Introduction
Multiple myeloma (MM) is the third most common hematologic malignancy in the European Union, with approximately 33 000 new cases and 20 000 deaths annually.1 The introduction of novel agents, such as proteasome inhibitors (PIs),2-4 immunomodulatory drugs (IMiDs),5-7 and anti-CD38 monoclonal antibodies8-10 along with high-dose melphalan followed by autologous hematopoietic stem cell transplant (auto-HSCT)11 have significantly improved the prognosis of patients with MM. However, most cases of MM are still incurable.
Recent studies using next-generation sequencing (NGS) approaches have provided evidence that MM is characterized by spatial and temporal genetic heterogeneity and is composed of multiple populations of genetically distinct subclones, which evolve over time following a pattern of branched, linear, or stable evolution.12-17 In this context, the clonal selection of treatment-resistant subclones during anti-myeloma therapy is now recognized as the main cause of treatment failure.12,13,15 Nevertheless, despite the great potential, tracking the clonal evolution of MM using NGS has not been applicable in routine clinical practice yet, and cytogenetic testing by interphase fluorescence in situ hybridization (FISH) remains the most commonly used method for determining the genetic features of MM both at the time of diagnosis and at subsequent relapses.18
The prognostic significance of baseline cytogenetic abnormalities (CAs) in newly diagnosed MM is well documented.19,20 The presence of the defined panel of CAs, ie, the deletion of the short arm of chromosome 17 (del[17p]) and / or translocations involving the IGH locus, namely, t(4;14) and t(14;16), is one of the criteria defining high-risk disease according to the Revised International Staging System (R-ISS).21 The group of patients bearing high-risk CAs is characterized by 5-year overall survival (OS) and 5-year progression-free survival (PFS) rates of only 40% and 24%, respectively.21 However, the evolution of these high-risk CAs during the treatment and its potential prognostic consequences remain unclear.
In this article, we assessed the impact of cytogenetic evolution (CE) detected in a routine FISH test on the prognosis of patients with relapsed or refractory MM (RRMM).
Patients and methods
Study population
We collected clinical and laboratory data from 650 patients who underwent baseline FISH with MM panel probes because of suspected or diagnosed MM at the Institute of Hematology and Transfusion Medicine in Warsaw (Poland) between the years 2014 and 2019. Out of this group, we selected 177 individuals with the confirmed diagnosis of MM and full clinical data available. A subpopulation of this group including 29 patients with MM who had FISH testing conducted twice during the course of the disease were involved in this retrospective analysis. The first FISH test (FISH1) needed to be performed at the time of the diagnosis of MM, and the second FISH test (FISH2) could be evaluated during any of the subsequent relapses.
The study was approved by the Ethics Committee of the Institute of Hematology and Transfusion Medicine in Warsaw (Poland) and conducted in accordance with the provisions of the 1964 Declaration of Helsinki with amendments and the International Conference on Harmonization Guidelines for Good Clinical Practice. Written informed consent to the use of their clinical and cytogenetic data was given by all study participants.
Cytogenetic evaluation
The FISH panel for MM routinely used at the Institute of Hematology and Transfusion Medicine in Warsaw (Poland) consisted of the following probes: 11q22.3 (ATM gene), 17p13.1 (TP53 gene), 14q32 (IGH gene), FGFR3 / IGH t(4;14) and IGH / MAF t(14;16).22
Plasma cells were magnetically isolated from the bone marrow aspirates with CD138 MicroBeads (Human Whole Blood and Bone Marrow CD138 Positive Selection Kit II, Stemcell Technologies, Vancouver, British Columbia, Canada) and evaluated with the FISH probes. A sequential FISH testing strategy was used, that is, the evaluation for t(4;14) and t(14;16) was only performed when the IGH rearrangement was present in the absence of the TP53 deletion. The cutoff values established in the local laboratory for a positive FISH test results were 7% for the 17p13.1 (TP53 gene) deletion, 4% for the 11q22.3 (ATM gene) deletion, and 8% for any translocation involving the 14q32 (IGH gene) locus.
For the purpose of this analysis, we defined the presence of CE as: 1) the acquisition of at least 1 new CA in the FISH2 test compared with the FISH1 test results (ie, a new additional copy or copies of the TP53, ATM, or IGH genes, new deletion of the IGH, MAF, or TP53 genes) or 2) loss of at least 1 CA in the FISH2 test that was present in the FISH1 test results (ie, loss of an additional copy or copies of the IGH gene or loss of an additional copy of the FGFR3 gene).
Definitions
Patients’ responses to treatment were defined according to the 2016 Revised International Myeloma Working Group Criteria.23 Refractory disease was defined as lack of any response during the treatment or disease progression during or within 60 days after the cessation of the therapy.
The study follow-up was defined as the time from the date of diagnosis of MM to death of any cause or to the date of the last follow-up visit with the cutoff date of September 6, 2019. The follow-up after FISH2 evaluation was defined as the time from the date of the FISH2 test to death of any cause or to the date of the last follow-up visit with the cutoff date of September 6, 2019. Progression-free survival was defined as the time between the initiation of the therapy received immediately after the FISH2 evaluation and disease progression or death. The patients who did not receive antimyeloma treatment after the FISH2 evaluation were excluded from the PFS analysis. Overall survival 1 (OS1) was defined as the time from the diagnosis of MM to death of any cause, and overall survival 2 (OS2) as the time from the FISH2 evaluation to death of any cause.
Statistical analysis
The Fisher exact test was used to assess the difference in the distribution of categorical variables between the study groups. Continuous variables were compared between the groups using the nonparametric Mann–Whitney test. The values of PFS, OS1, and OS2 were estimated by the Kaplan–Meier method. The effect of prognostic factors on time-dependent variables, OS1, OS2, and PFS, was assessed with the log-rank test. The Cox proportional hazards model was used to identify factors affecting PFS and OS2 at the time of the FISH2 evaluation. Statistical analysis was performed using the MedCalc for Windows, version 19.1.3 (MedCalc Software, Ostend, Belgium), and GraphPad Prism, version 8.3 (GraphPad Software, Inc., San Diego, California, United States), software. For all statistical tests, a P value less than 0.05 was considered significant.
Results
Patients’ baseline characteristics and cytogenetic evaluation
The mean time from the diagnosis of MM to the FISH2 evaluation was 2.2 years (95% CI, 1.8–2.6 years). In 19 patients (66%), the FISH2 test was evaluated at the first clinical (n = 17) or biochemical relapse (n = 2). In the remaining cases, the FISH2 test was performed at the second (n = 6 [21%]), third (n = 3 [10%]), or fourth (n = 1 [3%]) relapse. Detailed clinical characteristics of the study patients are shown in Table 1.
Parameter | Before FISH2 evaluation | At the time of or after FISH2 evaluation |
|---|---|---|
Age, y, median (range) | 64 (46–72) | 66 (49–76) |
Female sex | 14 (48) | – |
ECOG score | ||
0 | 2 (7) | 4 (14) |
1 | 19 (66) | 18 (65) |
2 | 6 (21) | 3 (10) |
3 | 2 (7) | 1 (3.5) |
Not reported | – | 3 (10) |
ISS stage | ||
I | 3 (10) | 6 (21) |
II | 13 (45) | 4 (14) |
III | 13 (45) | 12 (41) |
Not reported | – | 7 (24) |
R-ISS stage | ||
I | 1 | Not evaluated |
II | 23 | Not evaluated |
III | 2 | Not evaluated |
Not reported | 3 | – |
High-risk CA | ||
t(4;14) | 1 (3.5) | 1 (3.5) |
t(14;16) | 1 (3.5) | 1 (3.5) |
del(17p) | 1 (3.5) | 7 (24) |
Lines of the previous therapy, n, median (range) | 1 (1–4) | 1 (0–4) |
Multiple antimyeloma therapy | ||
Bortezomib-based regimensa | 26 (90) | 12 (41) |
Kd | 1 (3.5) | 3 (11) |
Lenalidomide-based regimensb | 7 (24) | 11 (38) |
Pomalidomide-based regimensc | 0 | 3 (11) |
Daratumumab-based regimensd | 0 | 7 (25) |
Other regimense | 10 (34) | 9 (31) |
Single auto-HSCT | 9 (31) | 2 (7) |
Tandem auto-HSCT | 4 (14) | 0 |
Refractoriness to treatment | ||
PIs | 11 (38) | 8 (28) |
IMiDs | 12 (41) | 11 (38) |
PIs + IMiDs | 9 (31) | 5 (17) |
Last line of the previous therapy | 11 (38) | 11 (38) |
Data are presented as number (percentage) unless otherwise indicated. a Bortezomib-based regimens: BVD, PAD, PanVD, VCD, VD, VMP, VTD, and VTD-PACE b Lenalidomide-based regimens: IRd and Rd c Pomalidomide-based regimens: Pd and PCd d Daratumumab-based regimens: DKd, DVd, DRd, DVTD, DBP, and daratumumab monotherapy e Other regimes: BP, DCEP, CTD, MPT, and VMBCP Abbreviations: auto-HSCT, autologous hematopoietic stem cell transplant; BP, bendamustine, prednisone; BVD, bendamustine, bortezomib, dexamethasone; CA, cytogenetic abnormality; CTD, cyclophosphamide, thalidomide, dexamethasone; DCEP, dexamethasone, cyclophosphamide, etoposide, cisplatin; DKd, daratumumab, carfilzomib, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; ECOG, Eastern Cooperative Oncology Group; FISH2, the second fluorescence in situ hybridization test; IMiDs, immunomodulatory drugs; IRd, ixazomib, lenalidomide, dexamethasone; ISS, International Staging System; Kd, carfilzomib, dexamethasone; MPT, melphalan, prednisone, thalidomide; PAD, bortezomib, doxorubicin, dexamethasone; PanVD, panobinostat, bortezomib, dexamethasone; PCd, pomalidomide, cyclophosphamide, dexamethasone; Pd, pomalidomide, dexamethasone; PIs, proteasome inhibitors; Rd, lenalidomide, dexamethasone; R-ISS, Revised International Staging System; VCD, bortezomib, cyclophosphamide, dexamethasone; VD, bortezomib, dexamethasone; VMBCP, vincristine, carmustine, cyclophosphamide, melphalan, prednisone; VMP, bortezomib, melphalan, prednisone; VTD, bortezomib, thalidomide, dexamethasone; VTD-PACE, bortezomib, thalidomide, dexamethasone; cisplatin, doxorubicin, cyclophosphamide, etoposide | ||
In all patients with MM, whose clinical data were available and who had the FISH test performed at the time of diagnosis (n = 177), high-risk CAs, such as t(4;14), t(14;16), and del(17p), were found in 18 (10%), 4 (2%), and 12 (7%) patients, respectively. In turn, in the group tested twice in the course of the disease, each of these abnormalities was found in a single patient (3.5%). Cytogenetic evolution between the FISH1 and FISH2 tests (eFISH) was seen in 14 patients (48%), whereas 15 patients (52%) had stable cytogenetics (sFISH) over time. New del(17p) was acquired by 7 patients: as a new isolated cytogenetic alteration in 2 individuals and as a part of complex cytogenetic changes in 5 individuals. The median (range) percentage of plasma cells with acquired del(17p) was 82% (13%–98%). No other acquired high-risk CAs, such as t(4;14) and t(14;16), were found. The overall spectrum of cytogenetic changes detected in FISH2 tests is shown in Table 2.
Cytogenetic change | n (%) |
|---|---|
New additional copy / copies of the TP53 gene | 3 (21) |
New additional copy / copies of the ATM gene | 7 (50) |
New additional copy / copies of the IGH gene | 1 (7) |
Loss of additional copy / copies of the IGH gene | 3 (21) |
Loss of additional copy / copies of the FGFR3 gene | 2 (14) |
New deletion of the IGH gene | 2 (14) |
New deletion of the TP53 gene / del(17p) | 7 (50) |
New deletion of the MAF gene | 2 (14) |
Patients with eFISH and sFISH were similar with respect to baseline clinical (age, ISS [1 to 2 vs 3] and R-ISS [1 to 2 vs 3] stage, Eastern Cooperative Oncology Group [ECOG] performance status [0 to 1 vs 2 to 3], percentage of bone marrow plasma cells, and the presence of extramedullary disease and osteolytic lesions) and laboratory investigations (hemoglobin, lactate dehydrogenase [LDH], creatinine, beta-2 microglobulin, and albumin levels; platelet, neutrophil, monocyte, and lymphocyte counts).
Patients received a median (range) number of 3 (2–6) lines of antimyeloma therapy. Importantly, all but 1 patient received PIs-based treatment combination (97%), and 26 patients (90%) were treated with IMiDs. Daratumumab as a single agent or in combination with PIs and / or IMiDs was used in 6 patients (21%). Almost half of the study patients received auto-HSCT (n = 14 [48%]). Between the diagnosis and the FISH2 test, patients with eFISH received significantly more treatment lines (median [range], 2 [1–4]) compared with those with sFISH (median [range], 1 [1–3]) (P = 0.04). Before the FISH2 evaluation, 11 (38%) and 12 (41%) patients were refractory to PIs (bortezomib or carfilzomib) and IMiDs (thalidomide or lenalidomide), respectively. Double refractoriness to PIs and IMiDs was observed in 9 patients (31%), whereas 11 patients (38%) were refractory to the last line of the previous therapy (Table 1). However, both the refractory status to PIs and / or IMiDs and refractoriness to the last treatment line before the FISH2 evaluation were not significantly associated with the occurrence of cytogenetic evolution. Similarly, there was no association between CE and the depth of response achieved to the last treatment line before the FISH2 evaluation (complete response or very good partial response versus partial response).
Prognostic significance of cytogenetic evolution on progression-free survival
After the FISH2 evaluation, 3 patients did not receive any further antimyeloma treatment (1 patient died before starting the next treatment line, and 2 patients had the FISH2 test performed during biochemical relapse) and were excluded from the PFS analysis. Of the remaining 26 patients, 17 (65%) experienced disease progression. A median PFS for the entire cohort was 7.1 months (95% CI, 6.4–12). The presence of CE was shown to have a negative impact on PFS (median PFS, 3.9 months and 9.3 months for eFISH and sFISH, respectively; hazard ratio [HR], 2.9; 95% CI, 1.05–7.9; P = 0.04) (Figure 1 and Table 3).
Figure 1. The effect of cytogenetic evolution on progression-free survival after the second fluorescence in situ hybridization test
Abbreviations: eFISH, cytogenetic evolution between fluorescence in situ hybridization tests 2 and 1; sFISH, stable cytogenetics observed after comparing the results of fluorescence in situ hybridization tests 2 and 1
Independent variable | PFS | OS2 | ||||||
|---|---|---|---|---|---|---|---|---|
Univariable analysis | Multivariable analysis | Univariable analysis | Multivariable analysis | |||||
HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
Cytogenetic evolution (eFISH) | 2.9 (1.05–7.9) | 0.04 | 1.8 (0.4–7.9) | 0.42 | 7.8 (2.2–27.9) | 0.002 | 2.7 (0.24–33.3) | 0.44 |
Acquired del(17p) | 18.8 (3.1–109.5) | 0.001 | 9.3 (2.0–44) | 0.005 | 41.6 (5.9–292.7) | <0.001 | 18.8 (2.6–134.9) | 0.004 |
LDH serum activity >ULN | 4.9 (1.1–21.9) | 0.04 | 5.0 (1.3–19.7) | 0.02 | 3.4 (0.64–18) | 0.05 | 5.7 (0.98–33.5) | 0.05 |
Bone marrow plasma cells >70% | 2.5 (0.9–7.2) | 0.09 | 3.3 (0.8–13.3) | 0.1 | – | – | – | – |
Abbreviations: del(17p), deletion of the short arm of chromosome 17; HR, hazard ratio; LDH, lactate dehydrogenase; OS2, overall-survival after the second fluorescence in situ hybridization test; PFS, progression-free survival; ULN, upper limit of normal; others, see Figure 1 | ||||||||
Patients who acquired del(17p) during the course of the disease achieved significantly shorter PFS compared with those who did not acquire del(17p) over time (median PFS, 1.5 months and 8.9 months, respectively; HR, 18.5; 95% CI, 3.1–109.5; P = 0.001) (Figure 2 and Table 3).
Figure 2. The effect of the acquisition of the chromosome 17p (del<17p>) deletion on progression-free survival after the second fluorescence in situ hybridization test
Laboratory and clinical factors assessed at the time of the FISH2 evaluation, such as age (≥65 years or <65 years), ISS stage (3 vs 1 to 2), ECOG performance status (2 to 3 vs 0 to 1), and percentage of bone marrow plasma cells (>70% vs ≤70%), refractoriness to PIs, IMiDs, or double refractoriness to PIs and IMiDs had no significant prognostic effect on PFS. On the other hand, higher LDH serum activity (above the upper limit of normal vs below the upper limit of normal) was associated with a significant reduction in PFS (HR, 4.9; 95% CI, 1.1–21.9; P = 0.04).
After univariable analysis, the presence of acquired del(17p), CE seen when comparing the results of the FISH1 and FISH2 tests, bone marrow plasma cell percentage higher than 70%, and LDH serum activity above the upper limit of normal had P <0.1 for predicting shorter PFS and were included in multivariable analysis (Table 3). In the multivariable Cox proportional model, only the presence of acquired del(17p) and a higher LDH serum activity significantly predicted shorter PFS with HR of 9.3 (95% CI, 2–44; P = 0.005) and 5 (95% CI, 1.3–19.7; P = 0.02), respectively (Table 3).
Prognostic significance of cytogenetic evolution on overall survival 1 and 2
In total, 10 deaths were reported during the follow-up. The median OS1 was 4.6 years (95% CI, 3.8–5.2 years). At a median (range) study follow-up of 3.1 (0.8–5.2) years, patients with sFISH had improved survival compared with those with eFISH (median OS1 not reached [NR] vs that of 3.8 years; HR, 0.15; 95% CI, 0.04–0.55; P = 0.04). The median OS1 in patients with acquired del(17p) was 2.95 years (95% CI, 2.16–5.2) compared with 4.7 years (95% CI, 4.1–4.8) in those who did not acquire del(17p) during the course of the disease (P = 0.16).
At a median (range) follow-up after the FISH2 evaluation of 0.6 (0.1–4.4) years, the median OS2 was 1.7 years (95% CI, 0.8–2.4) and was significantly longer in the sFISH group compared with the eFISH group (median OS2, NR vs 0.8 years; HR, 0.13; 95% CI, 0.04–0.45; P = 0.002) (Figure 3 and Table 3). The study patients with acquired del(17p) achieved a significantly shorter median OS2 compared with those who did not acquire del(17p) over time (median OS2, 0.5 years [95% CI, 0.13–0.8] and 2.4 years [95% CI, 1.12–2.4], respectively; HR, 41.6; 95% CI, 5.9–292.7; P <0.001) (Figure 4 and Table 3). After excluding the group with acquired del(17p) from the analysis, the median OS2 in the sFISH group was still significantly longer compared with the eFISH group (median OS2, NR vs 1.12 years [95% CI, 1.12–2.4], respectively; HR, 0.13; 95% CI, 0.02–0.88; P = 0.04).
Figure 3. The effect of cytogenetic evolution on overall survival after the second fluorescence in situ hybridization test
Abbreviations: see Figure 1
Figure 4. The effect of the acquisition of the chromosome 17p (del<17p>) deletion on overall survival after the second fluorescence in situ hybridization test
Other laboratory and clinical factors assessed at the FISH2 evaluation, such as age (≥65 years or <65 years), ISS stage (3 vs 1 to 2), ECOG performance status (2 to 3 vs 0 to 1), percentage of bone marrow plasma cells (>70% vs ≤70%), LDH serum activity (above the upper limit of normal vs below the upper limit of normal), refractoriness to PIs, IMiDs, or double refractoriness to PIs and IMiDs had no significant prognostic impact on OS2.
After univariable analysis, the presence of acquired del(17p), CE seen between the FISH1 and FISH2 tests, and LDH serum activity above the upper limit of normal showed P <0.1 for predicting shorter OS2 and were included in multivariable analysis (Table 3). In the multivariable Cox proportional model, only the presence of acquired del(17p) significantly predicted shorter OS2 with HR of 18.8 (95% CI, 2.6–134.9; P = 0.004) (Table 3).
Discussion
Although the survival of patients with MM has dramatically improved over the past decades,24 the disease still presents a relapsing clinical course, and treatment for subsequent relapses remains a major challenge in routine clinical practice.
In recent years, studies using NGS have provided a new insight into the molecular biology of MM, highlighting its intratumor genetic heterogeneity and evolutionary nature. Myeloma is now considered a mosaic of genetically distinct subclones that compete with each other over time following different patterns of clonal evolution.12,13,15,16 Both the tumor microenvironment and the antimyeloma treatment exert selection pressure on subclones, ultimately shaping the clonal architecture of the disease in time.12,14,17 However, the potential of NGS has not been translated into routine clinical practice yet, and FISH testing remains the basic and widely used method for assessing the genetic status of MM.18
On one hand, there is a general consensus that cytogenetics evaluated by FISH is essential for risk stratification and should be part of the initial diagnostic workup in all patients with newly diagnosed MM.25-29 On the other hand, relatively little is known about the occurrence and prognostic significance of CE at the time between the diagnosis of MM and disease progression. Clinical practice guidelines differ with respect to recommendations for re-evaluation of FISH tests at MM relapse. The European Society for Medical Oncology guidelines do not recommend clinicians to reassess FISH tests during the MM relapse,26 whereas the National Comprehensive Cancer Network clinical practice guidelines advocate FISH test re-evaluation depending on the clinical situation.29 In contrast, the American Society of Clinical Oncology28 and Mayo Clinic27 guidelines recommend full cytogenetic restaging in every MM relapse. Conversely, the routine diagnostic approach in Poland is solely based on the FISH evaluation at the time of MM diagnosis,22 which may explain a relatively low percentage of patients in our database who had 2 FISH tests evaluated during the course of the disease.
In this study, we showed that in a significant proportion of patients (48%), the signs of CE can be detected in a routine FISH MM panel using a limited number of probes. The occurrence of CE in our study cohort was independent of the ISS and R-ISS stage and other commonly used laboratory and clinical prognostic factors for survival in MM. Therefore, our findings suggested that CE is not easily predictable, and basic clinical data are not useful for reliable identification of patients who require the second FISH evaluation.
The univariable analysis revealed that the occurrence of CE between the time of the diagnosis of MM and relapse had a significant negative impact on OS and survival after the second FISH evaluation in the study patients. These findings are consistent with the results of a recent large-scale, retrospective study of 164 patients with MM who underwent serial FISH evaluations, which demonstrated that the development of additional CAs during the 3 years following the diagnosis of MM was associated with increased subsequent mortality with HR of 3.3 (P <0.001).30
In the era of novel antimyeloma agents, the presence of primary high-risk CAs, such as t(4;14), t(14;16), t(14;20), and, in particular, del(17p), still negatively impacts the outcomes in patients newly diagnosed with MM.31,32 The prevalence of primary high-risk CAs is significant, with 15%, 3% to 5%, and 5% to 8% of patients with newly diagnosed MM affected by t(4;14), t(14;16), and del(17p), respectively.33,34 In our database, the incidence of high-risk CAs at the time of the diagnosis of MM was in accordance with previously reported data with t(4;14), t(14;16), and del(17p) found in 10%, 2%, and 7% of patients, respectively. Nevertheless, in the group of patients in whom the FISH analysis was performed twice during the course of the disease, each of these primary high-risk CAs was found in a single patient (3.5%).
In contrast to the well-defined prognostic significance of primary high-risk CAs, the prognostic impact of high-risk CAs acquired during the progression of MM is less documented. In our cohort, del(17p) was the only high-risk CA acquired in the course of MM progression and no other acquired high-risk CAs, such as t(4;14) and t(14;16), were found. This could be explained by the fact that IGH-involving translocations are one of the initiating genetic events in the genesis of myeloma.35 These findings are in line with the results recently reported by Merz et al.36 In that retrospective study evaluating cytogenetic changes in 128 patients with MM who relapsed after auto-HSCT, there were no new t(4;14), t(11;14), or t(14;16) translocations found at relapse. However, in opposite to our study, IGH translocations with other unknown partner genes were observed.36 In another study, the acquisition of t(4;14) during relapse was observed in 14 out of 268 patients with MM.37 However, the detailed analysis showed that t(4;14) was already present at the time of the diagnosis of MM in a minor subclone that had not been initially detected by FISH. That subclone underwent positive selection during antimyeloma therapy and became the dominant clone during relapse.37
Our results indicated that the acquisition of del(17p) during the progression of MM is associated with an extremely poor prognosis in the population of patients with MM with the median OS after the gain of del(17p) of 6 months (HR, 18.8; 95% CI, 2.6–134.9) and the median PFS from the start of the next line of therapy of 1.5 months (HR, 9.3; 95% CI, 2–44). Recently, Lakshman et al24 reported outcomes of 76 patients with MM and acquired del(17p) who were treated at Mayo Clinic. The median OS from detection of del(17p) was 18.1 months (95% CI, 11.9–25), and the median PFS from the start of the next line of therapy was 5.4 months (95% CI, 2.7–7.7).24 These clinically significant differences in the outcomes of patients with acquired del(17p) between our study group and the Mayo Clinic cohort may, at least partly, result from differences in access to modern antimyeloma agents,38 as more patients were treated with daratumumab-, pomalidomide-, carfilzomib- or ixazomib-containing regimens in the Mayo Clinic cohort.
It should be emphasized that cytogenetic reassessment has had only prognostic significance so far and currently no prospective data are available indicating clinical benefits of adapting the therapeutic strategy to the current cytogenetic profile of RRMM. Nevertheless, data from the subgroup analysis of randomized clinical trials have provided some information that may prompt a clinician to choose a specific therapy depending on patient’s current cytogenetics. In this context, there are data suggesting that patients with RRMM and del(17p) could benefit from pomalidomide-dexamethasone37,39,40 or lenalidomide-dexamethasone in combination with carfilzomib39,41 or ixazomib2,39 or daratumumab.9
Admittedly, our study was limited by its retrospective design. Despite the fact that the data came from a large European hematology center, a relatively small group of patients was evaluated by FISH twice during the course of the disease. Moreover, the FISH data were limited by their routine character, which was associated with the restricted number of probes used for analysis. Finally, patients were not treated uniformly and novel antimyeloma drugs, such as carfilzomib, pomalidomide, and daratumumab, were administered relatively rarely.
In conclusion, we showed that CE and, in particular, the acquisition of del(17p) detected in routine FISH testing negatively affects the outcomes of patients with RRMM. Given the extremely poor prognosis of patients with acquired del(17p), the re-evaluation of FISH tests at each subsequent MM relapse should be included in routine clinical practice.
Aleksander Salomon-Perzyński, MD, Department of Hematology, Institute of Hematology and Transfusion Medicine, ul. Indiry Gandhi 14, 02-776 Warszawa, Poland, phone: +48 22 349 63 21, email: salomon.perzynski@gmail.com
February 1, 2020.
April 22, 2020.
April 27, 2020.
This study was supported by the IntraMMclo „Multiple myeloma intraclonal heterogeneity: evolution and implications of targeted therapy” grant (ERA- NET TRANSCAN2/intraMMclo/2/2017), financed by the Polish National Center for Research and Development within the ERA-NET: Aligning national / regional translational cancer research programmes and activities TRANSCAN 2 project.
ASP and KJ conceived the concept of the study. All authors were involved in data collection. ASP and NJ performed statistical analysis. ASP, AB, AK, JB, and NJ analyzed the data. ASP, JB, and KJ drafted the manuscript. KJ coordinated funding of the project. All authors edited and approved the final version of the manuscript.
None declared.
Salomon-Perzyński A, Bluszcz A, Krzywdzińska A, et al. The impact of cytogenetic evolution and acquisition of del(17p) on the prognosis of patients with multiple myeloma. Pol Arch Intern Med. 2020; 130: 483-491. doi:10.20452/pamw.15316
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