Mechanistic and translational insights into plant-derived natural products in preclinical multiple myeloma research: Current evidence

Highlights

• •This revised manuscript clarifies that the article is a structured narrative review and standardizes terminology and literature search descriptions.
• •Mechanistic evidence for fourteen plant-derived natural products is updated with added discussions on pharmacokinetics, toxicity, and clinical translational challenges for each compound.
• •The “Summary and Future Perspectives” section has been substantially strengthened with comparative mechanistic analysis, discussion of MM molecular subtypes, and modern-therapy resistance.
• •Six new mechanistic diagrams have been added to visualize the major signaling pathways of key compounds.
• •Clinical relevance and limitations are more comprehensively addressed, emphasizing poor bioavailability, dose unreachability, toxicity, and the absence of phase II/III MM trials.

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of abnormal plasma cells, with marked heterogeneity and therapeutic refractoriness. Despite the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, relapse and drug resistance remain major challenges that urgently need to be addressed. Plant-derived natural products have attracted increasing attention in recent years due to their multi-target synergistic effects, demonstrating unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment—making them a rising focus in translational medicine research. In this structured narrative review, we systematically summarize the anti-myeloma mechanisms of fourteen plant-derived natural products, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts (Strychnos nux-vomica root extract, dandelion flavonoids, Hedyotis diffusa polysaccharides). This review highlights their multi-target regulatory effects on signaling pathways, cell cycle modulation, and immune regulation, and further discusses their potential translational value in overcoming drug resistance and optimizing combination treatment strategies. Literature was retrieved from PubMed, Web of Science, and CNKI databases, covering studies published up to January 2025. Although plant-derived natural products exhibit promising multi-target regulatory mechanisms in MM therapy, their clinical translation remains limited by poor bioavailability of single compounds and the lack of standardized extracts. Future research should integrate systems pharmacology with clinical studies to elucidate multi-component synergistic networks and develop novel targeted formulations, thereby accelerating the efficient translation of phytochemicals from bench to bedside.

Graphical abstract

Introduction

Multiple myeloma (MM) is a malignant disease characterized by the abnormal proliferation of clonal plasma cells, representing the second most common hematologic malignancy in many countries [1]. The clinical manifestations of MM are driven by monoclonal proteins, malignant cells, or cytokines secreted by malignant cells, and include signs of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and/or bone disease with lytic lesions (i.e., lesions caused by the disease process) or pathological fractures. These symptoms significantly impair patients' quality of life and survival rates [2]. Despite significant therapeutic advances in recent years, including the emergence of novel treatments such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, the persistent challenges of drug resistance and high relapse rates remain [3]. While existing treatment strategies, such as conventional chemotherapy, radiotherapy, or autologous stem cell transplantation (ASCT), have extended patient survival to some extent, their limitations and side effects cannot be overlooked. Therefore, exploring novel therapeutic approaches and agents represents an urgent research priority.

Plant-derived natural products have garnered increasing interest due to their structurally diverse chemical constituents and multi-target synergistic mechanisms. These compounds have demonstrated unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment. Preclinical studies indicate that their anti-myeloma activity is mediated through key signaling pathways, including NF-κB, PI3K/AKT, and JAK/STAT, and some agents exhibit synergistic effects when combined with standard-of-care therapies, suggesting their promise as adjunct or combination treatments. However, substantial barriers continue to impede their clinical translation, including poor bioavailability, unclear pharmacokinetic profiles, a lack of standardization of botanical extracts, and potential toxicity associated with certain compounds. Moreover, most current evidence remains limited to in vitro or animal models, with insufficient validation across molecular subtypes and a lack of systematic safety evaluation, resulting in a persistent gap between laboratory findings and clinical application.

To address these challenges, this study adopts a structured narrative review approach to comprehensively synthesize preclinical progress on fourteen plant-derived natural products with reported anti-MM activity, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts (Strychnos nux-vomica root extract, dandelion flavonoids, Hedyotis diffusa polysaccharides). Selection criteria were based on documented in vitro and/or in vivo anti-MM efficacy, mechanistic clarity, and potential advantages in overcoming drug resistance or modulating the immune microenvironment. This review aims to provide a critical synthesis of their molecular mechanisms, pharmacological activities, pharmacokinetic characteristics, and translational barriers, thereby offering scientific insights and future directions for developing natural product–based integrative therapeutic strategies for MM.

In summary, the objective of this review is not only to consolidate current mechanistic evidence but also to elucidate common preclinical bottlenecks, translational potential, and optimization pathways of plant-derived natural products, ultimately contributing to the development of clinically applicable multi-target phytotherapeutics.

Baicalein

Baicalein (Fig. 1A), a major bioactive flavonoid isolated from the root of Scutellaria baicalensis, possesses broad-spectrum pharmacological properties, including antioxidant, anti-inflammatory, and antitumor activities [4]. Its multi-target regulatory capacity enables intervention in key oncogenic pathways of MM, demonstrating significant potential as an adjunct chemotherapeutic agent.

Fig. 1.

Chemical structures of plant-derived bioactive compounds used in the treatment of MM.

Studies have shown that baicalein blocks the nuclear factor kappa B (NF-κB) pathway by inhibiting the phosphorylation of inhibitor of κB-alpha (IκB-α), thereby reducing the expression of interleukin-6 (IL-6) and X-linked inhibitor of apoptosis protein (XIAP) [5]. It specifically induces apoptosis in MPC-1⁻ immature myeloma cells (IC₅₀ = 16.8 μM) by activating the mitochondrial-mediated caspase-9/caspase-3 apoptotic pathway, while exhibiting minimal toxicity toward mature subtypes and normal cells. This effect has been validated in MM cell lines (e.g., U266, ILKM2) and patient-derived primary cells, supporting its potential as a novel therapeutic strategy targeting immature myeloma cells [5]. IL-6 is a critical factor for MM cell survival and growth. Baicalein (10–50 μM) significantly inhibits IL-6-induced phosphorylation of Janus kinase 1/tyrosine kinase 2 (Jak1/Tyk2), signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), and protein kinase B (Akt), while downregulating the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), thereby inducing apoptosis in U266, NOP2, AMO1, and ILKM2 cells. Furthermore, its combination with dexamethasone enhances the inhibition of proliferation in both dexamethasone-resistant U266 cells and sensitive ILKM2 cells. Baicalein is effective against both IL-6-dependent and IL-6-independent cells and does not interfere with the insulin-like growth factor 1 (IGF-1)/Akt pathway, indicating a specific mechanism of action [6].

Side Population (SP) cells, characterized by high expression of the ATP-binding cassette subfamily G member 2 (ABCG2) transporter, are associated with tumor chemoresistance [7]. Scutellaria baicalensis extracts and their main flavonoid components target SP cells by modulating ABCG2 protein expression, providing a new strategy for targeting MM cancer stem cells [8]. Further research revealed that baicalein significantly reduces the proportion of SP cells in the MM RPMI 8226 cell line (IC₅₀ = 168.5 μM) and enhances their sensitivity to chemotherapeutic drugs by downregulating ABCG2 protein expression. In vitro experiments demonstrated that baicalein dose-dependently inhibits SP cell activity within the concentration range of 10–50 μM. Molecular docking studies indicated that baicalein shares a similar binding site (e.g., the TM5–TM6 region and the key residue Arg482) with the classical ABCG2 inhibitor fumitremorgin C (FTC), suggesting it functions through competitive inhibition of ABCG2 [9]. Additionally, baicalein suppresses the proliferation of U266 cells and promotes early apoptosis in a dose- (40–80 μM) and time-dependent (24–30 hours treatment) manner. This is achieved by upregulating cereblon (CRBN) mRNA expression and post-transcriptionally downregulating the protein levels of key transcription factors Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) via the proteasomal degradation pathway [10]. In vitro, baicalein (5.2×10² μM) combined with bortezomib significantly inhibited the viability and induced apoptosis in MM.1R and IM-9 cells. In vivo, intravenous administration of baicalein (120 mg/kg) combined with bortezomib significantly reduced tumor volume in nude mice bearing MM xenografts without significantly affecting body weight [11]. A schematic illustration of the major signaling pathways modulated by baicalein in MM cells is provided in Fig. 2.

Fig. 2.

Mechanistic actions of baicalein in multiple myeloma.

Although baicalein has demonstrated antitumor potential in vitro and in animal models through the modulation of NF-κB, STAT3, and Akt-related signaling pathways, its clinical translation remains significantly limited by pharmacokinetic constraints. Pharmacokinetic studies indicate that baicalein exhibits extremely low oral exposure due to poor solubility, rapid glucuronidation, and extensive first-pass metabolism, resulting in plasma concentrations that are often far below the effective in vitro range [12]. Although baicalein is generally considered to have a favorable safety profile, dose-dependent hepatotoxicity has been reported, and variations in purity caused by different botanical sources or preparation methods pose additional challenges for quality control and clinical consistency [13]. To date, no clinical trials targeting multiple myeloma have been conducted, and clinical evidence remains extremely limited. Future research should prioritize strategies to enhance its bioavailability—such as phospholipid complexes, nanocarriers, or structurally modified derivatives—and further evaluate its anti-myeloma efficacy in models that more closely recapitulate the bone marrow microenvironment [14].

Artemisinin

Artemisinin (Fig. 1B), a natural sesquiterpene lactone compound isolated from Artemisia annua [15], was first isolated and characterized through breakthrough research by Chinese scientist Tu Youyou's team. Artemisinin-based Combination Therapies (ACTs) are now the WHO-recommended first-line treatment for malaria. In recent years, artemisinin and its derivatives have demonstrated significant potential in anti-tumor applications through various mechanisms [16], with dihydroartemisinin (DHA) and artesunate (ART) receiving particular attention for MM treatment.

Studies show that ART (1.04×10³ μM) inhibits proliferation and induces apoptosis in the mouse MM cell line SP2/0 in a dose- and time-dependent manner [17]. This mechanism may involve downregulating nuclear NF-κB p65 protein levels while upregulating cytoplasmic IκBα expression, thereby suppressing NF-κB signaling activity [17]. ART (0.3–16.6 µM) significantly inhibits MM cell proliferation and induces apoptosis by downregulating MYC and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-xL, Mcl-1), concurrently activating caspase-3 cleavage. Furthermore, in co-culture systems with patient-derived bone marrow stromal cells, ART effectively induced apoptosis in primary MM cells, with IC₅₀ values approximately 10 µM for some clones, suggesting clinical feasibility [18]. Notably, ART primarily relies on non-caspase-mediated pathways to induce MM cell apoptosis. This process involves mitochondrial outer membrane permeabilization (MOMP), nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG), and is accompanied by increased reactive oxygen species (ROS) and mitochondrial superoxide levels. These changes precede apoptosis and correlate with intracellular ferrous iron (Fe²⁺) levels [19]. DHA (1–100 µmol/L) significantly induces apoptosis in U266 cells by activating the c-Jun N-terminal kinase (JNK) signaling pathway and upregulating caspase-3 expression [20]. Through in vitro (U266, CAG, JJN3, etc.) and in vivo (xenograft mouse model) experiments, DHA was confirmed to induce MM cell death via complex regulation of autophagy and apoptosis. Importantly, autophagy—a highly conserved cellular self-degradation process—typically maintains intracellular homeostasis and stress responses. In the MM context of this study, DHA-induced autophagy exhibited pro-death functions. Specifically, DHA critically regulates the interplay between autophagy and apoptosis by activating P38 mitogen-activated protein kinase (MAPK) and inhibiting Wnt/β-catenin signaling, collectively promoting MM cell death [21]. This dual mechanism reveals DHA's core pathway for inducing MM cell death and highlights its potential for synergistic anti-tumor effects across multiple signaling pathways. Additionally, both DHA and ART target the tumor microenvironment: Using RPMI8226 cells and the chicken chorioallantoic membrane (CAM) angiogenesis model, DHA (3–12 mmol/L) inhibited MM-mediated angiogenesis under hypoxia by downregulating vascular endothelial growth factor (VEGF) expression and suppressing phosphorylation of ERK1/2 [22]. Similarly, ART (3–12 μmol/L) inhibited neovascularization by suppressing VEGF and angiopoietin-1 (Ang-1) secretion via ERK1/2 pathway inhibition [23].

Research utilizing in vitro MM cell lines (ARP1, H929, and resistant model MM.1R), primary CD138⁺ MM cells, and NOD-SCID mouse xenografts confirmed that DHA overcomes dexamethasone resistance in MM cells through Fe²⁺-dependent ROS generation. This activates the mitochondrial apoptotic pathway and reverses dexamethasone-induced Bcl-2 overexpression. DHA combined with dexamethasone significantly enhanced anti-tumor efficacy [24]. ART induces ferroptosis in MM cells by inhibiting nuclear localization of sterol regulatory element-binding protein 2 (SREBP2), downregulating isopentenyl pyrophosphate (IPP) and glutathione peroxidase 4 (GPX4) expression. Treatment with 40 μM ART (below IC₅₀) significantly increased ROS, Fe²⁺, and lipid peroxidation markers (e.g., malondialdehyde [MDA], Liperfluo fluorescence) in MM cells—effects reversible by ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFO) [25]. This ART-induced ferroptosis via the SREBP2-IPP-GPX4 axis provides a novel strategy for resistant MM. Artemisinin derivatives exhibit synergistic effects with frontline drugs like bortezomib and are effective against both primary and resistant MM cells [18,19]. The principal oxidative stress–related and mitochondrial pathways affected by artemisinin derivatives are summarized in Fig. 3.

Fig. 3.

Mechanistic actions of DHA/ART in multiple myeloma.

Artemisinin and its derivatives have shown antitumor potential in preclinical studies of hematological malignancies, including multiple myeloma, primarily through the induction of iron-dependent ROS production, mitochondrial damage, apoptosis, autophagy, or ferroptosis, as well as through the inhibition of key signaling pathways such as NF-κB and MYC. However, artemisinin-type compounds are characterized by rapid metabolism and short elimination half-lives, posing significant challenges in achieving and maintaining therapeutically effective plasma concentrations following oral administration [26]. Although these agents are generally well tolerated in antimalarial use, their long-term safety profile in oncologic settings has not yet been systematically evaluated [27]. At present, there is no validated clinical evidence supporting their efficacy in multiple myeloma. Future research should therefore focus on strategies to prolong systemic exposure and enhance bioavailability, as well as on evaluating their feasibility and mechanistic rationale in combination with standard-of-care therapies using models that better recapitulate the bone marrow microenvironment [28].

Curcumin

Curcumin (Fig. 1C), the core polyphenolic active constituent extracted from the rhizomes of Curcuma longa, possesses diverse pharmacological properties including anti-inflammatory, antioxidant, and anti-tumor effects [29]. It plays a crucial role in multi-target regulation of the MM pathological process and reversal of drug resistance.

Studies demonstrate that curcumin (50 μM treatment for 4–8 hours) effectively inhibits constitutively activated NF-κB signaling in multiple MM cell lines (e.g., U266, RPMI 8226, MM.1, and MM.1R). Its mechanism involves inhibiting IκB kinase (IKK) activity, reducing IκBα phosphorylation and its degradation, thereby preventing NF-κB nuclear translocation. This downregulates the expression of NF-κB-regulated anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) and pro-proliferative factors (e.g., cyclin D1, IL-6), ultimately inducing G1/S phase cell cycle arrest and activating caspase-dependent apoptotic pathways in MM cells [30]. Curcumin is also a potent inhibitor of STAT3 phosphorylation. By inhibiting IL-6-induced STAT3 phosphorylation and its nuclear translocation, it suppresses MM cell survival and proliferation, an effect more rapid and significant than that of the Janus Kinase 2 (JAK2) inhibitor AG490 [31]. Furthermore, curcumin (25–50 μM) inhibits IL-6/sIL-6R-mediated phosphorylation of STAT3 and Extracellular Regulated Protein Kinases (Erk), and reduces the secretion of pro-inflammatory factors like VEGF by interfering with the interaction between bone marrow stromal cells (BMSCs) and MM cells. This effect was significant in U266 cells and three separate BMSC samples [32]. Notably, the cytotoxic effect of curcumin in vitro exhibits molecular subtype heterogeneity: among 29 human myeloma cell lines (HMCLs) covering major molecular subtypes, cell lines harboring the t(11;14) translocation showed lower sensitivity to curcumin (median LD50 32.9 μM), while non-t(11;14) cell lines, including high-risk subtypes t(4;14) and t(14;16), were more susceptible to killing (median LD50 17.9 μM, p=0.023). This difference was independent of TP53 gene status but closely associated with downregulation of myeloid cell leukemia 1 (Mcl-1) in primary MM cells [33]. Curcumin also induces apoptosis in a dose- (5–15 μmol/L) and time-dependent (24–72 h) manner by upregulating p53 and the pro-apoptotic gene Bax, while inhibiting the MDM2 gene [34]. Further research revealed that curcumin not only downregulates Enhancer of Zeste Homolog 2 (EZH2) expression and reduces the modification level of its catalytic product histone H3 lysine 27 trimethylation (H3K27me3) by regulating the miR-101–EZH2 negative feedback loop, but also induces DNA hypermethylation in the promoter region of mTOR gene, thereby suppressing its expression [35,36]. These mechanisms collectively contribute to curcumin's anti-tumor effects, providing a theoretical basis for developing novel MM therapeutic strategies based on natural compounds.

In drug resistance modulation, curcumin significantly reverses resistance to the chemotherapeutic agent melphalan in the MOLP-2/R cell line by blocking the Fanconi Anemia/Breast Cancer Susceptibility Gene (FA/BRCA) pathway. Specifically, treatment with 10 μM curcumin combined with melphalan reduced the IC₅₀ of MOLP-2/R cells from 45.5 μM to 19 μM. Curcumin dose-dependently inhibited FANCD2 monoubiquitination expression, thereby reducing DNA damage repair and promoting G2/M phase arrest and apoptosis [37]. Preclinical studies indicate that curcumin enhances the efficacy of proteasome inhibitors (e.g., bortezomib, carfilzomib): its combination with bortezomib synergistically inhibits STAT3/Erk phosphorylation and enhances cytotoxicity against H929 cells by activating the JNK pathway [38,32]; combination with carfilzomib potentiates G0/G1 phase arrest and apoptosis by synergistically activating the p53/p21 axis [39]. Clinical trials show that curcumin improves free light chain levels (rFLC, dFLC, iFLC) in patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM), and reduces levels of the bone resorption marker urinary deoxypyridinoline (uDPYD) and serum creatinine, suggesting its potential to delay disease progression (Trial Registration: ACTRN12610000962033) [40]. However, due to the small sample size and limited follow-up, its long-term efficacy and safety require further validation. To improve efficacy, researchers have developed curcumin derivatives (e.g., GO-Y030, GO-Y078) and hybrid compounds (e.g., thalidomide-curcumin hybrids 5 and 7), which exhibit significantly enhanced inhibitory capacity against pathways like NF-κB, PI3K/AKT, and JAK/STAT3 [41,42]. Additionally, a synthetic compound containing isovanillin, harmine, and curcumin, GZ17-6.02, can induce autophagic death by regulating the ATM/AMPK/mTORC1/NF-κB signaling network and shows strong synergy with bortezomib [43]. Although the challenge of curcumin's low bioavailability remain [44], its antioxidant/anti-inflammatory effects mediated through the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway provide a novel strategy for MM treatment [45]. The major signaling cascades targeted by curcumin in MM are depicted in Fig. 4.

Fig. 4.

Mechanistic actions of curcumin in multiple myeloma.

Unlike many other natural products, curcumin exhibits a distinctly multi-pathway and systemic regulatory profile in multiple myeloma. It suppresses key signaling axes such as NF-κB and STAT3 and downregulates their downstream target genes, thereby exerting effects on both tumor cells and the bone marrow microenvironment. Multiple in vitro studies have indicated synergistic interactions with bortezomib, lenalidomide, and dexamethasone, suggesting enhanced proteasome inhibition or mitigation of inflammation-driven drug resistance. However, its clinical translation is markedly limited by extremely low oral bioavailability and restricted systemic exposure, which makes it difficult to achieve in vivo concentrations comparable to those effective in vitro [46]. Although early studies have reported a generally favorable safety profile, clinical evidence supporting its therapeutic efficacy in multiple myeloma remains insufficient. Future investigations should clarify its biological activity at clinically achievable concentrations and further define its potential value in combination with standard therapies [47].

Celastrol

Celastrol (Fig. 1D), a pentacyclic triterpenoid compound extracted from the medicinal plant Tripterygium wilfordii, exhibits broad-spectrum anticancer activity [48]. It inhibits cancer cell proliferation and induces apoptosis through multiple mechanisms, positioning it as a focal point in MM research.

Celastrol demonstrates significant antitumor activity in various MM cell lines (e.g., LP-1, RPMI 8226, U266). Mechanisms include inhibition of NF-κB and STAT3 signaling pathways, downregulation of pro-proliferative proteins (e.g., cyclin D1) and anti-apoptotic proteins (e.g., Bcl-2, Mcl-1, survivin), activation of JNK, and suppression of Akt phosphorylation, thereby inducing cell cycle arrest (G0/G1 phase) and caspase-dependent apoptosis [[49], [50], [51], [52]]. These findings provide a robust experimental basis for celastrol as a potential therapeutic agent. Additionally, celastrol inhibits Toll-like receptor 4 (TLR4)-mediated NF-κB signaling, significantly reducing lipopolysaccharide (LPS)-induced VEGF secretion, thereby suppressing migration and invasion of human umbilical vein endothelial cells (HUVECs) induced by LP-1 cells. At concentrations of 0.025–0.1 μM, celastrol dose-dependently decreased VEGF levels by 64.8%–92.9% and blocked nuclear translocation of the NF-κB p65 subunit [53]. Celastrol inhibits the activity of purified human 20S proteasomal β1, β2, and β5 subunits (IC₅₀ = 7.1, 6.3, and 9.3 μmol/L, respectively) and proteasomal activity in MM.1S cells (IC₅₀ = 2.3, 2.1, and 0.9 μmol/L), inducing G0/G1 arrest and caspase-dependent apoptosis. This leads to aberrant protein aggregation and disruption of proteostasis [54]. Notably, its promiscuous modification of multiple proteins (e.g., PRDX1, PRDX2) may cause off-target effects, limiting clinical translation [55].

Celastrol exhibits potential in overcoming chemoresistance. Its derivative, dihydrocelastrol (DHCE), suppresses JAK2/STAT3 and PI3K/Akt signaling pathways, downregulating the expression of the resistance-associated proteasomal subunit PSMB5, thereby overcoming bortezomib resistance [56]. DHCE also downregulates cyclin D1 and CDK4/6 expression by inhibiting IL-6/STAT3 and ERK1/2 pathways, inducing G0/G1 arrest and caspase-dependent apoptosis in MM cells. Furthermore, its combination with the histone deacetylase inhibitor panobinostat (LBH589) enhances antitumor effects, suggesting synergistic therapeutic value [57]. In a xenograft mouse model (established using patient-derived CD138⁺ MM cells), celastrol combined with bortezomib synergistically inhibited tumor growth and reduced levels of inflammatory cytokines (e.g., IL-6, TNF-α) [58]. The multifaceted inhibitory effects of celastrol on oncogenic signaling pathways are illustrated in Fig. 5.

Fig. 5.

Mechanistic actions of celastrol in multiple myeloma.

Celastrol exhibits multi-target inhibitory effects in multiple myeloma, blocking key signaling axes such as NF-κB and STAT3 and inducing ROS generation, apoptosis, and autophagy, thereby suppressing cell survival and, in certain models, reversing drug resistance. However, its clinical translation is hindered by a narrow therapeutic window and pronounced dose-dependent toxicity, including hepatic, renal, and systemic toxic reactions observed in multiple animal studies [59]. In addition, the poor aqueous solubility, low oral bioavailability, and rapid systemic clearance of celastrol make it difficult to maintain therapeutically effective exposure levels without increasing toxicity risks [60]. Future studies should focus on defining tolerable dosing ranges and developing strategies to reduce systemic toxicity in order to more accurately assess its true therapeutic potential in malignant diseases.

Gambogic acid

Gambogic Acid (GA, Fig. 1E), a caged xanthone dimer isolated from the resin of Garcinia hanburyi, exhibits diverse pharmacological effects including anticancer, antiviral, anti-inflammatory, and anti-infective activities [61]. It demonstrates potent anticancer activity in certain solid tumors and hematological malignancies.

GA exerts significant antitumor effects in RPMI-8226 cells by inducing the accumulation of ROS. Experimental results demonstrated that treatment with 1.5–2.0 µM GA dose-dependently inhibited cell proliferation and induced apoptosis, manifested by caspase-3 activation and PARP cleavage. Furthermore, GA treatment led to downregulation of silent information regulator 1 (SIRT1) expression, and SIRT1 inhibition contributes to overcoming resistance to chemotherapeutic agents [62,63]. In tumor microenvironment regulation, stromal cell-derived factor-1α (SDF-1α) and its receptor CXC chemokine receptor 4 (CXCR4) are recognized as modulators of bone resorption. GA not only reduced CXCR4 expression in U266 and NCI H929 MM cells by inhibiting NF-κB binding to DNA but also, at concentrations as low as 5 nmol/L, inhibited RANKL-induced differentiation of RAW264.7 macrophages into osteoclasts. Additionally, it prevented myeloma cell self-induced osteoclastogenesis by suppressing IL-6 expression [64]. Under hypoxic conditions, GA inhibited PI3K/Akt/mTOR pathway, reducing the generation of hypoxia-inducible factor-1α (HIF-1α) and its downstream effector VEGF, thereby suppressing tumor angiogenesis in U266 cells. In a U266 xenograft mouse model, intravenous administration of GA at 2 or 4 mg/kg every two days significantly inhibited tumor growth and the expression of CD31, VEGF, and HIF-1α [65]. The pro-apoptotic and stress-associated pathways activated by gambogic acid are shown in Fig. 6.

Fig. 6.

Mechanistic actions of GaVmbogic acid in multiple myeloma.

Gambogic acid has demonstrated preclinical potential in multiple myeloma by suppressing tumor growth and inhibiting signaling pathways associated with bone destruction. It modulates NF-κB, STAT3, and the CXCR4/SDF-1 axis, and induces apoptosis, with some models showing synergistic trends when combined with standard therapies. However, its poor aqueous solubility, low oral bioavailability, limited plasma and in vivo stability, and dose-dependent toxicity constitute major barriers to clinical translation. Consistent with these findings, recent reviews have identified pharmacokinetic and safety limitations as central bottlenecks, underscoring the need for formulation optimization or structural modification to broaden the therapeutic window [66]. Systematic clinical evidence in the context of multiple myeloma is currently lacking. Future studies should define tolerable dosing ranges and characterize exposure–response relationships, while mechanistically evaluating the feasibility of combining gambogic acid with existing therapeutic regimens [67]. To mitigate systemic toxicity and enhance exposure and stability, pharmaceutical strategies such as nano-delivery systems and carrier-based formulations have been extensively reviewed and are considered promising approaches to improve bioavailability and safety. These strategies warrant further validation in models that more closely recapitulate the bone marrow microenvironment to determine their true translational benefit [68].

Resveratrol

Resveratrol (Fig. 1F), a natural polyphenol compound widely present in plants such as grapes, peanuts, and berries [69], exerts anti-MM effects through multimodal mechanisms including activation of the mitochondrial apoptotic pathway, inhibition of signaling pathways, and modulation of epigenetic modifications, effectively reversing drug resistance.

In drug-resistant non-Hodgkin lymphoma (NHL) and MM cell lines, the combination of resveratrol (10 μM) with paclitaxel (10 nM) selectively downregulated anti-apoptotic proteins Bcl-xL and Mcl-1 while upregulating pro-apoptotic proteins Bax and Apaf-1. This induced mitochondrial membrane potential loss, cytochrome c/Smac/DIABLO release, and activation of the caspase cascade, achieving synergistic apoptotic effects [70]. Resveratrol inhibits the NF-κB and STAT3 signaling pathways, downregulating the expression of multiple gene products associated with cell survival and proliferation, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF2, VEGF, and MMP-2/9. It also enhances the apoptosis-inducing effects of bortezomib and thalidomide on MM cells. Mechanisms involve blocking IKK-mediated IκBα/p65 phosphorylation, inhibiting IL-6-induced STAT3 activation, and attenuating sustained AKT signaling [[71], [72], [73]]. These effects collectively lead to cell cycle arrest, reduced invasion, and increased apoptosis, highlighting its potential as an adjunctive therapeutic agent for MM. Resveratrol also targets the unfolded protein response (UPR), activating inositol-requiring enzyme 1α (IRE1α) to induce X-box binding protein 1 (XBP1) mRNA splicing in ANBL-6, OPM2, and MM.1S cell lines. Concurrently, it represses the transcriptional activity of XBP1s through Sirtuin 1 (SIRT1)-mediated epigenetic regulation, promoting pro-apoptotic endoplasmic reticulum stress [74].

Resveratrol exhibits significant synergistic effects when combined with conventional and novel anti-MM agents. The combination of resveratrol (50 µM) and the proteasome inhibitor carfilzomib (40 nM) showed marked synergistic pro-apoptotic effects in MM cell lines (e.g., LP-1, MM.1S). Mechanisms include induction of mitochondrial dysfunction, promotion of Smac release, significant increase in ROS generation, and downregulation of SIRT1 and its downstream target survivin, thereby enhancing oxidative stress. Furthermore, the combination induced protective autophagy, and co-treatment with the autophagy inhibitor 3-MA amplified ROS accumulation and apoptosis, suggesting that simultaneously targeting oxidative stress and autophagy pathways represents a promising combinatorial strategy [75]. Resveratrol (60 µM) combined with rapamycin (20 nM) synergistically induced apoptosis in MM1.S cells by inhibiting mammalian target of rapamycin complexes 1/2 (mTORC1/mTORC2), reducing cyclin D1 levels, and activating caspase-3/PARP cleavage [76]. Resveratrol effectively inhibited proliferation, migration, and invasion of MM cells by downregulating long non-coding RNA nuclear-enriched abundant transcript 1 (lncRNA NEAT1) expression, thereby suppressing the Wnt/β-catenin signaling pathway and UPR. These effects were validated in U266 and LP1 MM cell lines, with resveratrol concentrations of 15-50 µM and IC50 values for proliferation inhibition of 33.74 µM (U266) and 40.72 µM (LP1), respectively [77]. In clinical research, resveratrol combined with trace copper (doses: 5.6 mg twice daily and 560 ng twice daily, respectively) significantly reduced transplantation-related toxicity in MM patients receiving high-dose melphalan. This combination therapy decreased the incidence of grade 3/4 oral mucositis from 100% in the control group to 40% (p=0.039) and significantly reduced exposure to the pro-inflammatory cytokines TNF- α(p=0.012) and IL-1β (p=0.009) in saliva (Trial Registration: CTRI/2018/02/011905) [78]. Despite promising results, limitations include small sample size, high risk of control group bias, unclear mechanisms for changes in some serum inflammatory markers, and low bioavailability of resveratrol. Thus, larger randomized controlled trials are needed to validate its clinical value. Screening of resveratrol derivatives pinostilbene (PIN) and piceatannol (PIC) in combination with bortezomib revealed that 5 µM PIN combined with 5 nM BTZ produced significant synergistic antitumor effects in RPMI 8226, U266, and NCI-H929 cells, characterized by induced apoptosis, upregulated cleaved caspase-3 and cleaved PARP1 expression, and enhanced oxidative stress (OS). This combination effectively induced apoptosis even in a Transwell co-culture model mimicking the bone marrow microenvironment, suggesting its ability to overcome stroma-mediated resistance [79]. Additionally, resveratrol significantly upregulated the expression of the tumor-suppressive lncRNA TERRA at six chromosomal regions (2q, 7p, 10q, 15q, XpYp, XqYq) by stabilizing its G-quadruplex structure in AMO-1 and NCI-H929 cells, with increases up to 17-fold. Concurrently, resveratrol induced the deposition of telomeric heterochromatin marks H3K27Me3 and H4K20Me3 and upregulated the pro-apoptotic marker cleaved-PARP-1, contributing to its antitumor effects [80]. The key regulatory pathways modulated by resveratrol in MM cells are summarized in Fig. 7.

Fig. 7.

Mechanistic actions of resveratrol in multiple myeloma.

Resveratrol inhibits proliferation and induces apoptosis in multiple myeloma by modulating key signaling pathways such as NF-κB, JAK/STAT3, and SIRT1/p53. Its anti-inflammatory and antioxidant properties may attenuate the protective effects of the bone marrow microenvironment on tumor cells and enhance the sensitivity of myeloma cells to proteasome inhibitors and immunomodulatory drugs. Despite its multi-target therapeutic potential, the clinical application of resveratrol is limited by its low bioavailability and rapid metabolism [81]. Current studies are predominantly cell-based, with limited in vivo validation and a lack of large-scale clinical evidence, making it difficult to establish standardized therapeutic recommendations. Therefore, future research should focus on developing novel drug delivery systems and molecular modification strategies to improve the bioavailability and stability of resveratrol. High-quality animal studies and clinical trials are also needed to support its transition from a nutraceutical to a clinically applicable therapeutic agent.

Mechanisms of anti-MM activity of other plant-derived natural products

Beyond the major categories discussed, numerous botanical constituents exhibit significant antitumor activity by targeting key signaling pathways and cell death mechanisms in MM cells.

Regarding the induction of apoptosis and regulation of the cell cycle, ginsenosides, the primary active constituents of Panax ginseng, exert anti-MM effects through various subtypes by modulating apoptosis-related pathways. Ginsenoside Rg3 (Fig. 1G) inhibits proliferation of U266 and RPMI8226 cells in a dose-dependent manner (0–80 µM). In U266 cells, it induces apoptosis by upregulating Bax mRNA expression and activating caspase-3-dependent pathways [82,83]. Ginsenoside Rg1 (Fig. 1I) reverses bortezomib resistance in RPMI8226R-resistant cells by inducing autophagy via the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. In vitro, Rg1 (10 μM, 24 h) significantly promotes apoptosis, inhibits proliferation, upregulates autophagy-related proteins LC3B-II/LC3B-I and Beclin1, and reduces p62 levels. In vivo, Rg1 (50 mg/kg) combined with bortezomib (2.06 μM) suppresses tumor growth and enhances apoptosis more effectively than monotherapy [84]. The ultra-low molecular weight ginsenoside compound K (KBB-N1) selectively activates p53 phosphorylation and upregulates apoptosis-related proteins (e.g., Bcl-2, HIF-1α, HO-1, p27/Kip1), inducing cell cycle arrest and apoptosis. It demonstrates significant antitumor activity in ARH77, U266, and RPMI8226 cell lines and murine MM models [85]. Despite its safety profile and selective action against MM cells—potentially beneficial for elderly patients—its poor aqueous solubility and low oral bioavailability (approximately 24%) limit clinical translation, necessitating further formulation optimization. Oridonin (Fig. 1K), a natural diterpenoid isolated from Rabdosia rubescens, exhibits potent antitumor activity in RPMI8226, U266, Jurkat, and MT-1 cell models. Studies show oridonin (1–64 µmol/L) concentration-dependently inhibits RPMI8266 cell proliferation (IC₅₀ = 6.74 µmol/L). Mechanisms include: suppression of NF-κB, modulation of Bcl-2/Bax balance, activation of caspase-3/PARP1 pathways, downregulation of Survivin, and induction of protective autophagy via the ROS/SIRT1 axis [[86], [87], [88]]. Proteomic analysis further identifies differentially expressed proteins (e.g., stathmin, dihydrofolate reductase [DHFR], pyruvate dehydrogenase E1 [PDHE1]) significantly downregulated during oridonin-induced apoptosis, suggesting their roles as potential therapeutic targets [89]. Strychnos nux-vomica (SN) root extract, rich in alkaloids (e.g., brucine and strychnine), exhibits potent anti-proliferative effects on RPMI 8226 and U266B1 cell lines in vitro, inducing apoptosis and cell cycle arrest in dose- and time-dependent manners. Mechanisms involve mitochondrial membrane potential disruption, cytochrome c release, and modulation of signaling molecules (e.g., IL-6, CD138) [[90], [91], [92]]. Brucine (Fig. 1N) downregulates receptor activator of nuclear factor kappa-B ligand (RANKL) while upregulaing alkaline phosphatase (ALP), osteocalcin (OC), and osteoprotegerin (OPG), thereby inhibiting osteoclast differentiation and promoting osteogenesis to ameliorate MM-related bone disease [93]. Plumbagin (5–50 µM) inhibits OPM1 cell proliferation and induces dose-dependent apoptosis by activating caspase-3, increasing lactate dehydrogenase release, and downregulating PI3K, p-Akt, and p-mTOR proteins [94]. Hedyotis diffusa polysaccharides (PEHD, 1–4 mg/ml) suppress RPMI 8226 cell proliferation and induce apoptosis by downregulating p-Akt and NF-κB expression while activating apoptosis-related proteins (caspase-3, -8, -9, PARP) [95].

Concerning the inhibition of pro-survival pathways, icaritin, the main active component of Epimedium species, induces cell cycle arrest and apoptosis in RPMI8226 and U266 cells by inhibiting the IL-6/JAK2/STAT3 pathway [96]. It also upregulates circular RNA circ_0000190, which sequesters microRNA-301a (miR-301a) to relieve its suppression of the tumor suppressor PTEN. This mechanism shows significant tumor suppression in in vivo xenograft models [97]. Its derivative C3, a novel DEP domain-containing mTOR-interacting protein (DEPTOR) inhibitor, enhances mTORC1/C2 activity to induce aberrant downstream signaling and cell death, demonstrating antitumor effects in animal models [98,99]. Although C3 shows specificity for DEPTOR, potential off-target effects on other DEP domain-associated proteins require further investigation. Formononetin (Fig. 1O) induces apoptosis and suppresses proliferation in MM cells by inhibiting STAT3/STAT5 phosphorylation and downstream signaling via ROS accumulation. In nude mouse xenograft models, it significantly inhibits tumor growth without apparent toxicity, indicating robust in vivo anti-MM activity [100]. It also downregulates oncoproteins linked to MM cell survival and progression by suppressing NF-κB, PI3K/AKT, and activator protein-1 (AP-1) pathways, while enhancing bortezomib-induced apoptosis [101]. Dandelion flavone (Fig. 1L) significantly reduces MM cell migration and invasion by inhibiting the PI3K/AKT pathway [102].

Regarding other unique mechanisms, ginsenoside Rh4 induces ferroptosis by modulating sirtuin 2 (SIRT2), inhibiting MM proliferation and promoting apoptosis in NCI-H929 cells [103]. This provides a novel direction for ferroptosis-targeted MM therapy, though the lack of in vivo validation and pharmacokinetic data limits clinical translation. The regulation of circRNA/miRNA pathways by icaritin also represents an epigenetic mechanism of action [97].

Summary and future perspectives

This review systematically integrates the preclinical evidence surrounding fourteen plant-derived natural products investigated for the treatment of multiple myeloma (MM) (Table 1). The representative plant-derived monomeric compounds discussed include baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icaritin, oridonin, plumbagin, and formononetin; well-characterized standardized plant extracts include Strychnos nux-vomica root extract (featuring a characteristic alkaloid profile), flavonoid-enriched dandelion flavone, and Hedyotis diffusa polysaccharides. A substantial body of preclinical research indicates that these plant-derived agents modulate MM biology through multiple layers of activity, including broad inhibition of key oncogenic signaling pathways (e.g., NF-κB, STAT3, PI3K/Akt), induction of apoptosis, ferroptosis, and autophagy, and regulation of the immunosuppressive bone marrow microenvironment.

Table 1.

Summary of mechanisms of plant-derived natural products in the treatment of MM.

Herbal medicine names	Primary active constituents	Experimental model	Main mechanism of action	Key targets/signaling pathways	Summary of efficacy	References
Scutellaria baicalensis	Baicalein	In vitro (U266, NOP2, etc. MM cell lines) + in vivo (mouse model)	Targeting multiple key pathways including apoptosis, autophagy, angiogenesis, and ferroptosis.	NF-κB,STAT3,Bcl-2,CRBN,IL-6/JAK/STAT3	Inhibiting proliferation, enhancing chemosensitivity, and reversing IMiD resistance	[6,5,7]; Liu 108 et al. 2018
Artemisia annua	Dihydroartemisinin;Artesunate	In vitro (SP2/0, U266 etc. MM cell lines) + in vivo (mouse model)	Intervening in key pathways such as IL-6, NF-κB, Akt, the Bcl-2 family, and ABCG2.	IL-6,NF-κB,Akt,Bcl-2,ABCG2,SP,CRBN	Overcoming drug resistance, inhibiting angiogenesis	[17,25,19,20,22,21]
Curcuma longa	Curcumin	In vitro (U266, H929 etc. MM cell lines) + in vivo (mouse model)	Intervening in multiple pathways including NF-κB, STAT3, epigenetic modifications, and cell cycle regulation.	NF-κB,STAT3,IL-6,p53,FA/BRCA	Targeting high-risk subtypes; enhancing proteasome inhibitor efficacy	Bharti et al. 2003; Bharti, Donato and Aggarwal 2003; [38,35,32,58,36,37]
Tripterygium wilfordii	Celastrol	In vitro (U266, MM.1S etc. MM cell lines) + in vivo (mouse model)	Intervening in NF-κB, STAT3, JNK/Akt, and proteasome activity.	NF-κB,STAT3,JNK,TLR4,VEGF	Reversing drug resistance, inhibiting angiogenesis, and producing synergistic effects	[56,53,58,52,55,54]
Garcinia gummi-gutta	Gambogic Acid	In vitro (RPMI 8226, U266 etc. MM cell lines)	Intervening in multiple pro-survival pathways such as STAT3, PI3K/Akt/mTOR, and CXCR4	STAT3,SIRT1,CXCR4,PI3K/Akt/mTOR	Inhibiting bone resorption and overcoming bortezomib resistance	[62,64,65,63]
Vitis vinifera	Resveratrol	In vitro (RPMI 8226, KM3 etc. MM cell lines)	Intervening in NF-κB, STAT3, Wnt/β-catenin, and epigenetic pathways.	NF-κB,STAT3,Wnt/β-catenin	Synergizing with carfilzomib, reducing transplant toxicity	[71,70]; SUN, Hu, Guo, et al. 2006; Sun, Hu, Liu, et al. 2006; [77,76,74]
Panax ginseng	Ginsenosides	In vitro (RPMI 8226, U266 etc. MM cell lines) + in vivo (mouse model)	Modulating SIRT2 to induce ferroptosis; inhibiting the AMPK-mTOR pathway; activating p53 phosphorylation	SIRT2,AMPK/mTOR,p53	Selective cytotoxicity, reducing hematopoietic toxicity	[85,82,84,83,103]
Epimedium	Lcaritin	In vitro (RPMI 8226, U266 etc. MM cell lines) + in vivo (mouse model)	Inhibiting the IL-6/JAK2/STAT3 pathway; upregulating circ_ 0000190 to regulate miR30la; targeting DEPTOR protein.	JAK2/STAT3,circ_0000190/miR-301a,DEPTOR	Inhibiting the cell cycle, inducing apoptosis	[98,99,97]
Rabdosia rubescens	Oridonin	In vitro (RPMI 8226, U266 etc. MM cell lines)	Inhibiting the NF-kB pathway; modulating the ROS/SIRT1 balance; downregulating Survivin.	NF-κB,ROS/SIRT1,Survivin	Dual regulation of cell death pathways	[[86], [87], [88], [89]]
Strychnos nux-vomica	Brucine	In vitro (RPMI 8226, U266 etc. MM cell lines)	Downregulating RANKL expression, upregulating ALP/OC/OPG; inhibiting osteoclast differentiation.	RANKL,ALP,OC,OPG	Improving MM bone disease. promoting bone formation	[90,93]

From a comparative perspective, these fourteen natural products exhibit both mechanistic convergence and marked heterogeneity. Curcumin, celastrol, and oridonin exert broad inhibitory activity across NF-κB, PI3K/AKT, and JAK/STAT signaling pathways. In contrast, baicalein, resveratrol, and ginsenosides demonstrate more selective pathway modulation with moderate potency, while additionally displaying immunomodulatory or anti-inflammatory effects that may indirectly influence the myeloma microenvironment. Importantly, not all agents rely on NF-κB–centered mechanisms: artemisinin, icariin, and Hedyotis diffusa polysaccharides primarily function through oxidative stress, immune regulation, or differentiation-related mechanisms. Moreover, research on molecular subtype-specific responses in MM (e.g., t(4;14), del17p) remains extremely limited. Aside from reports of subtype-selective activity for curcumin, most compounds have not been evaluated within clearly defined genomic backgrounds, representing a key knowledge gap that may limit the clinical relevance of existing preclinical findings.

Integrating mechanistic profiles, the breadth of preclinical evidence, pharmacokinetic and safety characteristics, and the potential for synergy with standard-of-care agents, the plant-derived compounds reviewed here display a stratified pattern of translational feasibility. Overall, curcumin, resveratrol, and certain ginsenosides show relatively higher translational potential, supported by more comprehensive mechanistic studies, manageable safety profiles, and preliminary evidence of treatment-sensitizing effects. Oridonin, icariin, and dandelion flavonoids demonstrate promising anti-myeloma activity in vitro and in vivo, but their translational potential remains moderate due to limited pharmacokinetic data or incomplete mechanistic coverage. In contrast, celastrol, gambogic acid, and Strychnos nux-vomica root extract exhibit pronounced toxicity or compositional complexity, posing greater challenges for clinical advancement. It should be emphasized that this stratification is not intended as a strict ranking, but rather as a translational framework to guide future research priorities.

From a translational standpoint, significant differences exist in pharmacokinetics, bioavailability, and safety among these compounds. Despite strong in vitro activity, agents such as curcumin and celastrol are limited by poor bioavailability and potential toxicity, whereas resveratrol, ginsenosides, and icariin exhibit comparatively more favorable pharmacokinetic features. Extract-based agents, including Strychnos nux-vomica root extract and Hedyotis diffusa polysaccharides, possess immunomodulatory potential but require rigorous safety assessment and compositional standardization to avoid risks associated with alkaloid toxicity or batch variability. Collectively, these findings underscore that high in vitro potency alone does not predict clinical translational success; greater emphasis should be placed on optimizing pharmacokinetics, improving delivery strategies, and ensuring toxicity controllability.

Notably, many plant-derived compounds demonstrate synergistic effects with existing standard MM therapies—including bortezomib, carfilzomib, lenalidomide, and dexamethasone—and some enhance drug sensitivity or reverse resistance phenotypes. In the context of rapidly evolving therapeutic landscapes, including anti-CD38 antibodies, CELMoDs, and bispecific antibodies, plant-derived natural products may serve as “adjunct sensitizers” or “resistance modulators” offering new avenues to improve therapeutic response and delay relapse.

Although many of the molecular targets modulated by these compounds are not MM-specific, they represent core drivers of MM pathophysiology, particularly within the bone marrow microenvironment where they regulate cell survival, proliferation, immune evasion, and bone destruction. Studies of baicalein, curcumin, gambogic acid, and brucine/strychnine-containing extracts have validated their ability to modulate these critical pathogenic pathways in MM models, supporting their disease relevance.

However, it must be emphasized that these conclusions are predominantly supported by preclinical data, and no plant-derived natural product has yet demonstrated confirmed efficacy in phase II/III clinical trials for MM. Most studies rely on supraphysiological doses or non-physiological administration routes, and results from animal models do not readily translate to humans. More comprehensive pharmacokinetic, toxicological, and formulation studies are required to assess translational feasibility. In particular, although Strychnos nux-vomica root extract exhibits in vitro anti-myeloma activity, its narrow therapeutic window and risk of neurotoxicity necessitate stringent safety evaluation and rigorous standardization.

Multiple limitations persist in the current evidence base. Many studies focus primarily on phenotypic observations with limited deep mechanistic interrogation of bone marrow microenvironment dynamics, long-term toxicity, or subtype-specific or clone-specific responses. Single-compound studies cannot fully represent the multi-component synergy characteristic of botanical medicines, and current model systems (e.g., cell lines and subcutaneous xenografts) inadequately recapitulate tumor heterogeneity and the pathological microenvironment. Additionally, the literature is biased toward positive findings, with few reports of negative or null results, increasing uncertainty in preclinical evidence.

Thus, clinical development of plant-derived natural products for MM remains at an early stage, constrained primarily by low bioavailability, insufficient pharmacokinetic data, and the lack of systematic clinical validation. Future research should focus on developing innovative drug delivery systems to improve solubility, stability, bioavailability, and bone marrow targeting. Complementarily, systems pharmacology and multi-omics approaches should be employed to elucidate multi-target networks and synergistic mechanisms. Integrating molecular subtyping and resistance profiling may help identify compounds or combinations most suitable for specific MM subgroups. Strengthening research on immunomodulation and non-apoptotic cell death pathways (e.g., ferroptosis, pyroptosis) and establishing models that better reflect clinical pathology will further enhance predictive value and translational efficiency.

In summary, plant-derived natural products offer multi-target, multi-level therapeutic strategies and constitute an important source of novel agents for MM, particularly in overcoming drug resistance and remodeling the tumor microenvironment. Realizing their clinical potential will require bridging the gap from “test tubes and mice” to “patients and clinics”. Through multidisciplinary collaboration, systematic optimization of drug-like properties and safety, deeper mechanistic investigation, and well-designed clinical trials, this ancient reservoir of natural compounds may ultimately be transformed into tangible therapeutic benefit for patients with MM.

CRediT authorship contribution statement

Lulu Li: Writing – review & editing, Writing – original draft. Jie Xu: Conceptualization. Liming Yu: Formal analysis. Jingbo Shi: Visualization. Changnian Li: Resources. Jiabao Gu: Investigation. Yaru Wang: Methodology. Siyuan Cui: Validation, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.