Синергистические механизмы традиционной китайской медицины и протеиновых ингибаторов в многократной терапии миеломы: всеобъемлющий обзор.

Introduction

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal proliferation in the bone marrow and the production of monoclonal immunoglobulins, leading to end-organ damage including bone lesions, anemia, renal failure, and hypercalcemia (the “CRAB” features). 1 Over the past two decades, the therapeutic landscape of MM has been revolutionized by novel agents, particularly proteasome inhibitors (PIs) like bortezomib, along with immunomodulatory drugs (IMiDs) and monoclonal antibodies. First-generation PI-based regimens have significantly prolonged progression-free survival (PFS) and overall survival (OS), transforming MM into a chronic disease with median survival now exceeding 5–6 years for many patients. 2

Despite therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. Most patients ultimately experience relapse or develop resistance to first-line agents, including proteasome inhibitors (PIs). Bortezomib, the first-in-class PI, revolutionized MM treatment; however, its clinical application is frequently limited by peripheral neuropathy, which occurs in 30–50% of patients and can lead to dose reduction or treatment discontinuation. 3 Although second-generation agents such as carfilzomib (an irreversible epoxyketone-based PI) and ixazomib (an oral PI) have partially addressed administration and resistance issues, they introduce new toxicities like cardiopulmonary complications and still face resistance in advanced disease settings. 4 , 5

In this context, Traditional Chinese Medicine (TCM)—including both complex herbal formulas and purified compounds—has emerged as a promising adjunct to standard MM therapies. A nationwide retrospective matched-cohort study conducted in Taiwan 6 found that MM patients who received adjunctive Chinese herbal medicine (CHM) exhibited significantly improved overall survival compared to those who received conventional therapy alone (adjusted hazard ratio ~0.35), suggesting a survival benefit for integrative treatment. This clinical evidence is increasingly supported by preclinical research identifying bioactive TCM-derived molecules—such as celastrol, curcumin, and berberine—that can synergize with PIs to overcome drug resistance, enhance tumor apoptosis, and reduce treatment-related toxicity. 7 , 8

Mechanistically, many of these compounds act on pathways central to MM biology, including the ubiquitin-proteasome system (UPS), NF-κB, JAK/STAT, and intrinsic apoptotic regulators, while also modulating the bone marrow microenvironment, thereby enhancing the cytotoxicity of PIs and protecting normal tissues. Given these complementary mechanisms, integrating TCM with PIs offers a promising strategy to enhance anti-myeloma efficacy and reduce toxicity. This review consolidates mechanistic and clinical evidence to clarify the translational potential of this combinational approach and its implications for improving patient outcomes ( Figure 1 and Table 1 ). Table 1 Summary of TCM-Derived Compounds Synergizing with Proteasome Inhibitors in Multiple Myeloma Ingredient Herb Source Proteasome Inhibitors Used in Combination Primary Mechanism Effects Icariin / Icaritin 9–11 Epimedii folium Bortezomib Inhibits JAK2/STAT3 cascade; upregulates Par-4; downregulates HSP27/P-gp; suppresses Bcl-2, Bcl-xL, survivin, COX-2, VEGF Reverses PI resistance; enhances apoptosis and G0/G1 arrest; anti-angiogenic Berberine 8 , 12 , 13 Coptis chinensis Bortezomib Reactivates p53 via promoter hypomethylation; targets UHRF1; modulates miR-21/NF-κB/SET9/miR-106b/miR-19a clusters Promotesapoptosis; overcomes resistance; inhibits proliferation Celastrol 14–16 Tripterygium wilfordii Bortezomib Inhibits NF-κB, IRAK4/ERK/p38 MAPK; induces ER stress/UPR; inhibits β5/β2/β1 proteasome subunits; increases Bax/Bcl-2 ratio Induces apoptosis; inhibits migration/invasion; enhances BTZ efficacy Ginsenoside Rg3 17 , 18 Panax ginseng Bortezomib Induces mitochondrial apoptosis (Bax↑/Bcl-2↓/Caspase-3↑); suppresses IGF-1/IGF-1R; inhibits VEGF Pro-apoptotic; anti-angiogenic; overcomes resistance Curcumin 19 , 20 Curcuma longa Bortezomib Inhibits STAT3, NF-κB, ERK1/2; suppresses Bcl-2, Bcl-xL, survivin; enhances PARP/caspase-3 cleavage; potentiatesproteasome inhibition Promotes apoptosis; reverses resistance; cell cycle arrest Resveratrol 21 , 22 Polygonum cuspidatum Carfilzomib Induces ER stress and UPR; suppresses XBP1, mTOR, NEAT1, Wnt/β-catenin; activates AMPK/caspase-3; potentiates oxidative stress with PIs Apoptosis; autophagy; chemosensitization with PIs; reduces toxicity Indirubin-3’-monoxime 23 , 24 Indigo naturalis (synthetic deriv). Bortezomib Inhibits STAT3 Tyr705 phosphorylation; suppresses survivin, Bcl-2, Mcl-1; directly inhibits β5 subunit of 20S proteasome Induces apoptosis; restores BTZ sensitivity; dual mechanism Gambogic acid 25 , 26 Garcinia hanburyi Bortezomib ActivatesROS/caspase cascade; inhibits SIRT1, PI3K/Akt/mTOR, VEGF, HIF-1α, CXCR4; blocks osteoclastogenesis Pro-apoptotic; anti-angiogenic; bone protection; overcomes resistance Figure 1 Integrated Mechanistic Pathways of Eight Key TCM Monomers Synergizing with Proteasome Inhibitors in Multiple Myeloma.

Current Status of Proteasome Inhibitors in the Treatment of Multiple Myeloma

Proteasome inhibitors (PIs) have become a fundamental component of multiple myeloma (MM) therapy by exploiting the malignant plasma cells’ reliance on the ubiquitin–proteasome system (UPS) to maintain protein homeostasis. The 26S proteasome is responsible for degrading misfolded, damaged, or regulatory proteins tagged with ubiquitin. 27 Due to their high production of abnormal immunoglobulins, MM cells place increased stress on this degradation pathway. Proteasome inhibition results in the accumulation of ubiquitinated proteins and misfolded proteins in the endoplasmic reticulum (ER), triggering ER stress and activation of the unfolded protein response (UPR), ultimately leading to apoptosis in MM cells. 28

A critical mechanism underlying PI-induced apoptosis is suppression of the nuclear factor-κB (NF-κB) pathway. 29 For example, bortezomib, a first-generation boronic acid dipeptide, reversibly inhibits the chymotrypsin-like activity of the β5 subunit within the 20S core particle of the proteasome. This prevents IκBα degradation and subsequent NF-κB nuclear translocation, reducing transcription of anti-apoptotic and pro-proliferative genes. 30 Since NF-κB is often constitutively activated in MM, its inhibition leads to decreased cytokine production, proliferation, and drug resistance. 31 Moreover, PIs modulate additional pathways by stabilizing pro-apoptotic proteins such as p53 and Bax and preventing the degradation of cell cycle inhibitors like p21 and p27. 32

Currently approved PIs include bortezomib, carfilzomib (a second-generation irreversible epoxyketone inhibitor), and ixazomib (a second-generation orally bioavailable boronate). All of them primarily target the β5 subunit but differ in pharmacokinetic profiles and specificity. 33 These agents, especially when combined with immunomodulatory drugs (IMiDs) and glucocorticoids, form the basis of standard regimens such as VRd (bortezomib, lenalidomide, dexamethasone), which significantly improves overall response rates and survival in both newly diagnosed and relapsed/refractory MM patients. 34 Carfilzomib-based combinations are preferred in PI-relapsed cases, while ixazomib is widely used in maintenance settings due to its oral availability and favorable safety profile. 35

Although proteasome inhibitors (PIs) have achieved remarkable efficacy in treating multiple myeloma (MM), drug resistance and toxicity remain major challenges. Mechanisms of PI resistance are multifaceted and include compensatory activation of the NF-κB pathway, mutations in proteasome subunits (e.g.PSMB5 G322A), epigenetic reprogramming (e.g.EZH2 upregulation), and activation of alternative protein degradation pathways, such as the HDAC6-mediated aggresome-autophagy system. 36 In addition, mesenchymal stem cells (MSCs) in the bone marrow microenvironment contribute to resistance by transferring non-coding RNAs (e.g.PSMA3-AS1 lncRNA) to MM cells via exosomes or direct cell–cell contact. 37

Among adverse effects, bortezomib-induced peripheral neuropathy (BIPN) is a major dose-limiting toxicity. Its pathogenesis involves proteasome inhibition and mitochondrial dysfunction in dorsal root ganglion neurons, resulting in decreased ATP production and axonal degeneration. 38 PIs also commonly cause hematologic toxicity, including thrombocytopenia and neutropenia, likely due to their inhibitory effects on hematopoietic stem cells. 39 While combination therapies (eg with the HDAC inhibitor panobinostat) may enhance efficacy, they can also exacerbate gastrointestinal side effects, fatigue, and infection risk. 40

In summary, PIs remain the backbone of MM treatment and have significantly improved patient survival and remission rates. However, their clinical utility is constrained by both adverse events—particularly neurotoxicity and, in newer agents, potential cardiotoxicity—and the development of resistance. These challenges highlight the urgent need for adjuvant therapies that can enhance anti-myeloma efficacy or alleviate treatment-related toxicities.

Research Progress in the Treatment of Multiple Myeloma with Traditional Chinese Medicine Combined with Proteasome Inhibitors

Flavonoids

Icariin (ICA)/Icaritin (ICT)

Epimedii folium (EF), known as Yinyanghuo, is a traditional Chinese herb derived from several Epimedium species. Its major active flavonoid glycoside, icariin (ICA), and its intestinal metabolite icariside II (ICA II) exhibit diverse pharmacological properties, including anti-inflammatory, bone-strengthening, and anticancer effects. In modern pharmacology, both ICA and ICA II have attracted interest for their synergistic anti-myeloma potential when combined with proteasome inhibitors (PIs) such as bortezomib (BTZ). 7

In bortezomib-resistant MM cell lines (eg, KM3/BTZ), ICA has been shown to partially reverse drug resistance by upregulating pro-apoptotic cytokine Par-4 and downregulating resistance-associated proteins such as HSP27 and P-glycoprotein (P-gp). 9 In U266 cells, co-treatment with ICA and BTZ significantly enhanced apoptosis and G0/G1 cell cycle arrest, which was mechanistically linked to inhibition of the JAK2/STAT3 signaling cascade and suppression of Bcl-2, Bcl-xL, and survivin. 10 , 41

ICA II exhibits even stronger anti-myeloma activity than its parent compound, promoting BTZ-induced apoptosis through inhibition of STAT3 phosphorylation and its downstream effectors including cyclin D1, COX-2, and VEGF, which are critical for MM cell survival, angiogenesis, and drug resistance. 11 , 42 ICA II–induced apoptosis in U266 cells has been directly confirmed through modulation of JAK2/STAT3-mediated intrinsic pathways. 11

Moreover, comparative pharmacokinetic studies reveal that ICA and ICA II differ significantly in absorption and bioavailability, offering distinct formulation strategies for clinical application. 43 Together, these findings underscore the potential of ICA and ICA II as natural, multi-targeted adjuvants in overcoming proteasome inhibitor resistance in multiple myeloma.

Alkaloids

Berberine

Berberine (BBR), a natural isoquinoline alkaloid derived from Coptis chinensis, has demonstrated promising anti-myeloma activity through multifaceted mechanisms involving epigenetic regulation, post-transcriptional modulation, and chemosensitization synergy with proteasome inhibitors.

At the epigenetic level, BBR reactivates tumor suppressor p53 by inducing hypomethylation of its promoter, thereby restoring p53-mediated transcriptional control and triggering intrinsic apoptotic pathways in MM cells. 12 Additionally, BBR directly targets UHRF1, a chromatin-associated epigenetic regulator involved in DNA methylation maintenance, further contributing to global reprogramming of the MM epigenome. 8

BBR also exerts post-transcriptional regulation via modulation of oncogenic microRNAs that contribute to MM pathogenesis and drug resistance. Most notably, BBR downregulates miR-21, a key oncomiR in MM, by suppressing NF-κB signaling and modulating the activity of the histone methyltransferase SET9. 44 , 45 It also attenuates the miR-106b/25 46 and miR-19a/92a 47 clusters, which are known to regulate proliferation, apoptosis, and therapeutic sensitivity, thereby reinforcing its broad transcriptomic influence.

From a therapeutic perspective, BBR has demonstrated synergistic cytotoxicity when combined with the proteasome inhibitor bortezomib. In vitro studies in U266 cells showed that this combination significantly enhances apoptosis and G0/G1 cell cycle arrest, suggesting its potential to overcome bortezomib resistance and improve treatment efficacy. 13 These findings align with the concept of integrating phytochemical adjuvants into MM therapy to potentiate standard regimens while minimizing toxicity.

Collectively, berberine’s multi-targeted molecular profile, origin from traditional Chinese medicine, and capacity to overcome drug resistance establish it as a strong candidate for inclusion in combinatorial MM treatment strategies. Its preclinical efficacy across epigenetic, transcriptomic, and proteasome-targeted pathways supports further translational exploration in clinical contexts.

Quinones & Terpenoids

Celastrol

Celastrol, a quinone methide triterpenoid isolated from the root and bark of Tripterygium wilfordii (Thunder God Vine), 48 has emerged as a multi-targeted compound with substantial therapeutic potential in multiple myeloma (MM). Its pharmacological effects are mediated through a dual mechanism involving both inhibition of key oncogenic signaling cascades and direct interference with proteasomal activity. 49 , 50

Mechanistically, celastrol attenuates MM cell proliferation and invasiveness by suppressing the NF-κB and IRAK4/ERK/p38 MAPK pathways. 14 , 15 , 50 These inhibitory actions lead to reduced transcription of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as decreased expression of metastasis-related proteins including CXCR4 and matrix metalloproteinase-9 (MMP-9). Moreover, celastrol induces G0/G1 cell cycle arrest and promotes apoptosis via intrinsic mitochondrial pathways, evidenced by increased Bax/Bcl-2 ratio, and triggers endoplasmic reticulum stress through the activation of the PERK/eIF2α axis of the unfolded protein response (UPR). 14 , 49 , 51

Importantly, celastrol has been identified as a direct inhibitor of the chymotrypsin-like (β5), trypsin-like (β2), and caspase-like (β1) subunits of the 20S proteasome. This interaction results in the accumulation of polyubiquitinated proteins and induction of proteotoxic stress, functionally resembling the mechanism of bortezomib. Such dual modulation renders celastrol particularly suitable for combinatorial strategies with proteasome inhibitors. 15 , 16

In preclinical models, celastrol enhances bortezomib-induced apoptosis in MM cells by amplifying caspase-3 activation and DNA fragmentation. 14 , 51 In vivo, co-administration of celastrol significantly reduced tumor volume in SCID mouse xenografts bearing MM.1S or RPMI 8226 cells, thereby supporting its synergistic potential and translational relevance. 14 , 16

Collectively, these findings underscore celastrol as a promising adjunct to proteasome inhibitor-based therapies in MM. Its dual targeting of pro-survival signaling and proteasomal degradation pathways offers a rational strategy to overcome drug resistance and potentiate therapeutic efficacy.

Ginsenoside Rg3

Ginsenoside Rg3, a bioactive saponin extracted from Panax ginseng, has demonstrated significant anti-myeloma activity through modulation of key survival, proliferation, and angiogenic pathways. Owing to its low toxicity profile and multi-targeted mechanisms, Rg3 has garnered interest as a natural adjuvant in proteasome inhibitor-based regimens.

Mechanistically, Rg3 induces mitochondrial-mediated apoptosis in MM cells. In U266 cells, treatment with Rg3 upregulates the pro-apoptotic protein Bax, downregulates Bcl-2, and activates caspase-3, culminating in programmed cell death. 17 Notably, this apoptotic response is selective to malignant cells, with minimal cytotoxicity observed in normal hematopoietic counterparts, supporting its potential as a safe pro-apoptotic enhancer.

In addition to its intrinsic cytotoxicity, Rg3 modulates growth factor signaling, particularly the IGF-1/IGF-1R axis, which is frequently implicated in MM progression and resistance to therapy. Rg3 has been shown to significantly reduce IGF-1 secretion, thereby attenuating downstream survival signaling and inducing cell cycle arrest in MM cells. 18 This suggests that Rg3 may overcome microenvironment-driven resistance mechanisms that limit proteasome inhibitor efficacy.

Moreover, Rg3 exerts anti-angiogenic effects through suppression of vascular endothelial growth factor (VEGF) expression. In vitro studies on U266 cells demonstrated that Rg3 reduced VEGF production in a dose-dependent manner, potentially disrupting the angiogenesis-dependent progression of MM within the bone marrow niche. 52

Collectively, Ginsenoside Rg3 exhibits a tripartite mechanism of anti-MM action—namely, mitochondrial apoptosis induction, IGF-1/IGF-1R inhibition, and VEGF-mediated angiogenesis suppression. These combined effects support its development as a multifunctional phytotherapeutic agent suitable for combinatorial strategies with proteasome inhibitors or immunomodulatory drugs in MM treatment paradigms.

Polyphenols & Stilbenes

Curcumin

Curcumin, a polyphenolic compound derived from Curcuma longa (turmeric), has been extensively investigated for its anti-inflammatory, antioxidant, and anticancer properties. In the treatment of multiple myeloma (MM), curcumin exhibits pleiotropic antitumor activities, particularly when used in combination with proteasome inhibitors (PIs) such as bortezomib or carfilzomib, offering a strategy to enhance therapeutic efficacy and overcome drug resistance.

Mechanistically, curcumin inhibits several survival signaling pathways that are constitutively activated in MM. In U266 cells, curcumin was shown to block IL-6-induced phosphorylation of STAT3 and ERK1/2, leading to downregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xL, and survivin. 19 This suppression promotes cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activation, thereby enhancing apoptosis when combined with PIs. Additionally, curcumin promotes cell cycle arrest at the G 0 /G 1 phase and enhances proteotoxic stress by potentiating proteasome inhibition. 20

Another critical mechanism involves inhibition of the nuclear factor-kappa B (NF-κB) pathway. Curcumin prevents the degradation of IκBα, resulting in decreased nuclear translocation of p65, reduced transcriptional activity of NF-κB, and subsequent downregulation of pro-survival genes such as IL-6, TNF-α, and COX-2. 53 These effects sensitize MM cells to the cytotoxic effects of bortezomib, as demonstrated in both RPMI 8226 and U266 cell lines. 54

To improve its pharmacokinetic limitations, several curcumin analogs with better solubility and bioavailability have been developed. Notably, an amino acid-conjugated analog (compound 12) exhibited superior synergistic efficacy with bortezomib, as evidenced by enhanced caspase-3 and PARP cleavage in vitro. 55

Collectively, these findings underscore curcumin as a promising adjuvant to proteasome inhibitor-based regimens in MM, acting through multi-pathway inhibition, apoptosis promotion, and reversal of resistance mechanisms.

Resveratrol

Resveratrol, a naturally occurring polyphenolic compound found in grapes, peanuts, and Polygonum cuspidatum, has demonstrated promising anti-myeloma activity through the modulation of multiple cellular pathways. In multiple myeloma (MM) models, it exerts both direct cytotoxicity and chemosensitizing effects when combined with conventional therapeutics, particularly proteasome inhibitors and mTOR-targeting agents.

Mechanistically, resveratrol induces endoplasmic reticulum (ER) stress by triggering the unfolded protein response, leading to apoptosis via downregulation of the X-box binding protein 1 (XBP1), a key transcription factor involved in MM cell survival. 21 In parallel, it activates autophagy and apoptosis by suppressing the AMPK/mTOR signaling pathway, disrupting energy metabolism and inhibiting cellular proliferation. 56

Resveratrol has also been shown to synergize with proteasome inhibitors. For instance, its combination with carfilzomib significantly enhanced oxidative stress-mediated cell death and increased caspase-dependent apoptosis in MM cells, suggesting its potential in overcoming drug resistance. 22 Another pathway through which resveratrol inhibits MM progression is via NEAT1-mediated Wnt/β-catenin suppression, which reduces proliferation, migration, and invasion of MM cells. 57

In terms of combination strategies beyond proteasome inhibition, resveratrol was shown to enhance the efficacy of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, in MM cells. This dual treatment significantly suppressed cell viability and promoted apoptosis through enhanced inhibition of the mTOR axis. 58 Furthermore, a novel clinical application has emerged with a resveratrol–copper pro-oxidant formulation (RESCU 001), which was found to reduce chemotherapy-related toxicities in MM patients undergoing high-dose melphalan therapy, marking a translational step toward supportive care in MM treatment. 59

Collectively, these findings position resveratrol as a multi-targeted adjuvant capable of enhancing the anti-MM effects of both proteasome inhibitors and targeted agents, while also offering benefits in reducing treatment-related adverse effects.

Indole Derivatives

Indirubin-3’-Monoxime

Indirubin-3’-monoxime (I3M) is a potent synthetic derivative of indirubin, the major active compound extracted from Qingdai (Indigo naturalis), a traditional Chinese medicine historically used for hematologic malignancies and inflammatory disorders. 60 , 61 In the treatment of multiple myeloma (MM), I3M exerts multi-targeted anti-myeloma activity, acting through two principal mechanisms.

First, I3M inhibits the phosphorylation of STAT3 at Tyr705, thereby suppressing the transcription of downstream anti-apoptotic genes including Mcl-1, Bcl-2, and survivin. This suppression leads to the activation of the intrinsic apoptotic cascade, notably through caspase-3/9 cleavage. 23 Second, I3M directly inhibits the chymotrypsin-like activity of the β5 subunit of the 20S proteasome, leading to the accumulation of ubiquitinated proteins and proteotoxic stress—a mechanism mechanistically similar to that of bortezomib. 24 , 62

Importantly, preclinical studies have shown that I3M can overcome bortezomib resistance in MM cells. This is likely due to its ability to simultaneously modulate the ubiquitin–proteasome system (UPS) and interfere with compensatory survival pathways such as STAT3 and NF-κB. 24 , 63 In bortezomib-refractory MM models, I3M restored drug sensitivity, suppressed tumor viability, and prolonged survival. 23 , 24 These findings underscore I3M as a promising synergistic candidate when used in combination with proteasome inhibitors.

Gambogic Acid

Gambogic acid (GA), a caged xanthone compound derived from the resin of Garcinia hanburyi, has emerged as a promising anti-myeloma agent due to its multifaceted molecular actions. GA exerts potent pro-apoptotic effects on MM cells by activating the caspase cascade and downregulating the SIRT1 pathway via the accumulation of reactive oxygen species (ROS), leading to enhanced mitochondrial dysfunction and cell death. 25 This redox-mediated cytotoxicity suggests GA’s potential to overcome redox resistance often seen in MM.

Beyond direct apoptotic induction, GA also disrupts the PI3K/Akt/mTOR signaling axis, suppressing hypoxia-induced HIF-1α and VEGF expression in MM cells, thereby inhibiting tumor angiogenesis and growth under hypoxic conditions. 64 Additionally, it interferes with the CXCR4 chemokine receptor pathway, effectively blocking MM-induced osteoclastogenesis, a critical component of MM-related bone disease. 65 These effects highlight GA’s dual role in both tumor cytotoxicity and modulation of the tumor microenvironment.

In combination regimens, GA has shown synergistic effects with bortezomib (BTZ) and nanomedicine strategies. For instance, dimercaptosuccinic acid (DMSA)-modified Fe 3 O 4 nanoparticles co-delivering BTZ and GA synergistically induced G0/G1 cell cycle arrest and apoptosis in RPMI-8226 cells. 29 These findings point to the potential of GA in overcoming proteasome inhibitor resistance and improving drug delivery efficiency.

Collectively, the evidence positions gambogic acid as a multi-targeted phytochemical that not only enhances conventional chemotherapeutic efficacy but also interferes with MM-supporting pathways such as hypoxia response and bone resorption, making it a compelling adjunct candidate in MM integrative therapy.

Other TCM Formulas with Synergistic Potential

In addition to the single compound bioactive ingredients discussed previously, many traditional Chinese medicine (TCM) formulations have shown the potential to synergize with proteasome inhibitors (PIs) in the treatment of multiple myeloma (MM), although clinical studies of these regimens need to be further deepened. For example, Duhuo Jisheng Decoction combined with Fuyuan Huoxue Decoction combined with VCD/VAD regimen can reduce tumor burden (plasma cell ratio from 25.1% to 9.7%; M protein decreased by 61.5%) and alleviate chemotherapy-related gastrointestinal and nervous system toxicity without increasing bone marrow suppression or thrombosis. 66 Notably, Duhuo Jisheng Decoction also significantly improved bortezomib-induced peripheral neuropathy (BiPN), with a clinical symptom improvement rate of 80%, while only 40% in the methylcobalamin group, and nerve conduction velocity was also significantly improved (P < 0.01). Bushen Huoxue Tongluo Decoction 67 combined with a modified Parkinson’s disease (PD) regimen treats multiple myeloma (MM)-related bone disease by restoring RANKL/OPG balance, promoting osteoblast differentiation (Runx2 increased 2.1-fold), and increasing bone mineral density (+12.5% vs 4.8%, P < 0.05). In addition, Huanglian Jiedu Decoction 68 and its main component baicalin promoted MM cell apoptosis by inhibiting NF-κB signaling and downregulating XIAP and IL-6, with clinical data showing a higher ORR (89.47% vs 73.68%, P = 0.03) and a 35% reduction in the incidence of peripheral neuropathy. Finally, Huayu Jiedu Decoction 69 induced apoptosis by regulating the expression of Bax, Bcl-2, and Survivin, while downregulating HMGB1 (mRNA expression decreased by 58%) and IL-6, and inhibiting the TLR4/NF-κB axis - these actions together reversed the immunosuppressive state in the tumor microenvironment and improved PI sensitivity.

These findings provide a theoretical basis for further research on TCM-based compound preparations as an adjuvant strategy for optimizing PI therapy for multiple myeloma.

Conclusion

The integration of traditional Chinese medicine (TCM) with proteasome inhibitors (PIs) has emerged as a promising approach for enhancing therapeutic efficacy in multiple myeloma (MM). TCM-derived compounds—classified by chemical structure into flavonoids, indole derivatives, terpenoids, quinones, polyphenols, and alkaloids—demonstrate the ability to modulate multiple oncogenic pathways, including PI3K/AKT/mTOR, JAK/STAT3, and NF-κB. These compounds exert synergistic effects with PIs by promoting apoptosis, inhibiting proliferation, reversing drug resistance, and in some cases, directly inhibiting proteasomal catalytic subunits such as β5 and β2.

Despite robust preclinical evidence supporting these synergistic mechanisms, translation into clinical practice remains limited. Most existing studies focus on isolated monomers or simplified in vitro models, which do not fully reflect the complexity of multi-herbal TCM formulations commonly used in clinical settings. Additionally, safety concerns—such as hepatotoxicity or nephrotoxicity associated with high-dose administration—highlight the need for optimized dosing strategies and rigorous toxicity evaluation, particularly in elderly or comorbid MM populations.

High-quality clinical evidence is currently insufficient, with few randomized controlled trials (RCTs) or real-world studies (RWS) evaluating TCM–PI combination regimens. To address these gaps, future investigations should prioritize the systematic evaluation of multi-component herbal formulations, elucidate drug–herb and compound–compound interactions, and design translational studies that align traditional practices with modern standards of evidence-based oncology.

In summary, this review provides a mechanistic foundation for the rational integration of TCM with proteasome inhibitors in MM therapy. By mapping the synergistic molecular interactions between natural compounds and targeted agents, it offers a framework for the development of safer and more effective combinatorial strategies, with the ultimate goal of improving clinical outcomes in patients with relapsed, refractory, or treatment-resistant MM.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Palumbo A , Anderson K . Multiple myeloma . N Engl J Med . 2011 ; 364 ( 11 ): 1046 – 1060 . doi: 10.1056/NEJMra1011442 21410373

2. Rajkumar SV . Multiple myeloma: 2020 update on diagnosis, risk-stratification and management . Am J Hematol . 2020 ; 95 ( 5 ): 548 – 567 . doi: 10.1002/ajh.25791 32212178

3. Richardson PG , Sonneveld P , Schuster MW , et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma . N Engl J Med . 2005 ; 352 ( 24 ): 2487 – 2498 . doi: 10.1056/NEJMoa043445 15958804

4. Facon T , Niesvizky R , Mateos MV , et al. Efficacy and safety of carfilzomib-based regimens in frail patients with relapsed and/or refractory multiple myeloma . Blood Adv . 2020 ; 4 ( 21 ): 5449 – 5459 . doi: 10.1182/bloodadvances.2020001965 33166401 PMC7656926

5. Moreau P , Masszi T , Grzasko N , et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma . N Engl J Med . 2016 ; 374 ( 17 ): 1621 – 1634 . doi: 10.1056/NEJMoa1516282 27119237

6. Huang CY , Wu MY , Kuo YH , Tou SI , Yen HR . Chinese herbal medicine is helpful for survival improvement in patients with multiple myeloma in Taiwan: a nationwide retrospective matched-cohort study . Integr Cancer Ther . 2020 ; 19 : 1534735420943280 . doi: 10.1177/1534735420943280 32783567 PMC7425229

7. Ding K , Jiang W , Jia H , Lei M . Synergistically anti-multiple myeloma effects: flavonoid, non-flavonoid polyphenols, and bortezomib . Biomolecules . 2022 ; 12 ( 11 ): 1647 . doi: 10.3390/biom12111647 36358997 PMC9687375

8. Gu C , Yin Z , Nie H , et al. Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1 . BMC Biol . 2020 ; 18 ( 1 ): 33 . doi: 10.1186/s12915-020-00766-8 32213189 PMC7098108

9. Li ZY , Li ZJ , Chen X , et al. Icaritin reverses multidrug resistance of multiple myeloma cell line KM3/BTZ . Zhongguo Shi Yan Xue Ye Xue Za Zhi . 2017 ; 25 ( 6 ): 1690 – 1695 . doi: 10.7534/j.issn.1009-2137.2017.06.020 29262899

10. Jung YY , Lee JH , Nam D , et al. Anti-myeloma effects of icariin are mediated through the attenuation of JAK/STAT3-dependent signaling cascade . Front Pharmacol . 2018 ; 9 : 531 . doi: 10.3389/fphar.2018.00531 29899697 PMC5989039

11. Kim SH , Ahn KS , Jeong SJ , et al. Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells . Eur J Pharmacol . 2011 ; 654 ( 1 ): 10 – 16 . doi: 10.1016/j.ejphar.2010.11.032 21172343

12. Qing Y , Hu H , Liu Y , et al. Berberine induces apoptosis in human multiple myeloma cell line U266 through hypomethylation of p53 promoter . Cell Biol Int . 2014 ; 38 ( 5 ): 563 – 570 . doi: 10.1002/cbin.10206 24843889

13. Tian Y , Li LH , Yang GZ , Chen WM . Study of the effects in vitro of berberine combined with bortezomib on multiple myeloma cell line U266 cells . Zhonghua Xue Ye Xue Za Zhi . 2016 ; 37 ( 11 ): 976 – 981 . doi: 10.3760/cma.j.issn.0253-2727.2016.11.010 27995884 PMC7348517

14. Hu L , Wu H , Li B , et al. Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways in vitro and in vivo . Acta Biochim Biophys Sin . 2017 ; 49 ( 5 ): 420 – 427 . doi: 10.1093/abbs/gmx021 28338993

15. Dai Y , DeSano J , Tang W , et al. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB . PLoS One . 2010 ; 5 ( 12 ): e14153 . doi: 10.1371/journal.pone.0014153 21170316 PMC3000808

16. Shanmugam MK , Ahn KS , Lee JH , et al. Celastrol attenuates the invasion and migration and augments the anticancer effects of bortezomib in a xenograft mouse model of multiple myeloma . Front Pharmacol . 2018 ; 9 : 365 . doi: 10.3389/fphar.2018.00365 29773987 PMC5943600

17. Luo Y , Zhang P , Zeng HQ , Lou SF , Wang DX . Ginsenoside Rg3 induces apoptosis in human multiple myeloma cells via the activation of Bcl-2-associated X protein . Mol Med Rep . 2015 ; 12 ( 3 ): 3557 – 3562 . doi: 10.3892/mmr.2015.3802 25998024

18. Li Y , Yang T , Li J , et al. Inhibition of multiple myeloma cell proliferation by ginsenoside Rg3 via reduction in the secretion of IGF-1 . Mol Med Rep . 2016 ; 14 ( 3 ): 2222 – 2230 . doi: 10.3892/mmr.2016.5475 27430248

19. Bharti AC , Shishodia S , Reuben JM , et al. Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis . Blood . 2004 ; 103 ( 8 ): 3175 – 3184 . doi: 10.1182/blood-2003-06-2151 15070700

20. Park J , Ayyappan V , Bae EK , et al. Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells . Mol Oncol . 2008 ; 2 ( 4 ): 317 – 326 . doi: 10.1016/j.molonc.2008.09.006 19383353 PMC5527772

21. Wang FM , Galson DL , Roodman GD , Ouyang H . Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells . Exp Hematol . 2011 ; 39 ( 10 ): 999 – 1006 . doi: 10.1016/j.exphem.2011.06.007 21723843 PMC3261654

22. Li Q , Yue Y , Chen L , et al. Resveratrol Sensitizes Carfilzomib-Induced Apoptosis via Promoting Oxidative Stress in Multiple Myeloma Cells . Front Pharmacol . 2018 ; 9 : 334 . doi: 10.3389/fphar.2018.00334 29867453 PMC5961230

23. Yu Z , Wei X , Liu L , et al. Indirubin-3’-monoxime acts as proteasome inhibitor: therapeutic application in multiple myeloma . EBioMedicine . 2022 ; 78 : 103950 . doi: 10.1016/j.ebiom.2022.103950 35344764 PMC8958548

24. Yu Z , Du J , Liu L , et al. PS1356 INDIRUBIN-3’-MONOXIME INDUCES APOPTOSIS AND OVERCOMES BORTEZOMIB RESISTANCE IN MULTIPLE MYELOMA VIA TARGETING THE UBIQUITIN AND PROTEASOME SYSTEM . HemaSphere . 2019 ; 3 ( S1 ): 619 . doi: 10.1097/01.HS9.0000563700.30344.94

25. Yang LJ , Chen Y , He J , et al. Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS . Oncol Lett . 2012 ; 3 ( 5 ): 1159 – 1165 . doi: 10.3892/ol.2012.634 22783411 PMC3389632

26. Zhang W , Qiao L , Wang X , Senthilkumar R , Wang F , Chen B . Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe3O4 magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells . Int J Nanomedicine . 2015 ; 10 : 3275 – 3289 . doi: 10.2147/IJN.S80795 25995634 PMC4425315

27. Gandolfi S , Laubach JP , Hideshima T , Chauhan D , Anderson KC , Richardson PG . The proteasome and proteasome inhibitors in multiple myeloma . Cancer Metastasis Rev . 2017 ; 36 ( 4 ): 561 – 584 . doi: 10.1007/s10555-017-9707-8 29196868

28. Ri M . Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma . Int J Hematol . 2016 ; 104 ( 3 ): 273 – 280 . doi: 10.1007/s12185-016-2016-0 27169614

29. Jayaweera SPE , Wanigasinghe Kanakanamge SP , Rajalingam D , Silva GN . Carfilzomib: a promising proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma . Front Oncol . 2021 ; 11 : 740796 . doi: 10.3389/fonc.2021.740796 34858819 PMC8631731

30. Narayanan S , Cai CY , Assaraf YG , et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance . Drug Resist Updat . 2020 ; 48 : 100663 . doi: 10.1016/j.drup.2019.100663 31785545

31. Bai Y , Su X . Updates to the drug-resistant mechanism of proteasome inhibitors in multiple myeloma . Asia Pac J Clin Oncol . 2021 ; 17 ( 1 ): 29 – 35 . doi: 10.1111/ajco.13459 32920949

32. Farrell ML , Reagan MR . Soluble and cell-cell-mediated drivers of proteasome inhibitor resistance in multiple myeloma . Front Endocrinol . 2018 ; 9 : 218 . doi: 10.3389/fendo.2018.00218 PMC5938346 29765356

33. Al-Odat OS , Guirguis DA , Schmalbach NK , et al. Autophagy and apoptosis: current challenges of treatment and drug resistance in multiple myeloma . Int J Mol Sci . 2022 ; 24 ( 1 ): 644 . doi: 10.3390/ijms24010644 36614089 PMC9820338

34. Paradzik T , Bandini C , Mereu E , et al. The landscape of signaling pathways and proteasome inhibitors combinations in multiple myeloma . Cancers . 2021 ; 13 ( 6 ): 1235 . doi: 10.3390/cancers13061235 33799793 PMC8000754

35. Moscvin M , Ho M , Bianchi G . Overcoming drug resistance by targeting protein homeostasis in multiple myeloma . Cancer Drug Resist . 2021 ; 4 ( 4 ): 1028 – 1046 . doi: 10.20517/cdr.2021.93 35265794 PMC8903187

36. Tyrna P , Procyk G , Szeleszczuk Ł , Młynarczuk-Biały I . Different strategies to overcome resistance to proteasome inhibitors-A summary 20 years after their introduction . Int J Mol Sci . 2024 ; 25 ( 16 ): 8949 . doi: 10.3390/ijms25168949 39201634 PMC11354503

37. Colao A , Lombardi G . Frontiers in cancer endocrinology . Front Endocrinol . 2011 ; 2 : 7 . doi: 10.3389/fendo.2011.00007 PMC3356056 22654790

38. Wallington-Beddoe CT , Sobieraj-Teague M , Kuss BJ , Pitson SM . Resistance to proteasome inhibitors and other targeted therapies in myeloma . Br J Haematol . 2018 ; 182 ( 1 ): 11 – 28 . doi: 10.1111/bjh.15210 29676460

39. Pakjoo M , Ahmadi SE , Zahedi M , et al. Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors . Cell Commun Signal . 2024 ; 22 ( 1 ): 105 . doi: 10.1186/s12964-023-01433-5 38331801 PMC10851565

40. Gazzaroli G , Angeli A , Giacomini A , Ronca R . Proteasome inhibitors as anticancer agents . Expert Opin Ther Pat . 2023 ; 33 ( 11 ): 775 – 796 . doi: 10.1080/13543776.2023.2272648 37847492

41. Zhang H , Xing WW , Li YS , et al. Effects of a traditional Chinese herbal preparation on osteoblasts and osteoclasts . Maturitas . 2008 ; 61 ( 4 ): 334 – 339 . doi: 10.1016/j.maturitas.2008.09.023 19004583

42. Zhai YK , Guo X , Pan YL , et al. A systematic review of the efficacy and pharmacological profile of Herba Epimedii in osteoporosis therapy . Pharmazie . 2013 ; 68 ( 9 ): 713 – 722 . 24147339

43. Cheng T , Zhang Y , Zhang T , Lu L , Ding Y , Zhao Y . Comparative pharmacokinetics study of icariin and icariside II in rats . Molecules . 2015 ; 20 ( 12 ): 21274 – 21286 . doi: 10.3390/molecules201219763 26633326 PMC6332156

44. Hu H-Y , Li K-P , Wang X-J . Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells . Acta Pharmacol Sin . 2013 ; 34 ( 1 ): 157 – 166 . doi: 10.1038/aps.2012.161 23247593 PMC4086496

45. Luo X , Gu J , Zhu R , et al. Integrative analysis of differential miRNA and functional study of miR-21 by seed-targeting inhibition in multiple myeloma cells in response to berberine . BMC Syst Biol . 2014 ; 8 : 82 . doi: 10.1186/1752-0509-8-82 25000828 PMC4096730

46. Gu C , Li T , Yin Z , et al. Integrative analysis of signaling pathways and diseases associated with the miR-106b/25 cluster and their function study in berberine-induced multiple myeloma cells . Funct Integr Genomics . 2017 ; 17 ( 2–3 ): 253 – 262 . doi: 10.1007/s10142-016-0519-7 27647143

47. Yin Z , Yang J , Ning R , et al. Signal pathways, diseases, and functions associated with the miR-19a/92a cluster and the use of berberine to modulate the expression of this cluster in multiple myeloma cells . J Biochem Mol Toxicol . 2018 ; 32 ( 6 ): e22057 . doi: 10.1002/jbt.22057 29687521

48. Kannaiyan R , Shanmugam MK , Sethi G . Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer . Cancer Lett . 2011 ; 303 ( 1 ): 9 – 20 . doi: 10.1016/j.canlet.2010.10.025 21168266

49. Ke B , Wan C , Li A , et al. Tripterygium wilfordii induces apoptosis in multiple myeloma H929 cells . Chin J Pathophysiol . 2020 ; 36 ( 3 ): 487 – 494 .

50. Xu X , Kang D , Zhu X , et al. Effects of tripterygium wilfordii on proliferation and apoptosis of multiple myeloma cells based on IRAK4/ERK/p38 signaling pathway . Chin J Exp Hematol . 2022 ; 30 ( 1 ): 175 – 182 . 10.19746/j.cnki.issn.1009-2137.2022.01.029 35123623

51. Jin S , Li B , Zhang B , et al. Dihydrocelastrol induces antitumor activity and enhances the sensitivity of bortezomib in resistant multiple myeloma by inhibiting STAT3-dependent PSMB5 regulation . Acta Biochim Biophys Sin . 2023 ; 55 ( 12 ): 1884 – 1891 . doi: 10.3724/abbs.2023260 38009004 PMC11294055

52. Song Y , Hou J , Kang L , Gao S . Effect of 20 (S)-ginsenoside Rg3 on the proliferation inhibition and secretion of vascular endothelial growth factor of multiple myeloma cell line U266 . Zhonghua Xue Ye Xue Za Zhi . 2014 ; 35 ( 6 ): 519 – 523 . doi: 10.3760/cma.j.issn.0253-2727.2014.06.010 24985176

53. Shishodia S , Amin HM , Lai R , Aggarwal BB . Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma . Biochem Pharmacol . 2005 ; 70 ( 5 ): 700 – 713 . doi: 10.1016/j.bcp.2005.04.043 16023083

54. Beevers CS , Chen L , Liu L , Luo Y , Webster NJG , Huang S . Curcumin disrupts the Mammalian target of rapamycin-raptor complex . Cancer Res . 2009 ; 69 ( 3 ): 1000 – 1008 . doi: 10.1158/0008-5472.CAN-08-2367 19176385 PMC4307947

55. Anand P , Thomas SG , Kunnumakkara AB , et al. Biological activities of curcumin and its analogues (Congeners) made by man and mother nature . Biochem Pharmacol . 2008 ; 76 ( 11 ): 1590 – 1611 . doi: 10.1016/j.bcp.2008.08.008 18775680

56. Ma R , Yu D , Peng Y , et al. Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells . Acta Biochim Biophys Sin . 2021 ; 53 ( 6 ): 775 – 783 . doi: 10.1093/abbs/gmab042 33891090

57. Geng W , Guo X , Zhang L , et al. Resveratrol inhibits proliferation, migration and invasion of multiple myeloma cells via NEAT1-mediated Wnt/β-catenin signaling pathway . Biomed Pharmacother . 2018 ; 107 : 484 – 494 . doi: 10.1016/j.biopha.2018.08.003 30107344

58. Jin HG , Wu GZ , Wu GH , Bao YG . Combining the mammalian target of rapamycin inhibitor, rapamycin, with resveratrol has a synergistic effect in multiple myeloma . Oncol Lett . 2018 ; 15 ( 5 ): 6257 – 6264 . doi: 10.3892/ol.2018.8178 29731844 PMC5920858

59. Agarwal A , Khandelwal A , Pal K , et al. A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001) . PLoS One . 2022 ; 17 ( 2 ): e0262212 . doi: 10.1371/journal.pone.0262212 35120140 PMC8815866

60. H R , L S , Ja E , et al. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases . Nature Cell Biology . 1999 ; 1 ( 1 ). doi: 10.1038/9035 10559866

61. E G , H F , J S , M S . Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine . Journal of Cancer Research and Clinical Oncology . 2004 ; 130 ( 11 ). doi: 10.1007/s00432-004-0579-2 PMC12161789 15340840

62. F T , L L , S H , et al. A novel indirubin- 3-monoxime derivative I3MV- 8b exhibits remarkable cytotoxicity against multiple myeloma by targeting TRIM28 . Biomarker Research . 2025 ; 13 ( 1 ). doi: 10.1186/s40364-025-00773-3 PMC11978164 40197552

63. Y L , L X , H W , R X , L Y . Pharmacological properties of indirubin and its derivatives . Biomedicine & Pharmacotherapy . 2022 ; 151 . doi: 10.1016/j.biopha.2022.113112 35598366

64. Wang F , Zhang W , Guo L , et al. Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells . Cancer Sci . 2014 ; 105 ( 8 ): 1063 – 1070 . doi: 10.1111/cas.12458 24890366 PMC4317858

65. Pandey MK , Kale VP , Song C , et al. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways . Exp Hematol . 2014 ; 42 ( 10 ): 883 – 896 . doi: 10.1016/j.exphem.2014.07.261 25034231

66. Xiang HJ . Clinical observation of Duhuo Jisheng decoction in the treatment of bortezomib-induced peripheral neuropathy [ dissertation ]. Hunan University of Chinese Medicine ; 2020 . [In Chinese] .

67. Cui SY , Yang Z , Cui X , et al. Clinical observation of Bushen Huoxue Tongluo formula combined with modified PD regimen in the treatment of newly diagnosed multiple myeloma . Liaoning J Tradit Chin Med . 2019 ; 46 ( 5 ): 987 – 990 . [In Chinese]

68. Xie WH , An N . Effects of Huanglian Jiedu decoction on Th1/Th2 balance and peripheral neuropathy in multiple myeloma patients . Acta Chin Med . 2020 ; 35 ( 1 ): 194 – 198 . [In Chinese] .

69. Li ZT , Li HL , Yan ZM , et al. Mechanism of Huayu Jiedu decoction in inhibiting malignant biological characteristics of multiple myeloma . J Exp Hematol . 2024 ; 32 ( 5 ): 1438 – 1443 . [In Chinese] . 10.19746/j.cnki.issn.1009-2137.2024.05.021 39479829