Clinical efficacy of Thalidomide combined with PAD Regimen in patients with multiple Myeloma.

INTRODUCTION

Multiple myeloma (MM) is a common hematological disease, accounting for 10% of all tumors of the hematopoietic system. 1 This disease is also a malignant clonal plasma cell disease. Most of such patients will develop bone diseases, manifested as bone pain, pathological fractures and nerve compression syndrome, which seriously affect their quality of life. 2 At present, chemotherapy is often used to treat MM. Although chemotherapy can alleviate the condition, the remission rate is not high. With the introduction of novel drugs, the therapeutic effect in patients with myeloma has been significantly improved. However, this disease is considered incurable and shows considerable heterogeneity in clinical manifestations, course of disease and survival rate. 3

PAD regimen consists of bortezomib, doxorubicin and dexamethasone. Bortezomib has a strong killing effect on myeloma cells, and is widely used in the adjuvant therapy of chemotherapy for MM. 4 Nevertheless, for the treatment of MM, combined therapy usually has a deeper response and better long-term outcomes than chemotherapy alone. 5 Thalidomide is a glutamate derivative, which not only has immunomodulatory and anti-inflammatory effects, but also can inhibit angiogenesis and reduce microvessel density in tumors, so as to play an anti-tumor role. 6 In our study, thalidomide combined with a PAD regimen was used to treat patients with MM, which achieved certain clinical results.

METHODS

It was a Clinical comparative study. A total of 120 patients with multiple myeloma (MM) were admitted at Beijing Aerospace General Hospital from September 2020 to June 2022 randomly divided into two groups, with 60 patients in each group. In the study group, there were 32 males and 28 females, aging 55-70 years (average, 60.75 ± 6.74 years). The control group included 35 males and 25 females, with an age of 58-69 years (average, 62.70 ± 6.61 years). The general data of the two groups showed no significant differences, suggesting comparability ( Table-I ).

Ethical Approval

The study was approved by the Institutional Ethics Committee of Beijing Aerospace General Hospital (No.: AF/SQ-02/01.0; Date: April 15, 2020), and written informed consent was obtained from all participants.

Inclusion criteria

Age< 70 years;

Meeting the diagnostic criteria of MM 7 ;

At least two or more osteolytic lesions by bone scanning;

Durie-Salmon (DS) stage I-III 8 ;

Good physical condition with the ability to take care of themselves (KPS score ≥ 70);

Complete case data and follow-up data.

Exclusion criteria:

Combined with other hematological diseases;

Combined with malignant tumors of other organs;

Poor physique and intolerance to treatment;

Mental disorders and nervous system abnormalities, or inability to cooperate with the study for other reasons;

Hepatic and renal dysfunction;

Allergy or intolerance to drugs used in this study;

Recent oral administration of drugs that affect the results, such as hormones and immunosuppressants; pregnancy or lactation.

Treatment methods

Blood cell analysis and detection of hepatic and renal function were performed in both groups, and the abnormal indexes were corrected correspondingly. One day before chemotherapy, hydration was conducted. During chemotherapy, the detection was carried out, and the patients were treated with antiemetic therapy, hepatic and renal function-protecting therapy and fluid replacement.

The study group was treated with thalidomide combined with a PAD regimen (bortezomib, doxorubicin and dexamethasone): bortezomib (1.3 mg/m 2 /d) was injected intravenously on the 1st, 4th, 8th and 11th day; dexamethasone (20 mg) was injected intravenously daily on the 1st~4th and 8th~11th day; doxorubicin (15 mg/m 2 /d) was injected intravenously on the 1st~4th day. Additionally, thalidomide was given at the initial stage of inductive chemotherapy, 25 mg orally, three times/d. Treatment was continued for 2-8 courses (every 11 day), with an interval of three weeks.

The control group was treated with a PAD regimen alone (bortezomib, doxorubicin and dexamethasone). After treatment, both groups underwent a routine blood test, detection of hepatic and renal function, electrocardiography (ECG) and chest X-ray, during which antibiotics were given according to the specific condition of the patients.

Observation indexes:

Evaluation of clinical efficacy

After treatment, the clinical efficacy of the two groups was evaluated as: complete remission (CR): after treatment, serum M protein test was negative, which lasted for six weeks, plasma cell tumors disappeared, the content of bone marrow plasma cells < 5%, and osteolytic lesions were not aggravated; nearly complete remission (nCR): after treatment, immunofixation electrophoresis was positive, plasma cell tumors disappeared, the content of bone marrow plasma cells < 5% and osteolytic lesions were not aggravated; partial remission (PR): after treatment, the content of serum M protein decreased by more than 50%, which lasted for > six weeks, 24-hour urinary light chain < 200 g or its decrease > 90% for more than six weeks, the reduction of plasma cell tumor > 50%, and osteolytic lesions were not aggravated; mild response (MR): after treatment, the content of serum M protein decreased by 25%~49%, which lasted for > six weeks, and 24-h urinary light chain decreased by 50%~89%; no change (NC): after treatment, the clinical symptoms and signs ranged from mild remission to progression; disease progression (DP): after treatment, absolute serum M protein content increased by more than 5 g/L, absolute 24-h urinary light chain increased by 200 mg, absolute bone marrow plasma cell content increased by 10%, and osteolytic lesions were aggravated. Total effective rate = (CR + nCR + PR)/total cases × 100%.

Evaluation of adverse drug reactions

The adverse drug reactions of the two groups within one month after treatment were recorded, including bone marrow suppression, hair loss, gastrointestinal reactions, hepatic and renal dysfunction and fever.

Comparison of bone metabolic markers before and after chemotherapy

About 5 mL of venous blood was collected before and after chemotherapy, followed by centrifugation and serum isolation. The levels of serum alkaline phosphatase (ALP) and osteocalcin (OCN) were detected using an enzyme-linked immunosorbent assay (ELISA). 4 Analysis of immune state: Fasting blood was collected at the morning before and after treatment to detect the levels of T-lymphocyte subsets CD3 + , CD4 + , CD8 + and CD4 + /CD8 + determined by flow cytometry, and the differences between the two groups before and after treatment were compared and analyzed.

Statistical analysis

All data were statistically analyzed using SPSS 20.0. The measurement data were expressed as ( χ̅ ± S ). Two-group independent samples t-test were used for inter-group comparison, paired t-test for intra-group comparison, and χ 2 test for rate comparison. P< 0.05 was considered as statistically significant.

RESULTS

The comparison of clinical efficacy between the two groups is shown in Table-II . It was suggested that the total efficacy in the study group after treatment was 90%, which was significantly higher than 70% in the control group ( p= 0.00).

The comparison in the incidence of adverse drug reactions after treatment between the two groups revealed that the incidence of adverse drug reactions was 40% in the study group and 38% in the control group, without statistically significant difference ( p= 0.85) ( Table-III ).

Before treatment, ALP and OCN levels presented no significant differences between the two groups ( p> 0.05). After treatment, ALP and OCN levels in the study group were significantly higher than those in the control group (ALP, p= 0.01; OCN, p= 0.00), as seen in ( Table-IV ).

Before treatment, the two groups showed no significant differences in CD3 + , CD4 + , CD8 + or CD4 + /CD8 + level ( p> 0.05). After treatment, CD3 + , CD4 + and CD4 + /CD8 + in the study group increased significantly compared with those in the control group (CD3 + , p= 0.02; CD4 + , p= 0.00; CD4 + /CD8 + , p= 0.00). However, no obvious change was detected in CD8+ ( p= 0.79) ( Table-V ).

DISCUSSION

Our study showed that the total effective rate of thalidomide combined with PAD regimen in patients with MM was 90%, which was significantly higher than 70% in the control group ( p= 0.00). The incidence of adverse drug reactions was 40% in the study group and 38% in the control group, without statistically significant difference ( p= 0.85). MM has extensive bone destruction and abnormal bone metabolism. Bone destruction is mainly caused by the imbalance between osteolysis and osteogenesis.

MM is characterized by extensive osteolytic destruction, abnormal rise in monoclonal plasma cell ratio, osteolytic lesions, pathological fractures, anemia, hypercalcemia, nervous system damage, etc. 9 In addition, monoclonal M protein increases in the patients, which inhibits the synthesis of polyclonal immunoglobulin and increases the risk of infections. It is incurable in the current clinical treatment. Although significant progress has been made in the treatment in the past few decades, satisfactory results still cannot be achieved 10 , seriously threatening the health of patients. In the last two decades, with the emergence of novel drugs, the five years survival rate of MM can only be close to 50%. 11 At present, chemotherapy is still the main treatmentli for MM 12 , and the commonly used regimens include VAD, PAD, MP, etc.

It has been confirmed that the effect of the PAD regimen on MM is significantly better than that of the VAD regimen. 13 Bortezomib is a protease inhibitor, which can bind to threonine at the active site of proteasome and inhibit proteasome activity, thus suppressing the degradation of nuclear factor-κB (NF-κB) and inhibitory factor-κB (I-κB) and inducing the apoptosis of tumor cells. 14 Sonneveld et al. 15 have pointed out in their study that bortezomib can coordinate the interaction between bone marrow tumor cells and stromal cells, so drug resistance hardly occurs and patients with multiple adverse cytogenetic abnormalities cannot benefit from these drugs. Glucocorticoids are the basis of the treatment of MM. Their compatibility with novel drugs improves the clinical response rate. 16 Another study 17 has found that bortezomib has a synergistic effect with dexamethasone, and can reverse the resistance of MM to melphalan, doxorubicin, etc.

The incurability of MM urges people to actively explore more favorable treatment regimens. According to the meta-analysis of Aguiar et al., the multi-target regimen has more obvious advantages than the chemotherapy regimen alone. 18 Immunotherapy that improves the immune state of the body is changing the treatment for patients with MM at all stages 19 , and achieves obvious effects. Thalidomide is a glutamate derivative, whose mechanisms include sedation and analgesia; immunomodulatory and anti-inflammatory effects and inhibition of angiogenesis and anti-tumor effect. Some cytokines, such as vascular endothelial growth factor and fibroblast growth factor, are stimulants of angiogenesis.

They bind to specific receptors to stimulate signal transduction and cause the proliferation of endothelial cells. This product can reduce their secretion and thereby inhibiting blood vessels. The metastasis and malignant transformation of tumor cells are related to the adhesion and angiogenesis of tumor cells and vascular endothelial cells. Thalidomide cannot only inhibit angiogenesis, but also reduce the synthesis of integrin subunits, which is also one of its anti-tumor mechanisms. Moreover, it reduces the microvessel density in tumors through the COX-2 pathway rather than inhibiting angiogenesis, so as to inhibit the proliferation of tumor cells. 20

The phase three clinical trial of Tacchetti et al. confirmed that the combined regimen of bortezomib and thalidomide was superior to the chemotherapy regimen alone. 21 Stork et al. 22 believe that bortezomib combined with thalidomide has an obvious short-term effect, and the long-term follow-up has verified that the combination with thalidomide provides additional advantages for the OS of patients. Jung’s study 23 has confirmed that thalidomide + dexamethasone-based regimen has great advantages in patients with recurrent/refractory MM (RRMM). Li et al. 24 believe that there is no increase in adverse reactions after thalidomide combined with chemotherapy, but thrombosis is still an important consideration in the treatment of MM. Furthermore, appropriate risk stratification and vigilant thrombosis prevention are essential to prevent this complication.

The combined effect of osteogenic differentiation disorders and osteoclastic hyper function leads to bone destruction. ALP and OCN mainly reflect the activity of osteoblasts. 25 It has been pointed out that the imbalance of T-lymphocyte subsets is closely related to the occurrence and development of MM. The main manifestations of the patients include the decrease in CD4 + level and the increase in CD8 + level. 26

Limitations

It includes asmall sample size and short follow-up time. In the future study, the number of samples will be gradually increased, the follow-up time will be extended, and the advantages and long-term effects of this treatment regimen will be further objectively evaluated.

CONCLUSION

Thalidomide combined with a PAD regimen is effective in patients with multiple myeloma, and it can obviously improve immune function and bone salt metabolism, with no increase in adverse reactions but high safety and effectiveness.

Authors’ Contributions:

YW: Designed this study and prepared this manuscript, and are responsible and accountable for the accuracy and integrity of the work.

QHM: Collected and analyzed clinical data.

CL: Data analysis, significantly revised this manuscript.

Footnotes

Declaration of conflicting interest: None.

Funding: None.

REFERENCES

1. Mosebach J, Thierjung H, Schlemmer HP, Delorme S. Multiple Myeloma Guidelines and Their Recent Updates:Implications for Imaging. Leitlinien zum multiplen Myelom und ihre aktuellen Anpassungen:Konsequenzen für die Bildgebung. Rofo. 2019;191(11):998–1009. doi: 10.1055/a-0897-3966. doi: 10.1055/a-0897-3966.

2. Joshua DE, Bryant C, Dix C, Gibson J, Ho J. Biology and therapy of multiple myeloma. Med J Aust. 2019;210(8):375–380. doi: 10.5694/mja2.50129. doi: 10.5694/ mja2.50129.

3. Castaneda O, Baz R. Multiple Myeloma Genomics - A Concise Review. Acta Med Acad. 2019;48(1):57–67. doi: 10.5644/ama2006-124.242. doi: 10.5644/ama2006-124.242.

4. Rosinol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019;134(16):1337–1345. doi: 10.1182/blood.2019000241. doi: 10.1182/blood.2019000241.

5. Goldschmidt H, Ashcroft J, Szabo Z, Garderet L. Navigating the treatment landscape in multiple myeloma:which combinations to use and when? Ann Hematol. 2019;98(1):1–18. doi: 10.1007/s00277-018-3546-8. doi: 10.1007/s00277-018-3546-8.

6. Mercurio A, Adriani G, Catalano A, Carocci A, Rao L, Lentini G, et al. A Mini-Review on Thalidomide:Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma. Curr Med Chem. 2017;24(25):2736–2744. doi: 10.2174/0929867324666170601074646. doi: 10.2174/0929867324666170601074646.

7. Brigle K, Rogers B. Pathobiology and Diagnosis of Multiple Myeloma. Semin Oncol Nurs. 2017;33(3):225–236. doi: 10.1016/j.soncn.2017.05.012. doi: 10.1016/j.soncn.2017.05.012.

8. Shaikh SP, Irfan SM, Sheikh SS. Disease staging according to international scoring system in newly diagnosed patients with multiple myeloma. Pak J Med Sci. 2019;35(1):90–94. doi: 10.12669/pjms.35.1.173. doi: 10.12669/pjms.35.1.173.

9. Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020;130(4):1565–1575. doi: 10.1172/JCI129205. doi: 10.1172/JCI129205.

10. Lei M, Kim EB, Branagan A, Lou U, Zemel M, Raje N. Current management and emerging treatment strategies for multiple myeloma. Rinsho Ketsueki. 2019;60(9):1243–1256. doi: 10.11406/rinketsu.60.1243. doi: 10.11406/rinketsu.60.1243.

11. Ailawadhi S, Mikhael JR, LaPlant BR, Laumann KM, Kumar S, Roy V, et al. Pomalidomide-dexamethasone in refractory multiple myeloma:long-term follow-up of a multi-cohort phase II clinical trial. Leukemia. 2018;32(3):719–728. doi: 10.1038/leu.2017.258. doi: 10.1038/leu.2017.258.

12. Raza S, Safyan RA, Lentzsch S. Immunomodulatory Drugs (IMiDs) in Multiple Myeloma. Curr Cancer Drug Targets. 2017;17(9):846–857. doi: 10.2174/1568009617666170214104426. doi: 10.2174/1568009617666170214104426.

13. Roussel M, Moreau P, Hebraud B, Laribi K, Jaccard A, Dib M, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA):health-related quality of life outcomes of a randomised open-label phase 3 trial. Lancet Haematol. 2020;7(12):e874–e883. doi: 10.1016/S2352-3026(20)30356-2. doi: 10.1016/S2352-3026(20)30356-2.

14. Xie Y, Liu J, Jiang H, Wang J, Li X, Wang J, et al. Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma. Oncogene. 2020;39(4):922–934. doi: 10.1038/s41388-019-1037-6. doi: 10.1038/s41388-019-1037-6.

15. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with highrisk cytogenetics: a consensus of the International MyelomaWorking Group. Blood. 2016;127(24):2955–2962. doi: 10.1182/blood-2016-01-631200. doi: 10.1182/blood-2016-01-631200.

16. Burwick N, Sharma S. Glucocorticoids in multiple myeloma:past, present, and future. Ann Hematol. 2019;98(1):19–28. doi: 10.1007/s00277-018-3465-8. doi: 10.1007/s00277-018-3465-8.

17. Holstein SA, McCarthy PL. Immunomodulatory Drugs in Multiple Myeloma:Mechanisms of Action and Clinical Experience. Drugs. 2017;77(5):505–520. doi: 10.1007/s40265-017-0689-1. doi: 10.1007/s40265-017-0689-1.

18. Aguiar PM, de Mendonca Lima T, Colleoni GWB, Storpirtis S. Efficacy and safety of bortezomib, thalidomide, and lenalidomide in multiple myeloma:An overview of systematic reviews withmeta-analyses. Crit Rev Oncol Hematol. 2017;113:195–212. doi: 10.1016/j.critrevonc.2017.03.014. doi: 10.1016/j.critrevonc.2017.03.01419.

19. Verkleij CPM, Korst CLBM, van de Donk NWCJ. Immunotherapy in multiple myeloma:when, where, and for who? Curr Opin Oncol. 2020;32(6):664–671. doi: 10.1097/CCO.0000000000000677. doi: 10.1097/CCO.0000000000000677.

20. Szudy-Szczyrek A, Mlak R, Mielnik M, Szczyrek M, Nowaczyńska A, Homa-Mlak I, et al. Prognostic value of pretreatment neutrophilto- lymphocyte and platelet-to-lymphocyte ratios in multiplemyeloma patients treated with thalidomide-based regimen. Ann Hematol. 2020;99(12):2881–2891. doi: 10.1007/s00277-020-04092-5. doi: 10.1007/s00277-020-04092-5.

21. Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, et al. Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3 open-label study. Lancet Haematol. 2020;7(12):e861, e873. doi: 10.1016/S2352-3026(20)30323-9. doi: 10.1016/S2352-3026(20)30323-9.

22. Stork M, Sandecka V, Boichuk I, Adam Z, Krejci M, Brozova L, et al. Bortezomib and Thalidomide Treatment Results in Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients are Comparable in Long-Term Follow-Up. Vysledky léčby bortezomibem a thalidomidem u novědiagnostikovaných netransplantovaných pacientůs mnohočetným myelomem jsou srovnatelne. Klin Onkol. 2019;32(6):445–452. doi: 10.14735/amko2019445. doi: 10.14735/amko2019445.

23. Jung KS, Kim K, Kim HJ, Kim SH, Lee JO, Kim JS, et al. Analysis of the Efficacy of Thalidomide Plus Dexamethasone-Based Regimens in Patients With Relapsed/Refractory Multiple Myeloma Who Received Prior Chemotherapy, Including Bortezomib and Lenalidomide:KMM-166 Study. Clin Lymphoma Myeloma Leuk. 2020;20(2):e97–e104. doi: 10.1016/j.clml.2019.10.017. doi: 10.1016/j.clml.2019.10.017.

24. Li A, Wu Q, Warnick G, Li S, Libby EN, Garcia DA, et al. The incidence of thromboembolism for lenalidomide versus thalidomide in older patients with newly diagnosed multiple myeloma. Ann Hematol. 2020;99(1):121–126. doi: 10.1007/s00277-019-03860-2. doi: 10.1007/s00277-019-03860-2.

25. Wei XF, Chen QL, Fu Y, Zhang QK. Wnt and BMP signalling pathways co-operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2. J Cell Biochem. 2019;120(4):6515–6527. doi: 10.1002/jcb.27942. doi: 10.1002/ jcb.27942.

26. Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–2221. doi: 10.1172/JCI126397. doi: 10.1172/JCI126397.