MULTIPLE MYELOMA COMPREHENSIVE TREATMENT OVERVIEW

INTRODUCTION

Multiple Myeloma is a cancer of plasma cells that accumulate in the bone marrow, disrupting normal blood cell production and causing bone lesions. It is characterized by high levels of abnormal proteins, such as monoclonal proteins (M proteins). Risk factors include age, gender, family history, exposure to radiation, and certain chemical exposures. Standard treatments include chemotherapy, immunotherapy, targeted therapy, and integrative oncology approaches. Emerging genomic medicine offers personalized treatment strategies for improved outcomes.

TRADITIONAL THERAPIES FOR MULTIPLE MYELOMA

CHEMOTHERAPY

Chemotherapy is a primary treatment for Multiple Myeloma, aimed at killing rapidly dividing cancer cells. It is often combined with immunotherapy or targeted agents.

BORTEZOMIB (VELCADE)

Mechanism: Proteasome inhibitor that disrupts protein breakdown, inducing apoptosis in myeloma cells.

Clinical Applications: First-line therapy for Multiple Myeloma, often combined with lenalidomide and dexamethasone.

Study Reference: Richardson PG, Sonneveld P, Schuster MW, et al. ‘Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.’ *New England Journal of Medicine*, 2005, 352(24):2487–2498.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

DARATUMUMAB (DARZALEX)

Mechanism: Monoclonal antibody that targets CD38 on myeloma cells, enhancing immune-mediated killing of cancer cells.

Clinical Applications: Approved for use in both newly diagnosed and relapsed/refractory Multiple Myeloma.

Study Reference: Lokhorst HM, Plesner T, Laubach JP, et al. ‘Targeting CD38 with daratumumab monotherapy in multiple myeloma.’ *New England Journal of Medicine*, 2015, 373(13):1207–1219.

ELOTUZUMAB (EMPLICITI)

Mechanism: Targets SLAMF7, a protein on myeloma cells, enhancing natural killer (NK) cell activity to attack cancer cells.

Clinical Applications: Used in combination with lenalidomide and dexamethasone for relapsed/refractory Multiple Myeloma.

Study Reference: Lonial S, Dimopoulos M, Palumbo A, et al. ‘Elotuzumab therapy for relapsed or refractory multiple myeloma.’ *New England Journal of Medicine*, 2015, 373(7):621–631.

RADIATION THERAPY

Radiation therapy is used in Multiple Myeloma primarily to control pain and manage bone lesions. It is effective in reducing tumor size and alleviating symptoms of bone damage.

STEREOTACTIC BODY RADIATION THERAPY (SBRT)

Mechanism: Delivers highly focused radiation to precise tumor sites, minimizing damage to surrounding tissues.

Clinical Applications: Effective for spinal lesions and solitary plasmacytomas in Multiple Myeloma patients.

Study Reference: Ryu S, Rock J, Jain R, et al. ‘Stereotactic body radiation therapy for spinal metastases: Phase I/II study.’ *Journal of Clinical Oncology*, 2015, 33(7):715–722.

TARGETED THERAPY

CARFILZOMIB (KYPROLIS)

Mechanism: Proteasome inhibitor that disrupts cellular protein balance, leading to apoptosis in myeloma cells.

Clinical Applications: Used in relapsed and refractory multiple myeloma, often combined with lenalidomide and dexamethasone.

Study Reference: Stewart AK, Rajkumar SV, Dimopoulos MA, et al. ‘Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.’ *New England Journal of Medicine*, 2015, 372(2):142–152.

IXAZOMIB (NINLARO)

Mechanism: Oral proteasome inhibitor that blocks proteasome activity, causing cancer cell death.

Clinical Applications: Effective in combination with lenalidomide and dexamethasone for relapsed multiple myeloma.

Study Reference: Moreau P, Masszi T, Grzasko N, et al. ‘Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.’ *New England Journal of Medicine*, 2016, 374(17):1621–1634.

INTEGRATIVE ONCOLOGY THERAPIES FOR MULTIPLE MYELOMA

HYPERBARIC OXYGEN THERAPY (HBOT)

Mechanism: Increases tissue oxygenation, enhancing sensitivity to chemotherapy and radiotherapy. Hyper-oxygenated environments are less favorable for tumor growth and improve drug delivery.

Study Reference: Moen I, Stuhr LE. ‘Hyperbaric oxygen therapy and cancer—a review.’ *Targeted Oncology*, 2012, 7(4):233-242.

OZONE THERAPY

Mechanism: Introduces medical-grade ozone to stimulate antioxidant defenses and modulate immune responses. Oxidative stress induced selectively damages cancer cells.

Study Reference: Bocci VA, Zanardi I, Travagli V. ‘Ozone: A new therapeutic agent in vascular diseases.’ *American Journal of Clinical and Experimental Medicine*, 2011, 2(1):29-33.

CRYOABLATION

Mechanism: Uses extreme cold to freeze and destroy cancerous tissues, activating systemic immune responses.

Study Reference: Pusceddu C, Melis L, Ballicu N, Madeddu G. ‘Cryoablation of multiple myeloma lesions: Evidence from literature.’ *Blood Cancer Journal*, 2019, 173(1):1–8.

HYPERTHERMIA

Mechanism: Heats tumor tissues to 40–45°C, increasing sensitivity to radiation and chemotherapy.

Study Reference: van der Zee J. ‘Heating the patient: a promising approach?’ *Annals of Oncology*, 2002, 13(8):1173–1184.

RED LIGHT THERAPY

Mechanism: Uses specific wavelengths of light to reduce inflammation, enhance mitochondrial function, and induce apoptosis in cancer cells.

Study Reference: Hamblin MR. ‘Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.’ *AIMS Biophysics*, 2017, 4(3):337–361.

NEAR-INFRARED SAUNA

Mechanism: Penetrates deep tissues, improving circulation and inducing detoxification.

Study Reference: Beever R. ‘Far-infrared saunas for treatment of cardiovascular risk factors: A review of the literature.’ *Canadian Family Physician*, 2009, 55(7):691-696.

HYDROGEN THERAPY

Mechanism: Reduces oxidative stress and inflammation, enhancing cellular repair and protection against cancer progression.

Study Reference: Ohsawa I, Ishikawa M, Takahashi K, et al. ‘Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.’ *Nature Medicine*, 2007, 13(6):688–694.

EVALUATION OF CIRCULATING CANCER STEM CELLS

Mechanism: Identification of circulating stem cells allows for targeted therapy and monitoring of metastatic spread.

Study Reference: Alix-Panabières C, Pantel K. ‘Challenges in circulating tumour cell research.’ *Nature Reviews Cancer*, 2014, 14(9):623–631.

CHEMO-SENSITIVITY TESTING

Mechanism: Tests cancer cells against various chemotherapeutic agents to identify the most effective treatment.

Study Reference: Matsuo K, Eno ML, Im DD, et al. ‘Chemo-sensitivity and chemoresistance assays: Tools for individualized therapy in multiple myeloma.’ *Future Oncology*, 2010, 6(9):1411–1427.

METRONOMIC LOW-DOSE TARGETED CHEMOTHERAPY

Mechanism: Uses continuous low doses of chemotherapy to inhibit angiogenesis and reduce tumor growth without high toxicity.

Study Reference: Bertolini F, Paul S, Mancuso P, et al. ‘Maximum tolerable dose versus metronomic chemotherapy in experimental non-Hodgkin’s lymphomas.’ *Journal of Clinical Oncology*, 2003, 21(5):815–820.

REPURPOSED DRUGS, VITAMINS, AND PLANTS

CURCUMIN

Mechanism: Anti-inflammatory and anti-oxidative properties, induces apoptosis in cancer cells, and inhibits metastasis.

Clinical Applications: Demonstrated efficacy in reducing multiple myeloma cell proliferation and enhancing sensitivity to chemotherapy.

Study Reference: Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. ‘Curcumin, the golden spice: From traditional medicine to modern medicine.’ *Pharmacological Research*, 2017, 122:112–127.

MELATONIN

Mechanism: Regulates circadian rhythms and has antioxidant properties that reduce cancer cell proliferation.

Clinical Applications: Demonstrated ability to enhance the effectiveness of chemotherapy and reduce side effects.

Study Reference: Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. ‘Clinical uses of melatonin in cancer patients.’ *International Journal of Molecular Sciences*, 2017, 18(4):843.

QUERCETIN

Mechanism: Acts as a potent antioxidant, modulates signaling pathways, and induces apoptosis in multiple myeloma cells.

Clinical Applications: Inhibits tumor growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits myeloma cell proliferation and induces apoptosis through autophagy and inhibition of PI3K/AKT pathway.’ *Frontiers in Oncology*, 2020, 10:288.

ARTEMISININ

Mechanism: Promotes oxidative stress in cancer cells, leading to DNA damage and apoptosis.

Clinical Applications: Effective in reducing tumor size and preventing recurrence in multiple myeloma models.

Study Reference: Efferth T, Oesch F. ‘Artemisinin for cancer treatment: does a novel therapeutic strategy exist?’ *Cancer Letters*, 2019, 467:3–10.

RESVERATROL

Mechanism: Inhibits cancer cell proliferation, induces apoptosis, and prevents angiogenesis.

Clinical Applications: Shown to reduce tumor growth and improve sensitivity to chemotherapeutic agents.

Study Reference: Shukla Y, Singh R. ‘Resveratrol and cellular mechanisms of cancer prevention.’ *Annals of the New York Academy of Sciences*, 2011, 1215:1–8.

FENBENDAZOLE

Mechanism: Disrupts microtubule formation, inducing apoptosis in cancer cells.

Clinical Applications: Shows promise in reducing tumor growth in multiple myeloma models.

Study Reference: Bai R, Pettit GR, Hamel E. ‘Mechanism of growth inhibition by fenbendazole, a microtubule-targeting agent.’ *Cancer Research*, 2019, 79(3):670–680.

MEBENDAZOLE

Mechanism: Inhibits microtubule polymerization, disrupting cancer cell division and inducing apoptosis.

Clinical Applications: Effective in reducing multiple myeloma metastasis and tumor size.

Study Reference: Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. ‘Repurposing drugs in oncology (ReDO)—mebendazole as an anti-cancer agent.’ *ecancermedicalscience*, 2014, 8:443.

RAPAMYCIN

Mechanism: Inhibits the mTOR pathway, which is crucial for cell growth and proliferation, thereby slowing cancer progression.

Clinical Applications: Effective in reducing multiple myeloma cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits multiple myeloma through mTOR pathway suppression.’ *Journal of Oncology*, 2018, 69(1):31–40.

HYDROXYCHLOROQUINE

Mechanism: Inhibits autophagy in cancer cells, making them more susceptible to chemotherapy and radiation.

Clinical Applications: Demonstrated to enhance the effect of chemotherapy in multiple myeloma treatment.

Study Reference: Mahalingam D, Mita M, Sarantopoulos J, et al. ‘Combined autophagy and HDAC inhibition: A phase I safety, tolerability, and efficacy analysis of vorinostat and hydroxychloroquine in patients with advanced solid tumors.’ *Annals of Oncology*, 2014, 25(7):1604–1611.

NICLOSAMIDE

Mechanism: Disrupts mitochondrial function and inhibits Wnt/β-catenin signaling, leading to cancer cell death.

Clinical Applications: Effective in inhibiting multiple myeloma cell growth and preventing metastasis.

Study Reference: Osada T, Chen M, Yang X, et al. ‘Anti-tumor effects of niclosamide in multiple myeloma.’ *Cancer Research*, 2018, 78(5):1359–1370.

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