​Kembara Xtra - Medicine - Multiple Myeloma

​Kembara Xtra - Medicine - Multiple Myeloma 
A single clone of plasma cells is involved in the malignant proliferation of multiple myeloma (MM).
As blood and urine are filtered by the kidneys, monoclonal protein (immunoglobulin [Ig]) is produced by malignant plasma cells.
Monoclonal gammopathy of undetermined significance (MGUS) is a common disorder with limited monoclonal plasma cell proliferation that can progress to smoldering MM (SMM) or symptomatic MM at a rate of 1% per year. MM is characterized by bony lytic lesions, hypercalcemia, increased susceptibility to infections, and renal impairment.


Epidemiology 

MM affects older persons with a median age of 65 to 74 years and is responsible for 17% of hematologic malignancies and 2% of all cancers in the US. Asians are less likely to be impacted than Caucasians, who are affected roughly two to three times less frequently.
Incidence
7 cases per 100,000 people in the US each year
Prevalence
There were around 160,000 confirmed cases worldwide in 2018.


Pathophysiology and Etiology 
It is most likely connected to a genetic modification involving random mutations and chromosomal abnormalities.
When an isotype switches, growing B cells suffer genetic harm.
Chromosomal abnormalities include deletions of 17p13 (the p53 gene) and Ig heavy chain translocations, with cyclin D1 t(11;14) being the most prevalent of these (2)[C].
Genetically, familial clusters of this condition are rare. A uncommon variant of the protein paratarg-7 may play a pathogenic role.

Risk Elements 
The risk of MM is increased by advanced age, immunosuppression, exposure to chemicals, heavy metals, and ionizing radiation, and the majority of cases have no identified hazards.


Accompanying Conditions 

Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) are frequent secondary amyloidoses caused by MM.

34% of patients had no symptoms when they are diagnosed, according to the statistics.
The majority of cases of MM appear as anemia (73%).
Hypercalcemia (28%): anorexia, gastrointestinal discomfort, sleepiness, polydipsia, polyuria, and dehydration
Acute renal damage (48% elevated creatinine), which can happen in MM, can be caused by a variety of distinct processes.
 Bony lesions (80%): pathologic fracture (26-34%), osteoporosis, or lytic lesions that cause bone pain (58%) (3)[C].
 Extra symptoms include cord compression, hyperviscosity syndrome, recurrent infections, weariness (32%), peripheral neuropathy (PN), weight loss (24%), and lethargy.

Clinical Examine 
Dehydration, pallor, and soreness in the bones. Hyperviscosity syndrome, which affects 7% of patients and causes ocular hemorrhages, protracted bleeding, and neurologic abnormalities.
Extramedullary plasmacytomas might appear as sizable, crimson-colored lumps under the skin.
 Waxy papules or plaques that may be visible on the eyelids, neck, inguinal, or anogenital regions are skin signs of amyloidosis.

SMM: no end-organ damage; CRAB: hypercalcemia, renal insufficiency, anemia, and bone lesions; differential diagnosis
 Waldenström macroglobulinemia Metastatic carcinoma (kidney, breast, non-small cell lung cancer)
Solitary plasmacytoma, reactive plasmacytosis, AL amyloidosis, and POEMS syndrome

Laboratory Results 
Standards for diagnosis The following are necessary for an MM diagnosis (4)[C]:
• A plasmacytoma or BM involvement with less than 10% plasma cells, as well as any one or more of the following myeloma-defining events:
- Proof that the underlying plasma cell proliferative disease has caused end-organ damage, specifically:
Hypercalcemia is defined as serum calcium levels that are either 2.75 or more times the upper limit of normal (>2.25 mmol/L or >11 mg/dL).
 Renal insufficiency: serum creatinine >177 mol/L (>2 mg/dL) or creatinine clearance 40 mL/min
Anemia is defined as a hemoglobin level of less than 10 g/dL or more than 2 g/dL below the lower limit of normal.
One or more osteolytic lesions on skeletal radiography, CT, or PET-CT are considered bone lesions.
- Any one or more of the results listed below are regarded as MM-defining events:
60% of BM plasma cells are clonal.
 Involved: serum free light chain (FLC) ratio of uninvolved serum >1 focal lesion on MRI or PET-CT


Initial examinations (lab, imaging)
CBC with differential for assessing cytopenias such as anemia
Serum lactate dehydrogenase (LDH), 2-microglobulin, serum protein electrophoresis (SPEP), and serum immunofixation electrophoresis (SIFE): BUN, creatinine, serum electrolytes, albumin, and calcium M protein level is higher
Quantitative serum FLC levels: and chains; Quantitative serum Ig levels: IgG, IgA, and IgM
 Elevated ESR and C-reactive protein
 Urine analysis: urine immunofixation electrophoresis (UIFE), urine protein electrophoresis (UPEP), and 24-hour urine for protein; 20% positive urine protein]:
- Because the protein in MM is Bence Jones (BJ) monoclonal protein, the urine analysis dip is frequently negative for protein.
For the detection of bone involvement, cross-sectional imaging (whole body low-dose CT) is favored over simple radiographs.
 Bone marrow (BM) biopsy: plasma cell percentage, histology, immunohistochemistry, flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH) Skeletal surveys are only performed on individuals who are unable to undergo low-dose whole body CT, MRI, and PET.

Tests in the Future & Special Considerations

A whole-body MRI or an MRI of the spine and pelvis is advised for patients with suspected SMM to check for cord compression.
A full body PET/CT is advised for patients with probable extramedullary illness outside of the spine.
Bone densitometry at baseline may be advised.
 BM aspiration and biopsy to track treatment response
SPEP with SIFE: M protein aids in monitoring myeloma development and therapeutic response.
A response or relapse can be tracked using serum Igs and FLCs.
Procedures for Diagnosis/Other Staging Multiple staging techniques are employed to estimate disease burden. The Revised International Staging System (R-ISS) is the most popular. Nowadays, the Durie-Salmon staging system is rarely employed.
International Staging System (ISS) Stage I: albumin less than 3.5 g/dL and 2-microglobulin less than 3.5 g/mL Stage II: neither stage I nor stage III Stage III: 2-microglobulin more than 5.5 g/mL
Standard risk: >t(11;14), t(6;14), and hyperdiploidy according to the Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) method.
- Intermediate risk conditions include t(4;14), del(13q), and hypodiploidy.
- At high risk: t(14;16), t(14;20), and del(17 p).
To provide improved predictive data for MM, R-ISS integrates ISS data with chromosomal aberrations and LDH.

Management 
Treatment varies according to risk, MM stage, and patient traits.
Establishing transplant candidacy, or whether the patient is a candidate for an autologous stem cell transplant (ASCT), is a key element in selecting a chemotherapy regimen. For suitable patients, ASCT is the standard of care after induction chemotherapy.
UNSPECIFED MEASURES
Keep yourself properly hydrated to avoid renal insufficiency. The majority of patients will need some kind of antibiotic prophylaxis throughout their treatment.


The three phases of the medication-based treatment for MM are the induction phase, consolidation (typically ASCT) eligible patients (6)[C], and maintenance.
Chemotherapy, proteasome inhibitors, immunomodulatory drugs, steroids, and monoclonal antibodies are some examples of agents.
 A 3- or 4-drug combination, such as bortezomib/ lenalidomide/ dexamethasone, bortezomib/ cyclophosphamide/ dexamethasone, or carfilzomib/ lenalidomide/ dexamethasone, may be used in the induction phase for ASCT-eligible patients.
Lenalidomide/low-dose dexamethasone or daratumumab/lenalidomide/dexamethasone are two examples of doublet or triplet induction chemotherapy that are appropriate for individuals who are ineligible for ASCT.
Lenalidomide is authorized for maintenance therapy following induction or transplant.
Investigations into further agents are ongoing.
Initial Line
Consider using acyclovir for herpes simplex virus (HSV) prevention. Proteasome inhibitors (6) - Blocks ubiquitin-proteasome catalytic pathway in cells by binding to the 20S proteasome complex.
- Bortezomib: IV or SC; SC has a lower PN risk. PN, cytopenia, nausea, anorexia, leukopenia, thrombocytopenia, dermatitis, and other toxic effects
- The second-generation proteasome inhibitor, carfilzomib.
Cardiomyopathy and other adverse cardiac events, fever, diarrhea, thrombotic microangiopathy, tiredness, and hypersensitive reaction are all examples of toxicity.
- The oral proteasome inhibitor ixazomib. Toxicity: back discomfort, edema, thrombocytopenia, neutropenia, diarrhea, and PN
Cyclophosphamide, an alkylating compound derived from nitrogen mustard Toxicity includes cytopenia, anaphylaxis, hemorrhagic cystitis, decreased fertility, and interstitial lung fibrosis. Immunomodulators thalidomide, lenalidomide, and pomalidomide work through immunomodulation, inhibiting tumor necrosis factor, and inhibiting angiogenesis.
- Deep vein thrombosis (DVT), bradycardia, rash, thalidomide-related birth abnormalities, and neuropathy are among side effects.
(40 mg/week) Dexamethasone dosage
IgG1 monoclonal Ab against CD38 is called daratumumab.
Fatigue, back discomfort, lymphocytopenia, neutropenia, anemia, including hemolytic anemia with Coombs test positive, thrombocytopenia, cough, flu-like symptoms, and infusion-related response are all indicators of toxicity.
Bisphosphonates have no mortality-reducing effects, but they do lessen pain, pathologic vertebral fractures, and fractures of other bones.
— Dose adjustment/renal function monitoring.
- Keep an eye out for jaw osteonecrosis.

Next Line
A rise in monoclonal M protein in the serum, urine, or serum FLC ratio along with new or worsening end-organ damage is typically used to detect the progression of MM.
(6) Salvage therapy can be used to treat relapsed or refractory myeloma using a variety of regimens.
Most patients with relapsed or resistant MM should get a transplant if one has not already been tried.
The preferred regimen depends on the previously unsuccessful lines; if relapse occurs more than six months after finishing the initial primary therapy, the same regimen can be used for retreatment.
Daratumumab, pomalidomide (an immunomodulator), elotuzumab, and other recently developed regimens may be utilized for second and subsequent relapses if they have not already been used. Selinexor, melphalan flufenamide, isatuximab, and the recently licensed CAR-T therapy drug idecabtagene vicleucel are available as alternatives.


Referral 

Orthopedics can provide guidance regarding spinal or other bone pathology.

Further Therapies 

 Local radiation therapy to treat plasmacytoma or excessive bone discomfort
NSAIDs should be avoided due to nephrotoxicity for effective pain treatment.
Patients receiving immunomodulators for DVT prevention are advised to take between 81 and 325 mg of aspirin daily.
 Erythropoietin for certain anemic patients
Patients receiving IVIG infusions for recurring, life-threatening infections
Patients should get the pneumococcus, influenza, and SARS-CoV-2 vaccinations.
 Avoid giving live virus vaccinations.


Surgical Techniques 
For symptomatic vertebral compressions, consider kyphoplasty or vertebroplasty.

Admission indicators include pain, infections, cytopenia, renal failure, bone problems, and spinal cord compression. Other recommendations include managing hypercalcemia and staying hydrated enough to prevent contrast-induced nephropathy.


The 5-year survival rate is approximately 50%.
Median survival according to R-ISS stage:
Stage I has not been reached, Stage II has been completed, and Stage III has been completed.

consequences Patients with MM are more likely to experience a variety of consequences from both the disease itself and available treatments. Infections, discomfort, fractures, hypercalcemia, hyperuricemia, spinal cord compression, hyperviscosity syndrome, amyloidosis, and dialysis are examples of complications.

---