stage (19 vs36) | 1.614 | 0.313-8.334 | 0.568 | |||
Less than vs at least VGPR before ASCT (19 vs 36) | 0.362 | 0.069-1.881 | 0.227 | 0.486 | 0.084-2.821 | 0.422 |
Less than vs at least VGPR at three months after ASCT (19 vs 36) | 0.769 | 0.149-3.978 | 0.754 |
t(11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p.
Hb, Hemoglobin; BMPC, Bone marrow plasma cells; ISS, International Staging System; LDH, lactate dehydrogenase; VGPR, very good partial remission; ASCT, autologous stem cell transplantation.
In this multicenter retrospective study, we investigated the clinical manifestation and survival of MM patients with t(11;14) in the era of novel agent in combination with ASCT. The higher proportion of light chain MM, or IgD myeloma for MM patients with t(11;14), are all similar to those in the prior studies. Our study showed patients with t(11;14) had poorer response to induction therapy, but patients in the t(11;14) group had comparable median PFS and OS to the standard risk MM. In addition, the survival tendency was still similar between these two groups regardless of with or without 1q21 gain. Last but not least, we found that both 1q21 gain and bone marrow plasma cell with CD20 expression had no impact on median PFS or OS for t(11;14) patients in multivariate analysis.
In conventional agent era, the early study showed that the outcomes were comparable between MM patients with or without t(11;14). In a transplant ineligible cohort with 336 evaluable patients (
However, in novel agent era, the results from some studies cast doubt on the outcomes between patients with or without t(11;14). Lakshman et al. compared PFS and OS between patients with t(11;14) (n=365) and matched controls (n=730). The controls included 132 patients with non-(11;14) abnormality and 598 patients with no chromosomal abnormality. Both PFS and OS of the t(11;14) group were significantly shorter than those of group with no translocation (
Opposite to the above point of view, several other studies suggested patients with t(11;14) still had the similar outcome compared with patients with standard risk when they received novel agents regimens as induction following ASCT. In the IFM 2009 study (
How do we explain the controversy among the above studies? The limited data from the above studies showed that if novel agents based induction therapy in combination with ASCT was used as treatment for all patients, the outcome of t(11;14) would be similar to a standard risk group. Otherwise, the survival for t(11;14) appeared to be inferior to patients with standard risk. All patients benefited from the novel agents, but it seemed that the outcome of standard risk patients benefited more from novel agents based induction than that of the t(11;14) patients. However, the difference of outcome between patients with t(11;14) and standard risk could be overcome by ASCT. A study from Sweden also confirmed our speculation (
A gain of 1q21 is prevalent in 30% to 50% of patients with NDMM (
In our study, although patients with t(11;14) had poorer response to induction, no differences were observed in the percentage of patients who achieved at least VGPR in the three groups after ASCT. It was possible for t(11;14) MM to benefit more from ASCT in terms of response compared to the other two groups. Further analysis did not confirm that busulfan containing regimens did better than melphalan containing regimens in terms of at least VGPR after ASCT. Patients with R-ISS-I have similar outcome to patients with R-ISS-II & III, which was attributed to the higher proportion of patients with R- ISS-II among the R-ISS-II & III group (R-ISS-II 58.2% versus R-ISS-III 7.3%). Although no variables can be confirmed to predict the outcome, there was a discrepancy for both PFS and OS of t(11;14) alone. Therefore, more research work should be done to risk-stratify the patients with t(11;14) alone.
There are some shortcomings that should be taken into account when interpreting our results, for instance, heterogeneity in terms of induction, conditioning regimens, and so on. It should be acknowledged that this is a retrospective study and our conclusions have to be tested in future prospective cohort studies.
With treatment of novel agents induction in combination with ASCT, MM patients with t(11;14) had lower at least VGPR to induction therapy, but had comparable median PFS and OS with standard risk patients. For MM patients with t(11;14), both bone marrow plasma cells with CD20 expression and 1q21 gain had no impact on median PFS or OS.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by the Ethics Committee of Beijing Chao-Yang Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
WC, JL, and WF were the principal study investigators for this study and participated in the study design and manuscript revision. WC, JL, and WF should be considered joint corresponding authors. WG, JD, JRL, and HZ participated in data collection, data analysis, and manuscript drafting. WG, JD, JRL, and HZ contributed equally to this work and should be considered joint first authors. ZZ and YJ participated in data collection. GY and GW participated in the execution of statistical analyses. YT, YL, and YW participated in following up with the patients. All authors contributed to the article and approved the submitted version.
This project was supported by grant and contract from clinical innovation project of Beijing Hospital Authority [grant XMLX201847]. The funder was not involved in the execution of the research or the preparation of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or ﬁnancial relationships that could be construed as a potential conﬂict of interest.
We thank all patients and their families as well as all doctors in the department of hematology, Myeloma Research Center of Beijing, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; department of hematology, the Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China; and department of hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We thank Yipeng Wang for language editing.
The Supplementary Material for this article can be found online at:
The Conditioning Regimens of the Study Populations at Diagnosis (n=455). t (11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p; Standard risk, defined as the absence of del17p, t(4;14), t(14;16), and t(11;14); High risk, defined as the presence of any of del17p, t(4;14), and/or t(14;16). P-value for Fisher’s exact test for categorical variables. BCE, busulfan and cyclophosphamide plus etoposide; TBI, total body irradiation
The Maintenance of the Study Populations at Diagnosis (n=455). t (11;14) group, defined as with t(11;14) and without t(4;14), t(14;16), and del 17p; Standard risk, defined as the absence of del17p, t(4;14), t(14;16), and t(11;14); High risk, defined as the presence of any of del17p, t(4;14), and/or t(14;16). P-value for Fisher’s exact test for categorical variables. Novel agents, defined as the presence of any of bortezomib, ixazomib, and/or lenalidomide. Conventional agents, defined as the presence of any of thalidomide, and/or interferon.
Impact of conditioning regimens on response in the t(11;14) group (n=55). Melphalan containing regimens, defined as Melphalan alone, Melphalan plus Bortezomib, and Melphalan plus TBI; Busulfan containing regimens, defined as busulfan and cyclophosphamide plus etoposide, and Busulfan plus Cyclophosphamide. P-value for Fisher’s exact test for categorical variables. VGPR, very good partial remission; ASCT, autologous stem cell transplant.
ASCT, Autologous stem cell transplantation, CR, complete response, FISH, fluorescence