1 INTRODUCTION

Multiple myeloma (MM) is a type of incurable clonal plasma cell disease that most frequently occurs in the elderly.¹ Epidemiology investigation by International Agency for Research on Cancer showed that, only in 2020, the new diagnosed and death cases of MM worldwide were approximately 176,400 and 11,7000, respectively, ranking third in all hematological malignancies.² The traditional therapeutic approach for MM is chemotherapy or chemotherapy combination with stem cell transplantation. In recent years, with the more uniform use of autologous stem cell transplantation and remarkable advance in developing novel agents, such as proteasome inhibitor, monoclonal antibody, and immunomodulator, the overall survival (OS) of MM has been obviously improved.^3-6 However, its 10-year survival ratio remains at only 17%.⁷ Therefore, it is imperative to develop new therapy regimens to improve prognosis.

Bortezomib, the first generation of proteasome inhibitor, is the first-line agent of MM recommended by the National Comprehensive Cancer Network guidelines,⁸ which distinctly improved the curative effect and survival time of MM patients. Despite being one of the most widely utilized and highly effective drugs for MM, bortezomib triggers untoward effects, such as peripheral neuropathy, skeletal muscle and cardiac, as well as myelosuppression, that possibly result in termination of treatment in advance with negative outcome of patients,⁹ emphasizing the necessity to develop safer and more effective alternatives. Regarded as a second-line recommended agent, ixazomib is a second-generation proteasome inhibitor and shows excellent therapeutic impact in patients with relapsed/refractory MM.¹⁰ But the efficacy and safety of ixazomib as the first-line treatment for MM patients in China has been barely reported and compared.

In this work, we retrospectively compared the efficacy and safety of Ixazomib/Lenalidomide/Dexamethasone (IRd) and Bortezomib/Lenalidomide/Dexamethasone (VRd) on newly diagnosed MM patients.

2 MATERIALS AND METHODS

3 RESULTS

3.2 Response assessment

Blood tests found that both IRd and VRd treatment increased the concentration of HGB, LDH, and decreased the concentration of WBC, PLT, β2-MG, CRE, and GLB. Although, some of them showed no significant statistical difference (Table 2). Among 21 patients in IRd group, 4 patients (4/21, 19.04%) achieved CR, 2 patients (2/21, 9.52%) achieved sCR, 4 patients (4/21, 19.04%) achieved VGRP, and 9 patients (9/21, 42.86%) achieved PR. Among 31 patients in VRd group, 5 patients (5/31, 16.13%) achieved CR, 3 patients (3/31, 9.68%) achieved sCR, 5 patients (5/31, 16.13%) achieved VGRP, and 13 patients (13/31, 41.94%) achieved PR. ORR were 90.48% (19/21) in IRd group, and 83.87% (26/31) in VRd group. SD was observed in 2 patients (2/21, 9.52%) in IRd group, and 4 patients (4/31, 12.90%) in VRd group (Table 3, Figure 1). PD was observed in 1 patient (1/31, 3.23%) in VRd group. Compared to VRd group, all of the corresponding responses showed no statistic difference (all p > 0.05) (Table 3).

TABLE 2. The changes of correlation indecators before and after chemotherapy of patients in the two groups

	IRd group			VRd group
Indicator	Preliminary diagnosis	Two course	Four course	Preliminary diagnosis	Two course	Four course
HGB (g/l)	85.50 ± 24.07	96.83 ± 6.59	102.83 ± 17.99	74.71 ± 22.13	106.86 ± 9.72	107.57 ± 29.09
WBC (109/l)	8.73 ± 7.52	3.92 ± 1.33	4.24 ± 1.57	5.21 ± 2.46	4.82 ± 2.65	4.50 ± 2.26
PLT (109/l)	247.67 ± 154.85	188.00 ± 67.63	169.83 ± 62.82	159.71 ± 67.75	209.43 ± 68.64	140.57 ± 61.88
β2-MG (mg/l)	8.97 ± 6.14	4.33 ± 1.69*	3.87 ± 2.35	5.66 ± 3.48	2.24 ± 0.83*	2.67 ± 1.01*
CRE (μmol/l)	96.50 ± 47.33	82.82 ± 46.15	83.67 ± 45.71	91.86 ± 27.26	71.57 ± 15.80*	66.50 ± 10.15*
LDH (μ/l)	131.17 ± 27.78	173.50 ± 41.98	166.00 ± 49.09	145.00 ± 56.91	181.33 ± 36.68	160.43 ± 32.87
GLB (g/l)	53.92 ± 19.71	29.40 ± 11.44*	27.95 ± 12.50*	49.91 ± 29.66	19.74 ± 2.14*	24.50 ± 14.65*
Ca (mmol/l)	2.41 ± 0.43	2.18 ± 0.10	2.23 ± 0.14	2.32 ± 0.25	2.25 ± 0.08	2.43 ± 0.28

• Abbreviations: β2-MG, β2-microglobulin; Ca, serum calcium; CRE, creatinine; GLB, globulin; HGB, hemoglobin concentration; LDH, lactate dehydrogenase; PLT, Platelets; WBC, white blood cells.
• * p < 0.05 vs. preliminary diagnosis.

TABLE 3. Treatment responses of patients in the two groups (n, %)

Group	Cases	CR	sCR	VGPR	PR	SD	PD	ORR(%)
IRd	21	4 (19.05)	2 (9.52)	4 (19.05)	9 (42.86)	2 (9.52)	0 (0.00)	90.48
VRd	31	5 (16.13)	3 (9.68)	5 (16.13)	13 (41.94)	4 (12.90)	1 (3.23)	83.87
X2		0.075		0.075				0.062
P		0.785		0.785				0.803

• Abbreviations: CR, complete response; ORR, overall response rate; PD, progressive disease; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

3.3 PFS and OS

The longest follow-up was 21.5 months. Due to the short follow-up period, the median OS and PFS were not achieved. As shown in Figure 2, there was no statistical difference of OS (Log-rank p = 0.61, 95%CI, 0.18–17.63) and PFS (Log-rank p = 0.70, 95%CI, 0.21–2.85) between patients in IRD and VRD groups. To better evaluate the PFS and OS in these two groups, longer follow-up is needed.

4 DISCUSSION

Proteinase is the vital constituent of the ubiquitin-proteasome pathway, playing an important function in protein homeostasis, cellular growth, and apoptosis regulation.¹¹ Bortezomib is a boronic acid-based potent proteinase inhibitor that interferes the degradation of ubiquitinated proteins induced by 26S proteasome, thereby preferential killing a variety of tumor cells.^12-14 Bortezomib has been initially approved as the third-line drug for relapsed and refractory MM treatment, and subsequently, as first-line regent for mantle cell lymphoma and MM.^15-17 Bortezomib-containing regimens such as VRd, bortezomib/cyclophosphamide/dexamethasone,¹⁸ and bortezomib/melphalan/prednisone,¹⁹ are considered as the standard first-line therapeutic strategy for newly diagnosed MM. A phase II portion of the single-arm study of VRd in newly diagnosed MM patients performed by Richardson et al. demonstrated that 100% of ORR with 74% of VGPR or better was observed after 4 cycles of treatment.²⁰ Moreover, The EVOLUTION study by Kumar and colleagues revealed that an ORR of 85%, with 51% of VGPR or better was achieved in newly diagnosed MM after four cycles of VRd treatment.²¹ In our current study, after 4 cycles of VRd treatment in newly diagnosed MM patients, the ORR was 83.87% with 41.94% of VGPR or better, which was similar to that of Kumar's study. Despite the preeminent anti-tumor activity of bortezomib, the lack of sensitivity, drug resistance, and adverse reaction to bortezomib restricted its clinical application.^22-24

Ixazomib is a first FDA-approved oral second-generation proteasome inhibitor that selectively binds to the β5 subunit of the 20S proteasome and inhibits its chymotrypsin-like activity, leading to apoptosis of multiple myeloma cells.²⁵ Compared to bortezomib, ixazomib shows better advantages upon improving the administration route and decreasing toxicity.²⁶ In addition, compared to bortezomib, ixazomib has shorter dissociation half-life with the proteasome, higher dissociation rate with the proteasome and enrichment in cancer, stronger capacity to penetrate the tissues, as well as the ability to trigger apoptosis of drug-resistant cell, therefore showing better anti-MM activity.^26-28 In November 2015, IRd was approved as the first oral regimens for the therapy of patients with relapsed/refractory MM.²⁹ Numerous studies have demonstrated the therapeutic effect of IRd on relapsed/refractory MM.^{30, 31} The phase III TOURMALINE-MM1 trial in patients with relapsed/refractory MM performed by Richardson and colleagues demonstrated that the median OS was up to 53.6 months after 18 cycles of treatment with IRd, which was the longest reported in phase III studies of IRd in relapsed/refractory MM.³² Few trials also investigated the efficacy and safety of IRd in newly diagnosed MM. An open-label, dose-escalation, phase 1/2 study of IRd in the United States newly diagnosed MM patients showed that the ORR was 88% with 32% of CR, and all the population was tolerated with IRd.³³ Another open-label, multicenter, phase 1/2 clinical trial in the United States newly diagnosed MM patients demonstrated that 94% of patients received ORR with 68% of VGPR or better and 24% of CR after IRd treatment.³⁴ However, much more trials were needed to explore the efficacy and safety of IRd in newly diagnosed MM. Moreover, the effect of IRd in Chinese newly diagnosed MM and its efficacy verses to VRd were barely reported. In the presents study, 52 newly diagnosed MM patients in Chinses were divided into IRd (n = 21) and VRd (n = 31) groups. The patients treated with IRd received 90.48% of ORR including 28.57% of CR, which was similar to previous study.^{33, 34} The ORR of patients in IRd group was higher than that of the patients in VRd group (83.87%). No statistical difference existed, indicating the similar efficacy of IRd and VRd. Additionally, the PFS and OS also showed no statistical difference between patients in IRd and VRd group. The double-blind, placebo-controlled TOURMALINE-MM2 trial reported by Facon et al showed that IRd treatment led to a 13.5-month improvement in median PFS in transplant-ineligible patients with newly diagnosed MM compared to placebo plus Rd treatment; however, no statistically significant outcome was observed and the trial did not technically meet its PFS endpoint.³⁵

Previous study showed that the adverse reactions of IRd were mainly reflected in peripheral neuropathy, rashes, neutropenia, thrombocytopenia, diarrhea, and fatigue.^{33, 34} Nevertheless, research suggested that the drug-related adverse reactions of IRd were mostly within the tolerable range.³³ Clinical test demonstrated that the adverse events’ incidence of bortezomib-associated regimes were higher than those of ixazomib-related regimes in the therapy of relapsed/refractory MM, especially peripheral sensory neuropathy.³⁶ Our current study indicated that among 21 patients in IRd group, 28.56% of patients occurred adverse reaction including 2 of grade 1–2 leukopenia, 2 of grade 1–2 hemocytopenia, 1 of grade 1–2 diarrhea and 1 of grade 3–4 diarrhea, respectively. Whereas, among 31 patients in VRd group, 51.61% of patients suffered from adverse reaction containing 2 of leukopenia, 5 of hemocytopenia, 6 of peripheral sensory neuropathy, and 3 of limb numbness. The adverse reactions incidence of VRd were much higher than those of IRd, especially peripheral sensory neuropathy.

As we know that the incidence of MM is increasing with the aging of population, and about 65% of patients diagnosed with MM are over 65 years. The elderly patients often have more basic diseases and poor physical status. In our retrospective study of 52 newly diagnosed MM, 13 patients with ECOG score of 3, accounted for 25%. These patients received low intensity of chemotherapy due to poor tolerance to adverse reactions of chemotherapy, which affected the treatment of the disease, thereby leading to disease progression and seriously reduced the quality of life of the patients. In addition, we found that the basic state of patients in IRd groups was worse than that in the VRd treatment group, as demonstrated by the higher ECOG scores of patients in IRd group. This may be associated with the way of administration, patients with poor condition prefer to choose the oral regimen (IRd), which is more convenient. In addition, oral regimen has more advantage under the condition of COVID-19 that patients can take medication at home, which also relieves the pressure on doctors to some extent. The TOURMALINE-MM2 trial reported by Thierry et al. also demonstrated that IRd is a feasible strategy for certain transplant-ineligible in newly diagnosed MM patients who often have limited mobility and reduced ability to frequently attend hospital.³⁵

A limitation of the current study was that this was a retrospective, single-center study and the sample size was too small to obtain the accurate conclusions. In addition, the short duration of follow-up may confuse the conclusion of prognosis. Collectively, the present data demonstrate the efficacy and safety of the oral regimen IRd for newly diagnosed MM after 4 cycles of chemotherapy. However, this study lacks transplant correlation analysis due to small sample size and the tolerability of prolonged IRd treatment was unclear. We will continue to expand the sample size and extend follow-up time to verify the conclusions of this study and uncover the tolerability of newly diagnosed MM patients to IRd.

5 CONCLUSION

In conclusion, this study retrospectively analyzed the efficacy, safety, PFS, and OS of different treatments in 52 newly diagnosed patients with MM, indicating the similar efficacy, PFS, and OS in patients treated by VRd and IRd. Moreover, IRd showed better safety than VRd, and it may be more convenient for patients with poor basic condition. Collectively, the present work indicated the efficacy and safety of IRd for newly diagnosed MM in the real-world clinical setting, providing an insight for physicians to use IRd as first-line treatment.

AUTHOR CONTRIBUTIONS

Z. J. Huo, F. Chen, and Z. M. Luo designed this study. Z. J. Huo, F. Chen, and P. Liu collected and analyzed the data. Z. J. Huo and F. Chen searched the literature and drafted the manuscript. Z. M. Luo acquired the funding and revised the manuscript. All authors read and approved the final manuscript.

FUNDING INFORMATION

The study was supported by China Hunan Provincial Science & technology Department (No. 2018SK52108).

CONFLICT OF INTEREST

Authors have no potential conflict of interest to declare.

ETHICS STATEMENT

This study was approved by the Medical Ethics Committee of Xiangtan Central Hospital (Approval number: 2019–01-007).