Multiple Myeloma Flashcards
Multiple Myeloma
Malignancy Associated Hypercalcemia
Signs and symptoms
fatigue, lethargy, weakness, malaise
obtunded/confusion
anorexia
pain
polyuria
polydipsia
constipation
nausea or vomiting
Hypercalcemia becomes an oncologic
emergency when calcium levels cause
significant physiologic dysfunction such as:
dehydration
mental status changes
cardiac arrhythmias
renal insufficiency or failure
Hypercalcemia of malignancy is common in multiple myeloma as well as
solid tumours with bone metastases (prostate, bone, lung)
Malignancy Associated Hypercalcemia
Normal serum Ca²
+ is 2.2 – 2.65 mmol/L
Hypercalcemia:
Mild is 2.65 – 3.0 mmol/L
Moderate is 3.0 – 3.5 mmol/L
Severe is 3.5 – 4.0 mmol/L
Life-threatening is > 4.0 mmol/L
Treat the patient not the number
Important to consider symptoms!
Calcium “Correction” Calculation
Highly protein bound, likes to stick to albumin
But free fraction is the active calcium
Calcium is highly protein bound
Physiologically active Calcium is “ionized” and the unbound fraction
Most laboratories report Calcium levels as total calcium
Total of the calcium that is protein bound and non-protein bound
Important to consider in patients with hypoalbuminemia!
These patients will have a higher proportion of their total Calcium as ionized (active) calcium
Total serum calcium concentration may be normal when physiologically important “free”
(ionized) calcium is elevated
Use “Corrected Calcium” for estimation of physiologic calcium
Corrected Calcium (mmol/L) level =
Measured Calcium (mmol/L) + ([40 - albumin (g/L)] × 0.02)
Lab reports total calcium
If pt has low albumin, you will have high free fraction of ca than it seems
It must be corrected to compare total calcium values against the normal range in setting of hypo or hyeralbuminemia (in cancer, usually hypo)
Treatment of Hypercalcemia
Hydration normal saline
Promotes calcium excretion and corrects dehydration
Bisphosphonates (enhances serum calcium elimination and inhibits skeletal calcium release
by tumours)
Examples:
Pamidronate 90 mg IV in 500 mL NS over 2 to 4 hours
Zoledronate 4 mg IV in 50 mL NS over 15 minutes
Onset in 1-2 days
Maximum effect in 2-4 days
Onset is 1-2 days,
If someone has mild can use but if they have cardiac arrhythmia can’t wait
Calcitonin 4 IU/kg s/c q12h (promotes renal excretion of calcium)
Onset in 2-6 hours
Efficacy is limited to first 48 hours (tachyphylaxis)They get used to it
REMEMBER: Discontinue/Hold medications that can cause hypercalcemia
Good bridge to wait for bisphosphonate to kick in
Multiple Myeloma - Definitions
Multiple Myeloma
Malignant expansion of PLASMA CELLS usually in the bone marrow
Monoclonal protein (“M-Protein”) in serum or urine
Plasma Cell
Plasma cells could be in bone marrow or circulting, not lymphoma
The function of a plasma cell is to produce antibodies (immunoglobulins, proteins)
Each type of Plasma Cell makes a specific type of immunoglobulin
M-Protein
A monoclonal protein secreted by the malignant plasma cell
Can be produced uncontrollably and are not functional (they just cause problems) , make proteins with no purpose
Multiple myeloma (MM) is an aggressive malignant neoplasm of plasma cells
* The malignant plasma cells secrete a monoclonal protein “M-protein”
The protein that acts like a clone is called M protein
* Myeloma cells highly express CD38 (low levels of CD38 on normal lymphoid and on myeloid cells)
Multiple Myeloma – Monoclonal Protein
see slide 48
they get this M spike of proteins they are not supposed to have
The problems with having a lot of malignant plasma cells
are….
Crowding in Bone Marrow
Less room for other blood cells to mature - Cytopenias
Anemia – fatigue
Neutropenia - infection
Bone Damage
Bone Marrow Crowding
Myeloma cell secretes IL-6, IL-1 that increases osteoclast function and decreases osteoblast function
Bone weakening, fractures, hypercalcemia, pain
Absence of normal plasma cell and immune globulin function
Hypogammaglobulinemia
Infections
Excessive proteins flowing in the bloodstream
Kidney Damage - multifactorial
Light chain (part of M protein) precipitation in tubules – cast nephropathy
Resorption of light chain into tubular cell
If kidneys are damaged then they produce less erythropoietin that can also contribute to anemia
Serum Viscosity - End up with thicker blood with the proteins
Headache, blurred vision, epistaxis, confusion
High calcium also injures kidney
Multiple Myeloma Diagnosis (simplified)
Diagnostic Criteria (simplified) for Active Multiple Myeloma
M-protein in serum and/or urine
Clonal bone marrow plasma cells or plasmacytoma
Presence of Myeloma Symptoms
Symptoms of Multiple Myeloma
CRAB or ROTI
CRAB
Calcium (corrected) > 2.75 mmol/L
Renal Impairment: Creatinine > 176 umol/L
Anemia: Hemoglobin < 100g/L or 20 g/L below lower limit of normal
Bone lesions or osteopenia with compression fractures
Just need to have any one of the symptoms, dont need to have all
ROTI
(Related Organ or Tissue Impairment)
Symptomatic hyper-viscosity
Amyloidosis
Recurrent bacterial infections
Goals of Therapy:
disease control, improved quality of life, prolonged survival
MM remains incurable despite many advancements
General treatment plan:
Transplant Eligible
* <65 years old
* Good organ function
* Well
* Consent
Transplant Ineligible
* Do not meet the criteria
* Do not consent
General treatment plan: “Transplant Eligible”
Induction
* Combination
pharmacotherapy
regimen to reduce
tumour burden
Consolidation
* High Dose Chemo followed
by Autologous Transplant (if
eligible)
Maintenance
* To hold the response and
maintain disease control
General treatment plan: “Transplant INeligible”
Pharmacotherapy
* Combination pharmacotherapy regimen to reduce tumour burden
Treatment Plan - Multiple Myeloma
AHS Clinical Practice Guideline LYHE-003 “Multiple Myeloma” Version Date : February 2015
Combination pharmacotherapy
Transplant Eligible induction & maintenance.
Transplant Ineligible
Agents include:
Chemotherapy – example is cyclophosphamide
Corticosteroids – example is dexamethasone
Novel Agents – example is bortezomib
Monoclonal antibody – example is daratumumab (targets CD38)
Immunomodulator drugs – example is lenolidomide
Bortezomib
Mechanism of Action:
Bortezomib is a reversible inhibitor of the 26S proteasome. Inhibition alters regulatory proteins
and results in cell cycle arrest and apoptosis
Can be given IV or SC
FATAL if given intrathecally
Adverse Effects:
Thrombocytopenia
Neuropathy
Constipation or Diarrhea
Herpes Zoster Reactivation
All patients should be given HSV/VZV prophylaxis (Acyclovir or Valacyclovir)
Drug Interaction – Green Tea
Interferes with bortezomib’s antiproliferative effect on myeloma cells
Increases risk of developing herpes
Zoster or simplex, need prophylaxis
Dexamethasone
Mechanism of Action
Cytotoxic to myeloma cells likely via apoptosis
Pulse Dosing
Example – 40 mg po once weekly
Adverse Effects
Hyperglycemia – watch patients with diabetes closely
Insomnia – take in the morning
Mood changes/irritiability
GERD/heartburn
Fluid and sodium retention
Daratumumab
Monoclonal antibody that targets CD38
Adverse Effects
Infusion reactions (up to 50%)!
Fever, chills, tachycardia, headache
Can have life threatening anaphylaxis, bronchospasm.
Premedications!
Cetirizine or loratidine 10 mg po 1 hour pre daratumumab
Acetaminophen 1000 mg po 1 hour pre daratumumab
Montelukast 10 mg po 2 hours pre daratumumab
Ranitidine 150 mg or Famotidine 20 mg po 1 hour pre daratumumab
If on a regimen that includes dexamethasone, take the dexamethasone before
daratumumab
Lenalidomide
Thalidomide derivative
MoA:
immunomodulatory, antiangiogenic, and antineoplastic characteristics via
multiple mechanisms
Adverse Effects
TERATOGENIC
Thrombocytopenia and neutropenia
Edema
DVT/PE risk
Requires renal dosing adjustment if kidney function is poor
Substantial DVT rsik with drug, need to be on prevention
Often just use aspirin
The REVAID program
Revaid for Lenalidomide, Pomalidomide, Thalidomide
Controlled distribution program to prevent fetal exposure to these highly
teratogenic drugs
Registration is required for prescribing physicians, dispensing pharmacists
and pharmacies, and for patients
Registered pharmacists are required to provide patient counselling with every prescription
of lenalidomide, thalidomide, pomalidomide
Do not share the medication with anyone
Do not donate blood
Men, do not donate semen/sperm
Female patients of child bearing potential must have a negative pregnancy test and agree to using 2
methods of birth control and monthly pregnancy tests (abstinence is considered a method of bc).
Male patients must wear a condom if partner is of child bearing potential (even if he has had a vasectomy).There is stilla small chance or prgnancy with vasectomy
Thalidomide derivatives increases the risk of blood clots. Patients must be on prophylaxis. Acceptable
options include ASA, LMWH, Warfarin
All suspected pregnancies and/or adverse events must be reported to REVAID immediately
Bisphosphonates in Multiple Myeloma
Bone Health is Very Important with Multiple Myeloma
A Cochrane meta-analysis and many trials have shown that bisphosphonates in Multiple
Myeloma patients:
Reduce vertebral fractures
Reduce skeletal related events
Reduce in pain
Bisphosphonate Guideline:
Intravenous bisphosphonates every 4 weeks for 2 years
pamidronate 30 - 90 mg
zoledronate 4mg
The use of vitamin D (1000 -2000 I.U. / day) is recommended with a daily calcium intake of 1500
mg/day in the absence of hypercalcemia
Bisphosphonates need to be dose adjusted for impaired renal function
Get it every month for 2 years shown to improve outcomes
Osteonecrosis of the Jaw
Bisphosphonates - Multiple Myeloma
ONJ is often precipitated by a dental intervention that involves manipulation
the mandibular and maxillary bones
root canal, dental extraction
Preventative measures to minimize risk of ONJ:
Prior to initiating therapy with bisphosphonates, a comprehensive dental evaluation
should be performed and all invasive dental procedures be completed.
Annual dentist visits and maximal preventive care.
Avoid dental extractions if possible.
If a patient needs a dental extraction:
Withhold bisphosphonates for at least one month before and do not resume until
recovery and healing is complete.
prophylactic antibiotic to promote healing and prevent infection.
Symptom Management in Multiple Myeloma
Symptom management presents many DRP’s
Huge opportunity for clinical role for pharmacists
Hypercalcemia – (first part of case)
Pain control – bone lesions and/or neuropathy
DVT prophylaxis – many myeloma therapies increase risk of DVT
Poor renal function – dosing recommendations for renally cleared medications.
Most patients are on steroids – diabetes and blood glucose control
Infection Prophylaxis
All Bortezomib patients should receive prophylaxis for VZV (Shingles) reactivation with Acyclovir
or Valacyclovir
What is an Autologous HSCT?
Too much chemo can kill them by killing the bone marrow and cannot make stem cells to replenish blood cells
- collection
- processing
- cryopreservation
- chemotherapy
- reinfusion
Save their stem cells and freeze them, can be resucred and can tolerate higher doses to kill as much myeloma possible
Purpose of Autologous HSCT
Primarily as a means to dose escalate (intensify) chemotherapy
Myelosuppression is the dose limiting toxicity of most chemotherapy
Infusion of autologous stem cells serves to “rescue” the patient from
myelosuppressive effects of high-dose chemotherapy.
By using stem cell transplant, chemotherapy doses can be escalated to
increase the tumour cell kill!
In Alberta, Auto-HSCT is part of the clinical guidelines for treatment of
appropriate patients with Aggressive Lymphoma, Multiple Myeloma, and select
patients with Indolent Lymphoma
Collecting the Stem Cells for Auto HSCT
Peripheral Blood Stem Cell Collection
Apheresis
Several litres of blood is processed over several
hours each day
Normally, the number of stem cells that circulate in
peripheral blood is low
Techniques known as “mobilization” are used to
increase the number of stem cells in peripheral blood.
Mobilization can include use of filgrastim or chemotherapy
(or both)
High Dose Chemotherapy + Auto-HSCT
High Dose Chemo
Often has steep dose-response curve and bone marrow toxicity is the dose limiting
toxicity (“Myeloablative”)
Collecting, storing, and then reinfusing patient stem cells provides a strategy of rescuing
the patient from severe myelosuppression from high dose chemotherapy
In Auto-HSCT, other organ toxicities relating to high-dose therapy become dose-limiting
example is mucositis which can be severe
Many different regimens depending on the indication and the institution
Example for Multiple Myeloma in Alberta – High Dose Melphalan
Toxicities include severe mucositis (grade3/4), infections, diarrhea, nausea/vomiting
