Multiple Myeloma (MM)

1. Incidence
a. Estimated multiple myeloma cases in the United States for 2022:
i. About 34,470 new cases will be diagnosed
ii. About 12,640 deaths are expected to occur
2. Pathophysiology
a. Myeloma is a cancer of plasma cells and
these cancerous cells, called myeloma cells,
build up in bone morrow
b. The myeloma cells overgrow in the bone
marrow and crowd out healthy blood cells
causing many problems:
i. Reduces the healthy blood cells in the
body increasing risk of infections
ii. Releasing large amounts of myeloma
proteins or M-proteins, which can
impair bodily functions (like kidney
function)
iii. Destroy bone tissue, causing high
calcium levels, bone pain, weakened
bones, and bone fractures
iv. Form tumors called plasmacytomas,
which people may have multiple in
different bones or areas of the body, which is why this cancer is called multiple myeloma
3. Types of Myeloma
a. Active myeloma
i. Active (or symptomatic) myeloma causes symptoms or affects organs.
b. Smoldering myeloma
i. When myeloma isn’t causing symptoms and doesn’t require immediate treatment, it’s called
smoldering myeloma.
ii. People with smoldering myeloma have M-protein in blood and plasma cells in the bone
marrow, but usually at lower levels than people with multiple myeloma.
iii. Smoldering myeloma sometimes turns into multiple myeloma.
4. Risk Factors
a. Age > 65 years
b. Male
c. Black
d. First-degree relative with MM
e. History of monoclonal gammopathy of undetermined significance (MGUS)
5. Signs/Symptoms
a. Bone damage and pain
b. Fatigue and weakness
c. Frequent infections and fevers
d. Bruising and bleeding
e. Thirst and increase urination
6. Testing for Myeloma
a. CBC with diff, Serum quantitative immunoglobulins, SPEP, SIFE, Serum free light chain assay
b. Blood chemistry tests: Albumin, Beta-2 microglobulin, BUN, Calcium, Creatinine, LDH, Uric acid,
Electrolytes, Liver function
c. Urine tests: Total protein, UPEP, UIFE
d. Tissue tests: Bone marrow biopsy and aspiration
 e. Imaging tests: Low-dose CT scan, PET, Bone survey, MRI scan
f. Other: Plasma cell proliferation, Serum viscosity, Light chain amyloidosis
7. Factors Considered High Risk MM
a. High risk multiple myeloma
refers to a subgroup of people
with multiple myeloma that may
not respond well to standard
therapies and have poorer
outcomes.
8. Standard Treatment
a. Proteasome inhibitor
i. Block the action of certain proteins (proteasomes) that allow the myeloma cells to survive.
Because these drugs specifically target cancer cells, they may be less likely to harm normal
cells throughout your body.
b. Immunotherapy medication
i. Help to boost specific parts of the immune system against cancer. The immune system is
your body’s natural defense against infection and disease. Immunomodulatory drugs improve
your body’s ability to find and attack cancer cells. The immunomodulators used for myeloma
also stop tumors from growing new blood vessels.
c. Corticosteroid
i. Can actually kill myeloma cells and can help other agents kill the myeloma cells even better.
d. Bone-building therapy
i. Either bisphosphonates or denosumab
e. Supportive Care
i. Bone Disease
1. All patients receiving therapy should be given bisphosphonates or denosumab for up
to 2 years
ii. Hypercalcemia
1. Hydration, biphosphates (zoledronic acid preferred), denosumab, steroids, and/or
calcitonin
iii. Anemia
1. Blood product infusions as necessary
iv. Infection
1. Intravenous immunoglobulin therapy should be considered in the setting of recurrent
serious infection and/or hypogammaglobulinemia (IgG ≤400 mg/dL)
2. Consider 12 weeks of levofloxacin 500 mg daily at the time of initial diagnosis for
MM
3. Pneumocystis jiroveci pneumonia (PJP) should be given if receiving steroids and 3-6
months after transplant
a. TMP/SMX, atovaquone, dapsone, or pentamidine
4. Administer herpes zoster prophylaxis for all patients treated with proteasome
inhibitors (PIs), daratumumab, isatuximab-irfc, or elotuzumab
a. Valacyclovir preferred over acyclovir
v. Renal Dysfunction
1. Treat the metabolic abnormalities causing renal disease (example: hypercalcemia or
hyperuricemia)
2. Dose adjust lenalidomide, pamidronate, or zoledronic acid based on CrCl
vi. Venous Thromboembolism (VTE)
1. Highest risk for VTE is in the first 6 months following new diagnosis of MM
2. VTE prophylaxis is administered assuming there are no contraindications to
anticoagulation agents or anti-platelets
9. Transplant
 a. Transplant Eligible
i. Recommended at least three to four cycles of induction therapy including an
immunomodulatory drug, proteasome inhibitor (PI), and steroids is advised prior to stem-cell
collection.
b. Transplant Ineligible
i. Initial treatment of patients with multiple myeloma who are transplant ineligible should
include at minimum a novel agent (immunomodulatory drug or PI) and a steroid.
10. Primary Treatment
a. Bortezomib/lenalidomide/dexamethasone
i. Lenalidomide
1. Oral: 25 mg daily days 1 to 14
2. Toxicities: teratogenic (REMS program), neutropenia, thrombocytopenia, increased
risk of DVT/PE
ii. Bortezomib
1. IV: 1.3 mg/m2/day days 1, 4, 8, and 11
2. Toxicities: neutropenia, thrombocytopenia, development/exacerbation of HF, herpes
reactivation, pulmonary toxicity, peripheral neuropathy
iii. Dexamethasone
1. Oral: 40 mg daily days 1, 8, and 15
b. Carfilzomib/lenalidomide/dexamethasone
i. Cycle 1: Treatment cycle duration is 28 days
1. Carfilzomib
a. IV: 20 mg/m2/day over 10 minutes days 1 and 2 (cycle 1) followed by: 27
mg/m2/day over 10 minutes days 8, 9, 15, and 16 (cycle 1)
b. Toxicities: cardiovascular, hemorrhages, renal (Consider hydration with both
oral fluids - 30 mL/kg at least 48 hours prior to day 1 of cycle 1 and with IV
fluids - 250 to 500 mL of appropriate IV fluid before each dose in cycle 1),
TLS, infusion related reactions, thrombocytopenia
2. Lenalidomide
a. Oral: 25 mg once daily days 1 to 21
3. Dexamethasone
a. Oral: 40 mg once daily on days 1, 8, 15, and 22
ii. Cycles 2 to 12: Treatment cycle duration is 28 days
1. Carfilzomib
a. IV: 27 mg/m2/day over 10 minutes days 1, 2, 8, 9, 15, and 16
2. Lenalidomide
a. Oral: 25 mg once daily days 1 to 21
3. Dexamethasone
a. Oral: 40 mg once daily on days 1, 8, 15, and 22
c. Daratumumab/lenalidomide/dexamethasone
i. Cycles 1 and 2 (weeks 1 to 8): Repeat cycle every 28 days for a total of 2 cycles
1. Daratumumab
a. IV: 16 mg/kg weekly on days 1, 8, 15, and 22
b. Toxicities: Premedicate 1 to 3 hours prior to each infusion with a
corticosteroid, an oral antipyretic, and an oral or IV antihistamine
2. Lenalidomide
a. Oral: 25 mg daily days 1 to 21
3. Dexamethasone
a. Oral: 40 mg days 1, 8, 15, and 22 (administer prior to daratumumab)
ii. Cycles 3 to 6 (weeks 9 to 24): Repeat cycle every 28 days for a total of 4 cycles
1. Daratumumab
 a. IV: 16 mg/kg every 2 weeks on days 1 and 15
2. Lenalidomide
a. Oral: 25 mg daily days 1 to 21
3. Dexamethasone
a. Oral: 40 mg days 1, 8, 15, and 22 (administer prior to daratumumab on days 1
and 15)
d. Daratumumab/bortezomib/melphalan/prednisone
i. Daratumumab (IV):
1. Cycle 1: 16 mg/kg once weekly for 6 doses (weeks 1 to 6)
2. Cycles 2 to 9: 16 mg/kg once every 3 weeks for 16 doses (weeks 7 to 54)
3. Cycle 10 and beyond (daratumumab monotherapy): 16 mg/kg once every 4 weeks
(weeks 55 and beyond) until disease progression or unacceptable toxicity
ii. Bortezomib (SubQ):
1. Cycle 1: 1.3 mg/m2 twice weekly weeks 1, 2, 4, and 5 of a 6-week cycle (8 doses)
2. Cycle 2 to 9: 1.3 mg/m2 once weekly weeks 1, 2, 4, and 5 of a 6-week cycle (4
doses/cycle) for 8 cycles
iii. Melphalan (Oral)
1. 9 mg/m2 days 1 to 4 of each 6-week bortezomib cycle
2. Toxicities: GI
iv. Prednisone (Oral)
1. 60 mg/m2 days 1 to 4 of each 6-week bortezomib cycle (dexamethasone at a dose of
20 mg was substituted for prednisone on day 1 of each cycle)
11. Conditioning Regimen Before Auto HCT
a. Mel140
i. IV: 140-200 mg/m2 two days prior to transplantation
12. Maintenance Therapy After Transplant
i. Maintenance therapy after the autologous stem cell transplant. Maintenance therapy is
medicine that’s given less often or in lower doses to keep (maintain) the good results of prior
treatments.
b. Lenalidomide
i. Oral: 10 mg once daily (begin after adequate hematologic recovery [ANC ≥1,000/mm3;
platelets ≥75,000/mm3]); continue until disease progression or unacceptable toxicity occurs
c. Bortezomib
i. IV: 1.3 mg/m2 once every 2 weeks for 2 years
13. Relapse
a. Early (1-3 prior therapies)
i. If relapse is >6 months, the regimen used for primary therapy may be repeated
ii. Ixazomib/lenalidomide/dexamethasone (category 1)
iii. If still sensitive to bortezomib and/or lenalidomide, below are the options:

b. Late (>3 prior therapies)

i. Bendamustine
 ii. Bendamustine/bortezomib/dexamethasone
iii. Bendamustine/carfilzomib/dexamethasone
iv. Bendamustine/lenalidomide/dexamethasone
v. High-dose or fractionated cyclophosphamide