Multiple myeloma case study

Multiple myeloma case study , Multiple myeloma (MM) is characterized by neoplastic proliferation of a
clone of plasma cells, which produces a protein in the majority of cases Monoclonal. This proliferation in bone marrow often invades bone adjacent, it produces destruction of the skeleton, and causes bone pain and fractures.

In addition, other important features are anemia, hypercalcemia, and failure Renal. The incidence is approximately 4 to 5 x 100,000, with higher incidence in the black population, and the average age at diagnosis is 65 years (only 3% of the) cases are under the age of 40). In recent years there is an increase in cases, the which seems to be related with the diagnosis more precocious.

OBJECTIVES

• Confirm or make accurate diagnosis of this disease
• Determine the extent (stage) in each patient.
• Determine the extent (stage) in each patient.
• Establish, in each case, the most appropriate therapeutic strategy that we achieve a prolonged survival.

DEVELOPMENT
The following steps are:

• Diagnosis of certainty and histological classification by the Department of Pathologic Anatomy of our hospital.
• Determination of the stadium.
• Definition and application of therapeutic
• Reassessment by completing the treatment and definition of the behavior
• Regular evaluation

Clinical aspects

• More than 70% of the cases presented bone pains, mostly located in the back and the chest. The pain is caused by the movements and usually does not arise at night while the patient sleeps. This It is a fact that may help in the differential diagnosis of metastasis bone.
• The patient’s height can be reduced in several inches as consequence of vertebral crushing.
• There may be symptoms related to the presence of anemia, infections, renal failure and hypercalcemia.
• Pallor is the sign most frequent physical examination. They are rare the hepatomegaly and splenomegaly. Manifestations may occur hemorragiparas and may occasionally appear plasmacytomas extramedullary.

Paraclinical aspects

• At most 70% of the cases a normocytic anemia occurs normochromic.
• 98% of cases have a paraprotein serum or urinary tract at the time the diagnostic
• Protein electrophoresis shows a peak monoclonal antibody in 80% of the patients, hypogammaglobulinemia in approximately 10% and is of normal appearance in the rest.
• Serum immunoelectrophoresis evidence a paraprotein IgG in 53 %, IgA in 20%, light chains only in 17%, IgD in 2% and a gammopathy biclonal at 1%, and 7% has no serum paraprotein.
• Urine studies demonstrate a paraprotein in 75% of the patients.
• The study of light chains shows a 2:1 kappa/lambda ratio
• In the medulograma and biopsy of bone marrow plasma cells can represent from 10% up to 100% of nucleated cells.
• Radiological studies of the skeleton show lesions in more than 80% cases which may be characteristics injured OSTEOLYTIC in punch, osteoporosis and fractures. The bones most affected are the vertebrae, skull, rib cage, pelvis and proximal region of the femur and humerus.
• Hypercalcemia and increased creatinine can be detected in 20% cases the diagnosis.

Diagnostic criteria

• The minimum criteria for the diagnosis of MM are:
  ¾ More than 10% of plasma cells in the bone marrow. ¾ a paraprotein serum presence (generally greater than 3 g/dL) Presence of a urinary paraprotein ¾ ¾ Osteolytic lesions
  1 and at least one of the other three criteria required
• These data are not related: metastatic carcinoma, conectivopatia, lymphomas or chronic infection.
• Must be in the differential diagnosis of monoclonal gammopathy of Myeloma latent and unknown cause

Stadiums Classification of Durie and Salmon

Diagnosis studies

• Interrogation
• Physical exam
• Imaging: ¾ x-ray bone survey (skull, spine, pelvis and areas of pain) ¾ Abdominal Ultrasound
• Hematological studies ¾ blood count, erythrocyte sedimentation rate, medullogram, bone marrow biopsy, coagulation studies, platelet function.
• Blood chemistry ¾ Glycemia, creatinine, urate, total protein, albumin, bilirubin, calcium, phosphorous, SGPT, SGOT, FAS, LDH, GGT, protein electrophoresis
• Serological studies: VDRL, HIV, HBV, HCV, HTLV-I
• Immunoelectrophoresis serum and light chains
• Quantification of immunoglobulins
• cyturia, proteinuria 24 hours
• Other studies ¾ Coombs Test ¾ Blood ¾ C-reactive protein Β ¾ – 2 microglobulin

Treatment
At present therapeutic options for patients with symptomatic MM ranging from pulse dexamethasone with or without thalidomide, conventional chemotherapy and high-dose chemotherapy with hematopoietic cell transplantation (HCT).

The choice of treatment depends on the age, general condition of the patient and the patient’s opinion or preference. The 5 current therapeutic strategies in the MM are:

• High doses of corticosteroids (dexamethasone or methylprednisolone)
• Thalidomide (alone or combined with high-dose dexamethasone)
• Conventional Chemotherapy: VAD, melphalan / prednisone, prednisone, cyclophosphamide, VMCP, MOAP.
• TCH, autologous or allogeneic, of peripheral blood progenitor cells.
• proteasome inhibitors (bortezomib)

Recommended

• If the patient is under 60 years and the possibility of autologous hematopoietic progenitor cells from peripheral blood is recommended induction treatments containing no alkylating agents such as VAD.
• If the patient is under 50 years Consideration should be given allogeneic transplantation and HLA study performed.
• In patients older than 60 years and patients without criteria for autologous HCT, the scheme is recommended melfalan- prednisone. This is not strict and depends on the condition of the patient.
• Patients with renal impairment should be treated with VAD, high-dose dexamethasone or dexamethasone-thalidomide.
• Induction therapy will remain at least 6 months until obtain a therapeutic response classified as favorable.
• It will study protein electrophoresis and blood chemistry during induction treatment every two months

High doses of corticosteroids

• Dexamethasone at a dose of 40 mg / day v / o, x 4 consecutive days, similar to VAD. 60-70% of responses were reported. Among the advantages to be indicated are the manageability, no hematological toxicity, usable in older patients or those with bad general condition, alkylating removal.
• It is recommended in patients who have a contraindication for cytotoxic chemotherapy have a severe pancytopenia or require extensive radiotherapy. It is useful as initial therapy in patients presenting with renal damage.
• Pulse methylprednisolone: ​​2 g 3 times / week for four weeks at least. Less toxicity than dexamethasone are reported.

Thalidomide

He has shown effect in patients at onset and relapse. Its mechanism of action is not well known, but considered that it involved an anti-angiogenic activity, interference with adhesion molecules and cytokine release.

• It is administered orally daily (0-200 usual dose 5 mg / day).
• Has been combined with high-dose dexamethasone has been reported 70-80% of responses. Dose Thalidomide 50-200 mg / day, dexamethasone 40 mg / day / ppr v / o, days 1-4 (or 1-4, 9-12, 17-20) every 28 days.
• combination with conventional chemotherapy is evaluated. Studies that use MPT scheme (melphalan 4 mg / m 2 v / o, x 7 x month; prednisone 40 mg / m 2 v / ox x 7 days month; thalidomide 100 mg / day, v / or and reported similar results when autologous HCT.
• The main toxic effects are sedation, constipation, peripheral neuropathy and deep vein thrombosis. No or minimal hematologic toxicity Conventional chemotherapy.

Conventional chemotherapy
GM conventional chemotherapy using alkylating agents prolong survival between 26 and 46 months, with a response in 60% of cases, the response varying according to stage. However, nowadays.

Many patients start with non-alkylating schemes with the aim of eliminating the initial exposure to these drugs, prior to TCH in which high doses of the same is used. The VAD scheme is effective in 60-80% of cases and is non-alkylating scheme of choice in patients for TCH, patients with renal impairment and patients where a quick response is required.

Chemotherapy regimens

• Melphalan-Prednisone
  ¾ Dose: -Melfalan 0.25 mg / kg / day x 4 days
  -Prednisona: 40 mg / m 2 / day x 7 days
  ¾ Frequency: every 6 weeks
  ¾ Food interfere with absorption of melphalan therefore be taken 30-60 minutes before meals.
  ¾ In the first cycles should be platelet and leukocyte mid-cycle (third week) to assess for response to melphalan (leucopenia and thrombocytopenia light) and increase the dose in the
  sixth week if not occur. Melphalan should not be given if the leukocyte count is less than 2000 x 10 9 / L or less neutrophil 1000 x10 9 / L or platelets less than 100,000 x 10 9 / L
• In patients with renal insufficiency (creatinine> 177 mmol / L) the initial dose of melphalan should be reduced by 25% to prevent severe myelosuppression. If not, the dose is increased in the next cycles.
• Treatment should be continued until the plateau phase (paraprotein levels stable for three months in a row) is reached.

Cyclophosphamide prednisone

• Dose: -Ciclofosfamida 1 g / m 2 / day, 1 dose iv or 250 mg / m 2 / day / days 1- 4 v / or -Prednisona 40 mg / m 2 / day / days 1-7
• Frequency: every 3-4 weeks
• Remarks: This would be the treatment of choice in patients with leucopenia and thrombocytopenia to debut. It is recommended that oral cyclophosphamide is taken as a single dose at breakfast. Use cautiously in patients with renal impairment

VMCP

• Dose: -Vincristina 1 mg / m 2 / IV / day 1
• Melfalan 6 mg / m 2 / for v / o, days 1-4
• Ciclofosfamida 125 mg / m 2 / for v / o, days 1-4
• Prednisona 60 mg / m 2 / for v / or days 1-4
• Frequency: every 3 – 4 days

Infusional VAD

• Dose: -Vincristina 0.4 mg / day / IC, days 1-4
• ƒ -Adriamicina 9 mg / m 2 / day / IC, days 1-4
• ƒ -dexamethasone 40 mg / day / IV or v / o, days 1-4, 9-12, 17 – 20
• Frequency: every 4 weeks.
• Dexamethasone can be used at a dose of 20 mg / m 2 / day

VAD option 1 (bolus)

• Dose: -Vincristina 0.4 mg / day / IV, days 1-4
  Adriamicina 9 mg / m 2 / day / IV, days 1-4
  dexamethasone 40 mg / day / IV or v / o, days 1-4, 9-12, 17-20
• Frequency: every 4 weeks
• Dexamethasone can be used at a dose of 20 mg / m 2 / day

VAD option 2

• Dose: -Vincristina 2 mg / IV, Day 1
• Adriamicina 40 mg / m 2 / IV, Day 1
• dexamethasone 40 mg / day / IV or v / o, days 1-4
• Frequency: every 4 weeks
• Dexamethasone can be used at a dose of 20 mg / m 2 / day

DAV (option 3)

• Dose: -Vincristina 1 mg / IV, Day 1
  Adriamicina 50 mg / m2 / IV, day 1
  dexamethasone 40 mg / day / IV or v / o, days 1-4
• Frequency: every 4 weeks
• Dexamethasone can be used at a dose of 20 mg / m 2 / day

Evaluation of response
The following criteria were considered as favorable response:

• Reduction of 50% or more of the initial concentration of the monoclonal protein in serum or urine (if not present in serum).
• In cases of non-secretory myeloma is considered 50% reduction of the initial bone marrow infiltration.
• Improvement of clinical symptomatology.
• stable without transfusion hemoglobin.
  All criteria must be present, otherwise it will evaluate as unfavorable response

Therapeutic aftercare to conventional treatment

• Treatment with interferon alfa-2b protein to meet the criteria favorable response to induction chemotherapy was used. May be associated with steroids.
• Interferon alfa-2b not be used in combination with the initial therapeutic.
• Before starting maintenance identical to diagnosis up studies will be performed.
• During treatment the following investigations were carried out:
  ¾ Monthly: CBC and Coombs test itself reticulocytosis
  ¾ Quarterly: ESR, creatinine, calcium, total protein, protein electrophoresis, Bence-Jones protein, anti-IFN antibodies.
  ¾ Semester: medullogram marrow biopsy and
• Dose Interferon alfa-2b: 3 x 10 6 U / SC three times a week
• Duration of treatment. 2 years or when presented a relapse or when anti-interferon antibodies are detected If after two years the response is favorable, will continue indefinitely

Hematopoietic cell transplantation TCH autologous

• Autologous TCH single is indicated in patients younger than 60 years, in first remission without associated diseases. Kidney damage is not absolute contraindication to TCH.
• The double autologous HCT can be performed in patients who do not obtain complete remission after the first transplant.
• Peripheral blood is the preferred source of CH, with a minimum of CD34 + cells 2×10 6 / kg.
• Melphalan should not be used in patients for TCH.
• The high-dose melphalan (200 mg / m 2) is the conditioning regimen recommended for patients with renal function
  Normal. The dose of 140-100 mg / m 2 are recommended for patients with renal impairment.
• Not defined the value of using a post-consolidation therapy TCH. Some groups recommend IFN-α (Alone or associated with steroids).
• The transplant-related mortality (TRM) is 5%, the median survival is about 3 to 5 years and median duration of response is 24-36 months. One plateau is not reached in the PFS.

TCH allogeneic

• Less than 10% of patients with MM have a donor and an age younger than 55 years to receive an allogeneic HCT.
• It is indicated as first-line treatment in patients
• We used different conditioning regimens (ICT + Cfm, Bu + Cfm) with no evidence of superiority of one.
• The results of non-myeloablative conditioning has been evaluated and reported a lower MRT with myeloablative. However, definitive long-term benefits of non-myeloablative HCT is not yet known. The non-myeloablative HCT has been used as post-autologous HCT consolidation. This strategy is still considered experimental.
• The procedure-related mortality is high (40-50%), even with non-myeloablative (20%).
• Peripheral blood is the source of CH preferred by many authors, but is not well defined.
• It is not intended to use some consolidation therapy post-TCH.
• Overall survival at 5 years post-TCH is 45-50% and progression-free survival is 34% at 6 years.

Bortezomib
The proteasome is an essential system that degrades many intracellular regulatory proteins of the cell cycle, apoptosis, transcription, cell adhesion, angiogenesis, and antigen presentation.

A proteasome inhibitor, bortezomib’s capable of inducing apoptosis, inhibits in vitro growth and surpasses drug resistance in human myeloma cells, and has shown significant activity in various refractory hematologic malignancies.

It has reported a 30-50% response in patients with refractory MM. The use of bortezomib alone or in combination with other drugs, such as first-line therapy in MM is under active investigation.
Relapse
Almost all patients with MM who respond to treatment, relapse. If relapse occurs more than 6 months after reaching the plateau phase, can reinstate the initial therapy.

However, this response is generally lower than at the beginning and if obtained, is short lived. Therapeutic rescue are indicated both relapse and primary refractory or progressive disease
Relapse criteria
The presence of one of the following:

• Increased concentration of monoclonal protein in serum (or urine in the absence of serum) ≥ 25% of the nadir reached.
• Onset of clinical symptoms related to myeloma: bone pain, fractures, transfusion requirements, hypercalcemia, etc.

Treatment of relapsed or refractory myeloma

• after autologous HCT Relapse: you can offer another second
  TCH if sufficient CD34 + cells available (mortality
  increased by 10%) or allogeneic HCT if you have an HLA identical donor. If not possible second TCH, offer a therapeutic rescue, preferably dexamethasone / thalidomide with or without chemotherapy.
• Relapse after allogeneic HCT. Donor Lymphocyte Infusion.
• relapse, progression or resistance to primary chemotherapy.
  ¾ Patients who received melphalan-prednisone: infusional VAD
  ¾ VAD patients who received thalidomide or other rescue scheme
  ¾ Patients who have received several schemes poliqiuimioterapia thalidomide or bortezomib.
  Methylprednisolone ¾: 2 g / IV / three times a week for 4 weeks
  If no response continue 1 g / weekly IV
  Cyclophosphamide-prednisone ¾: can be applied to patients resistant to melphalan in the following doses:
  or cyclophosphamide 200 mg / m 2 v / o, weekly
  Prednisone 50 mg or v / or every other day
  Thalidomide ¾ ​​(200-600 mg / day) with or without dexamethasone (20 mg / m 2 / day on days 1-5 every 4 weeks)
  ¾ CAP: 40 mg -CCnU v / o, Day 1
  -Adriamicina 30 mg / IV day 1 100 mg -Prednisona v / o, days 1-5
  ¾ VAMP-vincristine and adriamycin VAD -Metilprednisolona equal to 1 g / IV or v / o, days 1-5
  -Vincristina VBAP ¾ 2 mg / IV, 1st -BCNU: 30 mg / IV, 1st -Adriamicina: 30 mg / IV, day 1
  100 mg -Prednisona v / o, days 1-5
  (Every 4-6 weeks)
  ¾ Scheme ESHAP

Other therapeutic measures General Care

• Ingestion of at least 3 liters of fluid every day to prevent kidney failure
• Maintain physical activity (walking) as the bedridden increases bone demineralization
• As prophylaxis of infections in the first three months of starting treatment the sulfaprim (2 tablets every 12 hours / three times a week) or IV immunoglobulin (500 mg / kg / month) is recommended
  Treatment of anemia
• Anemia is present in two thirds of patients at the time of presentation and is more frequent in cases relapse or progression. The slight anemia is common during treatment during chemotherapy. Blood transfusion should be given with caution to patients with high levels of paraprotein because of the risk of exacerbating hyperviscosity.
• Traditionally symptomatic anemia has been managed with transfusions. In recent years, there is growing evidence of the efficacy of recombinant erythropoietin (EPOr) in the treatment of anemia associated with chemotherapy in patients with MM and other tumors.
• Dose: 150 U / kg, although lower doses can be used; for example, you 10,000 x 2 or 3 times a week.
• In cases not improve EPOr anemia with blood transfusions should be used at the discretion of the physician.

Radiotherapy

• Palliative radiotherapy dose 20-30 Gy should be limited to patients with well-localized pain, unresponsive to chemotherapy.
• It is not indicated in patients with systemic disease.
• It is advisable, given the synergistic myelosuppression chemotherapy and radiotherapy, the latter end three weeks before starting chemotherapy. Bifos cough ONAF
• Long-term treatment with bisphosphonates for all MM patients requiring treatment for the disease, regardless of whether or not have obvious bone lesions is recommended.
• are equivalent oral clodronate (1600 mg / day or an equivalent dose according to the formulation) and IV pamidronate (90 mg / month). Zoledronate (4 mg / monthly) is equivalent in efficacy to pamidronate.

Hypercalcaemia

• Hydration saline (unless otherwise contraindicated), at least 2000 mL / 24 hours.

• Furosemide at intermediate doses; for example, 40 mg every 6-8 hours; after dehydration is corrected. The refractory patients can be treated with high doses of furosemide (80 mg every 2 hours) but under strict medical supervision.

• Corticosteroids can prednisone (40-60 mg / m 2 / day v / o) or dexamethasone (6-9 mg / m 2 / day IV) or methylprednisolone (30-50 mg / m 2 / day used IV ). Steroids should be reduced and discontinued as soon as possible.

• Start as soon as possible specific chemotherapy.

• If the above four measures fail to be assessed bisphosphonates, calcitonin or mithramycin

 

Renal impairment

• Always keep adequate fluid intake
• Avoid some imaging studies such as IV pyelogram and barium enema.
• Use allopurinol (300 mg / day) if hyperuricemia
• In case of acute renal failure resort to hemodialysis or peritoneal dialysis

Hyperviscosity syndrome

• Plasmapheresis
• Start ASAP specific chemotherapy cord compression
• Radiation dose of 30 Gy
• Dexamethasone 9.6 mg / m 2 / day, IV.
• In selected cases, the patient should be evaluated (early) with orthopedics and neurology services to determine if you have surgical indication (corpectomy with bracket)

Coordination with other services
Coordinating with the various services for conducting investigations to diagnose the disease stage and treatment decision will be established.

Income
Patients were entered in the hematology and come from the other hospital, the second hospital level of care and in-hospital consultation.
Consultation
Patients will be followed as outpatients in the consultation of malignant blood diseases hematology department. Chemotherapy is given in the designated for this function in the hospital area. Radiotherapy was applied in the nuclear medicine department

EVALUATION AND CONTROL
Structure

• Fundamental human resources will be integrated by specialists of Hematology in coordination with the head of protocol.
• Material resources are available in the hospital for the study and treatment of these malignancies.

Processes
Include all patients in the database service haemopathies.
Results

• Achieve a higher overall survival of 5 years.
• Evaluate the overall and disease free survival at 3, 5 and 7 years after completion of treatment.

Information for patients and relatives
On admission he was inform the patient and family about the procedures which will be submitted to make the diagnosis and / or stage or extent of disease. When these procedures involve some risk is information detail patient and family, and consent to the realization of the same request. Completed studies will provide information about the disease, treatment advice, prognosis and follow-up. This information will be made with greater clarity and understanding.

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