Multiple Myeloma: Incidence, Risk Factors & Pathogenesis

• Multiple myeloma is a plasma cell disorder.

Incidence & Prognosis

• The 5-year survival rate is 61.1%.
• The overall incidence is rising in developed countries.
• It accounts for 2% of cancer diagnoses and over 2% of cancer deaths in the US.
• Approximately 0.9% of men and women will be diagnosed with myeloma in their lifetime, based on 2017-2019 data.

Risk Factors

• The average age of diagnosis is 69
• Over 60% of diagnoses occur in people older than 65.
• African Americans are more than twice as likely to be diagnosed.
• Men have a 1.5x higher risk than women.
• Family history is a risk factor.

Pathogenesis

• It is characterized by a monoclonal proliferation of plasma cells.
• This results in the production of monoclonal antibodies and end-organ damage.
• It leads to bone marrow damage, resulting in cytopenia, frail brittle bones, and/or renal failure.

Clinical Presentation ("CRAB")

• Hypercalcemia can occur.
• Fatigue, lethargy, depression, and confusion are symptoms.
• Renal failure may be due to hypercalcemia and increased light chains filtered by the kidneys.
• Anemia can manifest as normocytic normochromic anemia.
• Bone pain is a common symptom, often precipitated by movement.
• Persistent localized pain is likely to indicate a fracture with "punched out lesions."
• Activation of osteoclasts breaks down bone while suppressing osteoblasts, with MM cells producing osteoclast activating factor.
• This leads to hypercalcemia and associated symptoms.
• Increased susceptibility to bacterial infections like pneumonia and UTIs, also a side effect of dexamethasone treatment.
• Raynaud's phenomenon can occur.
• Hyperviscosity can cause headaches, fatigue, SOB, visual disturbances, vertigo, retinopathy, and coma.
• Spinal cord compression and radicular pain are possible.

Work-Up & Diagnosis

• Patients often present with CRAB symptoms requiring further work-up.
• Blood and urine electrophoresis are needed to check for monoclonal light chains.
• Diagnosis includes serum or urine electrophoresis and free light-chain assay, plus bone marrow biopsy.
• Blood levels of IgG, IgM, and IgA can identify the light-chain isoform and, if elevated but under 3 g/dL, it can be classified as SM or MGUS.
• Smoldering Myeloma (SM) involves proliferation of plasma cells in bone marrow and high antibody levels without CRAB symptoms.
• MGUS is when they have no symptoms and with an M-protein below 1.5 g/dL and is classified as plasma cell monoclonal gammopathy of undetermined significance
• Both MGUS and SM are precursors to MM with a 1% and 10% risk of progression per year.
• Whole body CT and PET scans are part of the workup.
• Blood work includes CBC (normocytic normochromic anemia), CMP (hypercalcemia), elevated uric acid, and liver function tests.

Conventional Treatment/General Principles

• Standard care includes induction therapy, autologous stem cell transplant, and maintenance therapy.
• Overall goal is to reduce M protein and eliminate MM cells from the bone marrow (measured by minimal residual disease testing/MDT).
• Induction therapy involves 3-6 cycles of triplet or quadruplet therapy.
• Consolidation involves stem cell collection >> ASCT.
• Stem cell collection can be incorporated as part of the initial therapy or delayed.
• Maintenance therapy uses single agent Revlimid.
• Radiation is primarily for palliation in patients with MM and can be given during systemic therapy.
• Glutamine as a radioprotector at 10g TID and Homeopathic X-ray and Radium is for radiation support.
• Radiosensitizers include Curcumin and Melatonin.

Chemotherapy

• Patients should receive at least a triplet regimen (2 drug classes and a steroid) if tolerated.
• For relapsed disease, if greater than 6 months after the end of the primary treatment, then the primary treatment can be repeated.
• IVIG should be considered for patients with an IgG < 400.

Preferred Regimen

• Bortezomib/lenalidomide/dexamethasone
• Carfilzomib/lenolidamide/dexamethasone

Valcade/Bortezomib

• This is a miscellaneous drug with anti-cancer applications
• Works through reversible inhibition of 26S proteasome, altering regulatory proteins to cause cell cycle arrest and apoptosis.
• The SubQ route is preferred.
• Side effects include herpes zoster reactivation (prophylactic antivirals suggested), neutropenia, thrombocytopenia, fatigue, insomnia, and hypotension (up to 12% of patients).
• Diarrhea is a common and potentially severe side effect.
• Other side effects include nausea & vomiting, epistaxis, hemorrhage, pneumonia, and peripheral neuropathy (sensory, with pain, paresthesias, burning and numbness; often affecting feet).
• Musculoskeletal (MSK) pain and hyperuricemia (due to cell lysis, leading to electrolyte disturbances or acute renal failure) can occur.
• Curcumin and ALA enhance its efficacy.

Lenalidomide (REVLIMID)

• This is an Immunomodulatory drug
• Serves as a structural and functional analogue of thalidomide.
• The mechanisms of action include increasing hemoglobin expression by erythroid cells, inhibiting proliferation of certain hematopoietic tumor cells, enhancing T cell, NK cell and NK T cell number and activity, and inhibiting angiogenesis.
• It inhibits production of proinflammatory cytokines and increases production of IL-2 and IFN gamma.
• A possible molecular target is the Akt core signaling pathway.
• Common/Major side effects include anemia, neutropenia, thrombocytopenia, palpitations, CV symptoms, fatigue, lethargy, malaise, pruritis, rash, hypothyroidism, constipation, diarrhea, dyspepsia, nausea, vomiting, hepatotoxicity, pneumonia, URI, peripheral edema, dizziness, and arthralgias.

Carfilzomib (KYPROLIS)

• It is a molecular targeted therapy,
• Carfilzomib is an irreversible inhibitor of the 20S core of the 26S proteasome
• It causes accumulation of polyubiquinated proteins, which induces cell cycle arrest and apoptosis.
• Common/Major side effects include cardiotoxicity (new onset/worsening of pre-existing cardiac failure), hypertension, herpes zoster reactivation (consider antiviral prophylaxis), anemia, diarrhea, nausea, fatigue, peripheral edema, pyrexia, pneumonia, URI, hypercalcemia, hyperglycemia, hyperuricemia, hypomagnesemia, MSK pain, headache, acute renal failure/renal failure, dyspnea, DVT, HTN, and infusion reactions.
• Infusion reactions are common but low grade when given dexamethasone prior to 24 hours.

Darzalex / Daratumumab

• This is a molecular targeted therapy.
• It serves as a human IgG1 kappa monoclonal antibody that targets the transmembrane glycoprotein CD38, inhibiting CD38-expressing tumor cells specifically.
• Side effects include herpes zoster reactivation (initiate antiviral prophylaxis within one week of starting treatment and continue for three months following treatment completion), hepatitis B reactivation (screening recommended), thrombocytopenia, neutropenia, anemia, nausea, vomiting, diarrhea, fatigue, pneumonia, hypomagnesemia, hyperuricemia, hyperglycemia, MSK pain, headache, and cough/dyspnea.
• Quercetin enhances efficacy
• Avoid NAD+ as it is a contraindication.

Integrative Support

• Dan Shen prevents thalidomide-associated thromboembolism in patients with MM.
• Ninkin'yoeito/Ren-Shen-Yang-Rong-Tang improves fatigue from lenalidomide and may extend treatment duration.
• Maintain Bone health with Vitamin D (low levels are associated with poorer outcomes and high prevalence of deficiency), K2, and Calcium (avoid if hypercalcemia or renal insufficiency).

Curcumin

• Provides long term stabilization, use 8g daily
• It induces cell death, inhibits proliferation of MM Cells
• Inhibits NFkB activation and down regulates cyclin D1, STAT3, and Bcl-xL
• It can prevent drug resistance and increase the effect of chemo agents
• Used for for MGUS
• Decreases paraprotein load and decreases urinary N-telopeptide
• May prevent progression to MM
• Has a Synergistic effect with bortezomib for inducing apoptosis in human MM cells
• Enhances cytotoxic effects to lenalidomide in MM cells
• Consider: Curcumin as adjuvant therapy to improve remission in myeloma patients: A pilot randomized clinical trial.

Nigella Sativa

• Thymoquinones = active constituent
• Modulates STAT3 signaling pathways in MM cells.
• Inhibits JAK2.
• Induces expression of Src homology-2 phosphatase 2 that correlated with suppression of STAT3 activation
• TQ also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells
• Suppresses Bcl2 expression
• It inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway

Quercetin

• It induces cell apoptosis of myeloma and displays a synergistic effect with dexamethasone in vitro and in vivo xenograft models
• It inhibits the proliferation of multiple myeloma cells by upregulating PTPRR expression
• Note: NOT WITH VALCADE/BORTEZOMIB (ALSO EGCG IS CI)

Omega 3 Fatty Acids

• It includes omega-3 fatty acids, EPA and DHA which induce apoptosis and enhance drug sensitivity in multiple myeloma cells but not in normal peripheral mononuclear cells
• It is suggested that EPA and DHA induce selective cytotoxic effects in MM and increase sensitivity to bortezomib and calls for further exploration into a potential application of these n-3 polyunsaturated fatty acids in the therapy of MM

Panax Ginseng

• Ginsenoside Rg3 induces apoptosis in human multiple myeloma cells via the activation of Bcl-2-associated X protein
• Inhibition of multiple myeloma cell proliferation by ginsenoside Rg3 via reduction in the secretion of IGF-1