Multiple myeloma and Homoeopathy

Dr  Candy Benny

INTRODUCTION
The plasma cell disorders are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the late B-lymphocyte lineage.

The clinical manifestations of all the plasma cell disorders relate

• to the expansion of the neoplastic cells,
• to the secretion of cell products (immunoglobulin molecules or subunits, lymphokines),
• and to some extent to the host’s response to the tumor.

DEFINITION

• Multiple Myeloma represents a malignant proliferation of plasma cells derived from a single clone.
• The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.

ETIOLOGY

• Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency.
• Myeloma has been seen more commonly than expected among farmers, wood workers, leather workers, and those exposed to petroleum products.
• A variety of recurrent chromosomal alterations have been found in patients with myeloma: hyperdiploidy (trisomies involving one or more of chromosomes 3, 5, 7, 9, 11, 15, 19, or 21) is observed in half of the patients, while the other half have translocations involving the 14q32 chromosome with variable partners including t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16).
• Interleukin (IL) 6 may play a role in driving myeloma cell proliferation.

INCIDENCE AND PREVALENCE

• Myeloma increases in incidence with age.
• The median age at diagnosis is 69 years; it is uncommon under age 40.
• Males are more commonly affected than females, and blacks have nearly twice the incidence of whites.
• In 2018, myeloma accounted for 1.8% of all malignancies, with incidence rates per 100,000 of 6.1 in whites and 13.6 in blacks

PATHOGENESIS

• MM cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu.
• These effects are due both to direct MM cell–BMSC binding via adhesion molecules and to induction of various cytokines, including IL-6, insulin-like growth factor type 1 (IGF-1), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1a
• Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively.
• The major myeloma supporting interactions are with endothelial cells and osteoclasts. Immune cells such as plasmacytoid dendritic cells (pDC), myeloid-derived suppressor cells (MDSC), and T helper 17 (TH 17) cells are increased in number and support myeloma growth, while antimyeloma immune responses, especially T helper and cytotoxic cells, B cells, and natural killer T cells, are suppressed
• Multiple myeloma has a number of untoward effects on the skeleton, the immune system, and the kidney, all of which contribute to morbidity and mortality:
• Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma -Of particular importance, myeloma derived factors upregulate the expression of the receptor activator of NF-κB ligand (RANKL) by bone marrow stromal cells, which in turn activate osteoclasts. Other factors released from tumor cells are potent inhibitors of osteoblast function. The net effect is increased bone resorption, leading to hypercalcemia and pathologic fractures
• Myeloma causes defects in humoral immunity-although the plasma has elevated levels of immunoglobulin owing to the presence of an M protein, the production of functional antibodies often is profoundly depressed. As a result, patients are at high risk for bacterial infections.
• Renal dysfunction -Most important are obstructive proteinaceous casts, which often form in the distal convoluted tubules and the collecting ducts. The casts consist mostly of Bence Jones proteins along with variable amounts of complete immunoglobulin, Tamm-Horsfall protein, and albumin. Light chain deposition in the glomeruli or the interstitium, either as amyloid or linear deposits, also may contribute to renal damage

CLINICAL FEATURES

BONE CHANGES

• Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. Persistent localized pain usually signifies a pathologic fracture. The bone lesions are lytic in nature.
• The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture .
• Localized bone lesions may cause the collapse of vertebrae, leading to spinal cord compression.

 INFECTIONS

• The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections.
• The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram- negative organisms in the urinary tract.

RENAL CHANGES

• Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in >50%.
• Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction.
• With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes.

HEMATOLOGY

• Normocytic and normochromic anemia occurs in ~80% of myeloma patients.
• Hyperviscosity syndrome may develop due to the presence of abnormal immunoglobulins. The signs of hyperviscosity include weakness, anorexia, impairment of cerebral circulation leading to neurological deficits, and retinal abnormalities.

DIAGNOSIS

 THE DIAGNOSIS OF MYELOMA REQUIRES-

• marrow plasmacytosis (>10%)
• a serum and/or urine M component
• and at least one of the myeloma- defining events
• Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma.
• The features responsible for higher risk of progression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/dL).
• Serum protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis.
• A 24-h urine specimen is necessary to quantitate Bence Jones protein (immunoglobulin light chain) excretion.
• The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine.
• A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated.
• Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated.
• Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity.
• Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia.
• Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes.
• 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) is a valuable tool to assess bone damage and detect extramedullary sites of the disease.

PROGNOSIS

• Serum β2 -microglobulin is the single most powerful predictor of survival and can substitute for staging.
• β2 -Microglobulin is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell.
• Combination of serum β2 -microglobulin and albumin levels forms the basis for a three-stage International Staging System (ISS).

MANAGEMENT

• No specific intervention is indicated for patients with MGUS.
• SYMTOMATIC MM-Three important classes of agents approved for treatment of newly diagnosed MM are immunomodulatory agents, proteasome inhibitors, and targeted antibodies.
• Thalidomide, when combined with dexamethasone, achieved responses in two-thirds of newly diagnosed MM patients

HIGH-DOSE THERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANTATION

• High-dose therapy (HDT) and consolidation/maintenance are standard practice in the majority of eligible patient.
• Randomized studies comparing standard-dose therapy to high-dose melphalan therapy with hematopoietic stem cell support have shown that HDT can achieve higher overall response rates.

THERAPY ENDPOINT

• Improvement in the serum M component may lag behind the symptomatic improvement due to longer serum half-life (~3 weeks) of the immunoglobulin.
• The fall in M component depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin.
• Serum and urine light chains with a functional half-life of ~6 h may fall much quicker within the first week of treatment

RELAPSED DISEASE

• Relapsed myeloma can be treated with a number of agents including lenalidomide and/or bortezomib, if previously not used.
• The second-generation proteasome inhibitor carfilzomib and immunomodulatory agent pomalidomide have shown efficacy in relapsed and refractory MM, even MM refractory to lenalidomide and bortezomib.

RUBRICS

SYNTHESIS

• GENERALS – TUMORS – myeloma: (1) Hecla_rmk1
• GENERALS – CANCEROUS AFFECTIONS – myeloma: (7) aur._zzz calc-f._zzz Hecla_rmk1 lach._zzz nit-ac._zzz phos._zzz syph._zzz
• GENERALS – CANCEROUS AFFECTIONS – myeloma – multiple: (6) aur._mtf calc-f._mtf lach._mtf nit-ac._mtf phos._mtf syph._mtf

COMPLETE REPERTORY

Generalities; tumors, benign; myeloma, multiple:
astra-e  calc-f  ION-RAD.

THERAPEUTICS

HECKLA LAVA

• It has marked action on the lower jaw, and has the power to arrest many forms of bone diseases, osteo-sarcoma, osteitis,caries and necrosis; exostosis, which are sensitive and painful to touch.
• Facial neuralgia from carious teeth and after extraction.

ASTRAGALUS EXCAPUS

• Pressing pain in the temples, in the maxillary sinuses.
• Shooting pains above the right eyebrow .
• Painful sensation of fullness in the left temporal and maxillary regions.
• Paretic weakness of the lower limbs .

ARANEA

• Spleen swollen. Bone-pains in extremities
• All symptoms are characterized by periodicity, and coldness, and great susceptibility to dampness.
• Patient feels cold to the very bones.
• Coldness not relieved by anything.
• Pain in os calcis. Sensation of swelling
• and of parts going to sleep.

AURUM METALLICUM

• Every opportunity is sought for self-destruction. Exostosis, caries, nightly bone-pains, especially cranial, nasal, and palatine.
• Destruction of bones, like secondary syphilis. Pain in bones of head, lumps under scalp, exostosis with nightly pains in bones. Caries of nasal, palatine and mastoid bones. Soreness of affected bones, better in open air, worse at night.

CALC FLOUR

• Neck and Back.–Chronic lumbago; aggravated on beginning to move, and ameliorated on continued motion. Osseous tumors. Rachitic enlargement of femur in infants. Pain lower part of back, with burning.
• Exostoses on fingers. Chronic synovitis of knee-joint.

ARSENICUM ALBUM

• Maintains the system under the stress of malignancy regardless of location.
• Among these the all-prevailing debility,exhaustion, and restlessness, with nightly aggravation, are most important.
• Great exhaustion after the slightest exertion
• Burning relieved by heat.
• Anaemia and chlorosis..
• Gradual loss of weight from impaired nutrition.
• Reduces the refractive index of blood serum (also China and Ferr. phos.).

BENZOLUM

• The most striking fact in the proving of Benzol seems to be the influence it had on the circulatory system.
• In the human provers it resulted in a decrease of the red and increase of white cells
• It ought to be of use in Leukaemia.

 CALC CARB

• Its chief action is centered in the vegetative sphere, impaired nutrition being the keynote of its action, the glands, skin, and bones, being instrumental in the changes wrought.
• Increased local and general perspiration
• Chill at 2 p.m. begins internally in stomach region. Fever with sweat.
• Night sweats, especially on head, neck and chest.

CALC PHOS

• Anemias after acute diseases and chronic wasting diseases.
• Anaemic children who are peevish, flabby,have cold extremities and feeble digestion.
• Numbness and crawling are characteristic sensations, and tendency to perspiration and glandular enlargement are symptoms it shares with the carbonate. Scrofulosis,chlorosis

CARCINOSIN

• Acts favorably and modifies all cases in which either a history of carcinoma can be elicited, or symptoms of the disease itself exist. (J.H. Clarke, M.D. ) .
• Indigestion, accumulation of gas in stomach and bowels;
• rheumatism -Cancerous cachexia.

CEONANTHUS

• This remedy seems to possess a specific relation to the spleen.
• Anemic patients where liver and spleen are at fault
• Active hemostatic, materially reducing the clotting of blood
• Deep-seated pain in left hypochondrium,hypertrophy of spleen.
• Leukaemia .
• Unable to lie on left side.
• Pain in liver and back.

NITRIC ACID

• Pains appear and disappear quickly (Bell). Hydrogenoid constitution. Sycotic remedy.
• excessive physical irritability. Cachexia, due to syphilis, scrofula, intermittent fever with liver involvement and anæmia, etc. Gravel; arthritis. Capillary bleeding after curettage.

 PHOSPHOROUS

• Destroys bone, especially the lower jaw and tibia; disorganizes the blood, causing fatty degeneration of blood vessels and every tissue and organ of the body and thus gives rise to hćmorrhages, and hćmatogenous jaundice.
• Burning in back; pain as if broken. Heat between the shoulder-blades. Weak spine.

REFERENCES

• Davidson’s principles and practice of medicine.
• Harrison’s principles of internal medicine.
• Complete dynamics
• Shroyens F. Repertorium Homoeopathicum Syntheticum. 9.1 edition. New Delhi: B Jain publishers; 2011.
• Boericke’s new manual of Homoeopathic Materia medica with Repertory. 3rd revised and augmented edition. New Delhi: B Jain publishers; 2016.
• JULIAN O. A., Materia Medica of New Homeopathic Remedies.

Dr Candy Benny
PG Scholar, Homoeopathic Repertory and Case taking,GHMC Calicut
Email: candybenny@ymail.com
Under the guidance of Dr. Mansoor Ali KR