Multiple myeloma (MM) makes up 10% of hematological malignancies and 1% of all cancers. It is mostly seen in men, and the median age is reported to be about 65 years old [1]. MM, which causes excessive production of monoclonal light chain and heavy chain, is a malign disease of plasma cell [2]. Autologous stem cell transplantation (ASCT) after high dose chemotherapy is the favored standard treatment in fit patients diagnosed with MM. The International Staging System (ISS) was made based on levels of serum albumin and beta-2 microglobulin. Yet in the revised ISS, in addition to the ISS, added factors such as serum lactate dehydrogenase (LDH) and deletion of 17p, t (4; 14), t (14; 16) are evaluated by interphase fluorescence in situ hybridization (FISH) [1-3].
The circadian clock (CC), which is governed via the main center of mammalian physiology in the superior chiasmatic nucleus, plays a role in the arrangement of behavior of biological and physiological, as per the light cycle and dark cycle in the daily period [4, 5]. This center forms a link with a complex neurohumoral network via temperature daily rhythms, photic signals by retina, social stimuli and diet. The circadian rhythm (CR) is regulated by CR pathway genes, the mammalian CC mechanism has interlocking transcription-translation feedback loops, controlled at the molecular level by a set of genes, including
The CC Protein
In this study, we intend to investigate the distributions and clinical efficacy of the
One hundred fifty patients (over 18 years old), diagnosed with MM in Hematology Clinic of Gaziantep University between January 2007 - 2009, and 100 healthy persons were included in this study. Demographic characteristics, first-line treatments, clinical scores (Durie-Salmon stages, ISS score, Eastern Cooperative Oncology Group (ECOG) score), laboratory variables, status of survival (overall (OS) and progression-free (PFS)) were recorded.
All patients were suitable for ASCT at first evaluation and following four courses on bortezomib-cyclophosphamide and dexamethasone (VCD) at partial remission (PR), ASCT was carried out. Following 24 months, lenalidomide-dexamethasone (LD) was used as maintenance.
The genotypes of 4R/4R-5R, 5R/5R and alleles of 4R and 5R on
DNA isolation via peripheral blood leukocytes was measured by the saline precipitation method [10]. Genotypes of
According to the Kolmogorov-Smirnov test, quantitative variables that fit the normal distribution were shown as mean±standard deviation, but those that did not fit were shown as median (minimum and maximum). Comparisons between qualitative measures expressed as numbers and percentages (%) were made using Chi-square or Fisher’s exact tests. Post-hoc analysis was evaluated with Bonferroni correction for intergroup comparisons. Variables associated with different gene variants were determined in the multivariate logistic regression model adjusted for gender and age. Regression results are shown with odds ratio (OR) and 95% confidence interval (CI). Hardy Weinberg Equilibrium (HWE) was performed via the De-Finetti program (online HWE and Association Testing-Institut für Humangenetik, Munich, Germany). All analyses were performed with IBM SPSS version v21.0 (IBM Corp, Armonk, NY, USA), and a p-value less than 0.05 was considered statistically significant.
The median age was 56 years (range: 32-70). The 10-years OS was 79%, while the 10-years PFS was 47% with a median of 52.7 months. The mortality rate was 15.3% (n:23) (Table 1.).
Clinical features and treatment regimens of MM patients
Multiple Myeloma | Control | Control | p | |||
---|---|---|---|---|---|---|
median | na (%) | median | nb (%) | |||
Age | 56 (32-70) | 53 (28-68) | 0.140* | |||
Gender | Female/Male | 77/73 (51.3/48.7) | 55/45 (55/45) | 0.367& | ||
MM Subtypes | κ/λ | 83/39 (68/32) | ||||
G/A | 79/18 (65/15) | |||||
Light chain | 25 (20) | |||||
Stage (Durie-Salmon) | II/III | 38/84 (25/75) | ||||
A/B | 91/31 (79/21) | |||||
IPI | I | 39 (32) | ||||
II/III | 34/50 (28/40) | |||||
ECOG | >1 | 12 (10) | ||||
Hemoglobin | gr/dL | 10.4 (6.2-15) | ||||
Leukocyte | mm3 | 7200 (2760-18500) | ||||
Platelet | 103μL | 172 (69-406) | ||||
C-reactive protein | mg/dL | 8 (2.1-352) | ||||
LDH | IU/L | 212 (93-1037) | ||||
B2-microglobulin | mg/L | 4.9 (1.5-48) | ||||
Albumin | gr/L | 3.5 (1.6-5.1) | ||||
Treatment | VCD, ASCT, LD | |||||
OS (10-years, %) | (79) | |||||
PFS (10-years, %) | (47) – 52.7 months | |||||
Relapse | 63 (42) | |||||
Mortality | 23 (15.3) | |||||
Follow-up duration, months, (range) | 36.1 (4.1-155.2) |
na = 150;
nb = 100;
median test,
Pearson Chi-Square
**MM: Multiple myeloma, IPI:International Prognostic Index, ECOG:Eastern Cooperative Oncology Group, CRP:C-reactive protein, LDH: Lactate dehydrogenase, OS: Overall survival, PFS: Progression free survival, VCD: Bortezomib-cyclophosphamide and dexamethasone, LD: Lenalidomide- dexamethasone, ASCT: Autologous stem cell transplantation
According to
Comparison of frequencies of PER-3 gene variants between patients with MM and healthy controls
PER3 | Genotype | Multiple Myeloma | Healthy Controls | OR Exp(B) | 95% CI | p |
---|---|---|---|---|---|---|
n=a (%) | n=100 (%) | |||||
4R/4R | 70 (46.7) | 42 (42) | 0.657* | 0.285-1.517* | 0.325* | |
4R/5R | 64 (43.3) | 44 (44) | 0.745* | 0.320-1.734* | 0.494* | |
5R/5R | 16 (10.7) | 14 (14) | 1.363& | 0.633-2.935& | 0.434& | |
4R | 204 (67.5) | 128 (64) | ||||
5R | 98 (32.5) | 72 (36) | 1.159& | 0.796-1.689& | 0.443& |
n= 150,
:OR (95%CI) was adjusted by age and sex,
Fisher’s Exact Test.
PER3: Circadian Clock Protein PERIOD 3
Table 3 shows the results of evaluating prognostic factors in terms of PFS and OS. In the 10-year survival analysis, the rate was shown as a percentage if it was above 50%, and as a month if it was below 50%. Median PFS in the 5R/5R genotype was found to be significantly longer, albeit low, at 86% (p = 0.046). In the statistical analysis performed between the 4R/4R genotype and other genotypes, the PFS of patients with this genotype was found to be significantly shorter with 40.4 months (p = 0.026).
Comparison of PFS and OS with prognostic factors of patients with MM
PFS* | Log Rank p-value | os*,# | Log Rank p | |||
---|---|---|---|---|---|---|
n | 52.7 | 77# | ||||
73/77 | 89.3 /39.2 | 0.080 | 66# / 69# | 0.690 | ||
130/20 | 54.3 / 40.4 | 0.230 | 56# / 54# | 0.058 | ||
38/84 | 28.5 / 54.3 | 0.257 | 87.1 / 99.1 | 0.229 | ||
91/31 | 40.4 / 65.0 | 0.277 | 55# / 51# | 0.301 | ||
39 | 69.3 | 99.1 | ||||
34 | 40.4 | 70# | ||||
50 | 52.7 | 0.764 | 88.2 | |||
109/12 | 47.1 / 28.5 | 0.959 | 53# / 31.4 | 0.301 | ||
116/7 | 52.7 / 17 | 0.086 | 53# / 17 | |||
51/71 | 54.3 / 52.7 | 0.686 | 85# /99.1 | 0.057 | ||
4R/4R | 70 | 40.4 | 74# | |||
4R/5R | 64 | 69.3 | 57# | |||
5R/5R | 16 | 86# | 100# | 0.349 | ||
4R/4R | 70 | 40.4 | 63# | |||
4R/5R -5R/5R | 80 | 89.6 | 99.1 | 0.738 |
: median months,
:10-yrs %
MM: Multiple myeloma, IPI:International Prognostic Index, ECOG:Eastern Cooperative Oncology Group, CRP:C-reactive protein, LDH: Lactate dehydrogenase, OS: Overall survival, PFS: Progression free survival, PER3: Circadian Clock Protein PERIOD 3
Table 4 shows the multivariate analysis. It was observed that patients with the 4R/4R genotype would have a risk of 2.049 times of shorter PFS (p= 0.009) (Figure 1.).
Multivariate analysis of 150 MM patients (Cox proportional hazard model backward)
PFS | ||||
---|---|---|---|---|
Exp (B) | %95 CI | p | ||
4R/4R | 0.488 | 0.284-0.837 | ||
≥480 | 0.441 | 0.170-1.141 | 0.091 | |
Female/Male | 0.604 | 0.357-1.022 | 0.060 |
MM: Multiple myeloma, PER3: Circadian Clock Protein PERIOD 3, LDH: Lactate dehydrogenase
Progression free survival curves: 4R/4R and 4R/5R-5R/5R
This study is the first to report on the association between CR and MM. Literature data on CR and hematological malignancies are also limited; there are related studies on solid malignancies.
In a current study from 2021 by Dagmura et al. [12], CR and pancreatic cancer (PC) were studied. The frequency of the 4R/3R, 3R/3R genotypes, and 3R allele of
Geng et al. [13] examined the association of
Clinical data on hematological malignancies and
The relationship of CR genes with sleep disturbance has been extensively studied. Guess et al. [6] found that the 4/4 genotype showed more physical fatigue and sleep disturbances. Sleep disturbance and increased inflammation or inflammatory markers have been the subject of many studies [18–20]. In these studies there is a positive correlation between sleep disturbance and increased vascular endothelial growth factor (VEGF) concentration. VEGF contributes to the pathogenesis of MM. It plays a role in myeloma development, bone marrow microenvironment interaction, disease progression and drug resistance. VEGF and VEGF receptor expression is increased in myeloma bone marrow [21]. Anti-VEGF treatment strategies are also discussed in the treatment of myeloma. In addition, proteosome inhibitors, immunomodulatory drugs (IMIDs) and bisphosphonates, which are the cornerstones of MM treatment, have also been shown to reduce VEGF levels [21]. In our study, the 4R/4R genotype, which is significantly associated with sleep disorder and physical fatigue, high VEGF level is thought to be related. Therefore, a significant short PFS constitutes the most important result of the study.
This study had also some important limitations. OS may not have differed significantly due to the narrowing of the patient population when the genotype was divided into gene variant subgroups. In addition, not evaluating synchronous cytokines is another important limitation. There were also deficiencies in patient data in terms of comorbidity or genetic mutation subtypes, and it was therefore not possible to analyze them together.
In conclusion, this study contributes to the literature in terms of MM and