Multiple Myeloma - symptoms, diagnosis and current treatment aspects -2020

1. MULTIPLE MYELOMA
BY
SoumyaKS

2. Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow,
resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of
other hematopoietic cell lines.
First described in 1848, MM is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown
significance (MGUS) to plasma cell leukemia.
Bone marrow aspirate demonstrating plasma cells of multiple myeloma.
Note the blue cytoplasm, eccentric nucleus,
and perinuclear pale zone (or halo).
Definition

3. MM can range from asymptomatic to severely symptomatic with complications requiring emergent treatment.
Presenting signs and symptoms of MM include the following
Bone pain
Pathologic fractures
Spinal cord compression (from pathologic fracture)
Weakness, malaise
Bleeding, anemia
Infection (often pneumococcal)
Hypercalcemia
Renal failure
Neuropathies
Signs and symptoms

4. Potential complications of MM include the following
Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal cord
compression)
Infection
Anemia
Renal failure
Amyloidosis
Complications

5. Multiple Myeloma is often discovered through routine blood screening when patients are being evaluated for
unrelated problems. In one third of patients, the condition is diagnosed after a pathologic fracture occurs, usually
involving the axial skeleton.
Examination for MM may reveal the following:
HEENT examination: Exudative macular detachment, retinal hemorrhage, or cotton-wool spots
Dermatologic evaluation: Pallor from anemia, ecchymoses or purpura from thrombocytopenia; extramedullary
plasmacytomas (most commonly in aerodigestive tract but also orbital, ear canal, cutaneous, gastric, rectal,
prostatic, retroperitoneal areas)
Musculoskeletal examination: Bony tenderness or pain without tenderness
Neurologic assessment: Sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal
cord compression), neuropathy, myopathy, positive Tinel sign, or positive Phalen sign
Abdominal examination: Hepatosplenomegaly
Cardiovascular evaluation: Cardiomegaly
Diagnosis

6. The International guidelines for standard investigative procedures in patients with suspected Multiple
Myeloma include the following
Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric
quantitation; immunofixation for confirmation)
Serum free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
Bone marrow aspiration and/or biopsy
Serum beta2-microglobulin, albumin, and lactate dehydrogenase measurement
Standard metaphase cytogenetics
Fluorescence in situ hybridization
Skeletal survey
MRI
Diagnostic Tests

7. Routine laboratory tests include the following
Complete blood count and differential
Erythrocyte sedimentation rate
Comprehensive metabolic panel (eg, levels of total protein, albumin and globulin, BUN, creatinine, uric acid)
24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein, and
creatinine clearance; proteinuria greater than 1 g/24 hr is a major criterion
C-reactive protein
Serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines also recommend the use of serum
free light chain assay and plasma cell fluorescence in situ hybridization (FISH) on bone marrow: del 13, del 17p13,
t(4;14), t(11;14), t(14;16), t(14;20), 1q21 amplification, 1p deletion as part of the initial diagnostic workup. [2]
Laboratory Tests

8. Serum electrophoresis- screening method for detection of Plasma cell disorders.
It reveals monoclonal component (narrow bandpeak: “church spike”)
found in 98% of patients, in serum, urine or both
“M” spike or church spike on Electrophoresis
Laboratory Tests

9. Simple radiography for the evaluation of skeleton lesions; skeletal survey, including the skull,
long bones, and spine
MRI for detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord
compression
PET scanning in conjunction with MRI potentially useful
Imaging studies

10. Radiology
Multiple, punched out, sharply demarcated, purely lytic lesion without surrounding reactive sclerosis

11. Imaging studies
Multiple myeloma –
PET Scan

12. There is currently no cure for MM. However, advances in therapy, such as autologous stem cell transplantation,
radiation, and surgical care in certain cases, have helped to lessen the occurrence and severity of adverse effects
of this disease and to manage associated complications
Several drug therapies are valuable in the treatment of symptomatic MM. Clinicians treat many patients with high-
dose therapy and peripheral blood or bone marrow stem cell transplantation.
Management

13. In patients with symptomatic MM, chemotherapy is required. In asymptomatic patients with MM, treatment
is delayed until disease clinically progresses or until serum or urine levels of M protein substantially
increase.
The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction after
chemotherapy is used as a sign of response. A 50% reduction in M-component is considered a good clinical
response (according to the Chronic Leukemia-Myeloma Task Force). The historical standard regimen of
melphalan plus prednisone induces a response in 50-60% of patients with MM. Disappearance of the M
component on electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.
Management

14. The first step before starting therapy in MM is to determine whether a patient is a candidate for an autologous stem
cell transplant. Eligibility depends primarily on the patient’s age and comorbidities. Typically an age of 65 years is
used as a cut-off point for transplant eligibility. Thus, treatment for MM is best looked at in terms of the following
three categories of patients:
Young, newly diagnosed patients who are potential transplant candidates
High-risk patients who are potential transplant candidates
Newly diagnosed elderly patients who are not transplant candidates
Young, newly diagnosed patients who are potential transplant candidates
Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy has been used to
decrease the tumor burden in MM as preparation for transplantation. VAD is administered as a 4-day continuous
intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a
central venous catheter for delivery of the infusion. In selected patients, this therapy can be performed in an
outpatient setting.
Management

15. Chemotherapy regimens used in patients with Multiple Myeloma include the following
Thalidomide, either as a single agent or in combination with steroids or with melphalan
Lenalidomide plus dexamethasone
Bortezomib plus melphalan
VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone)
Melphalan plus prednisone
For primary induction therapy in patients with MM who are candidates for transplantation, NCCN guidelines recommend the
following combinations as preferred regimens
Bortezomib/lenalidomide/dexamethasone (category 1)
Bortezomib/cyclophosphamide/dexamethasone (preferred initial treatment in patients with acute renal insufficiency)
Other recommended regimens include
Carfilzomib/lenalidomide/dexamethasone
Ixazomib /lenalidomide/dexamethasone (category 2B)
Although triplet regimens should be used as the standard, patients not considered candidates for a 3-drug regimen can be started on
a 2-drug regimen, with the third drug added once performance status improves
Chemotherapy and immunosuppression

16. The NCCN (National Comprehensive Cancer Network) also considers the following regimens useful in certain
circumstances
Bortezomib/doxorubicin/dexamethasone
Carfilzomib/cyclophosphamide/dexamethasone
Ixazomib/cyclophosphide/dexamethasone
Bortezomib/thalidomide/dexamethasone (category 1)
Cyclophosphamide/lenalidomide/dexamethasone
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomib (VTD-PACE)
In September 2019 the US Food and Drug Administration approved the combination of
bortezomib/thalidomide/dexamethasone with daratumumab for newly diagnosed young patients with MM
who are eligible for transplantation.

17. For primary induction therapy in patients who are not transplant candidates, the NCCN guidelines list the following
as preferred regimens
Bortezomib/lenalidomide/dexamethasone (category 1)
Daratumumab/lenalidomide/dexamethasone (category 1)
Lenalidomide/low-dose dexamethasone (category 1)
Bortezomib/cyclophosphamide/dexamethasone
Other NCCN-recommended regimens for these cases include the following
Carfilzomib/lenalidomide/dexamethasone
Ixazomib /lenalidomide/dexamethasone
Daratumumab/bortezomib/melphalan/prednisone (category 1)
primary induction therapy in patients who are not transplant
candidates

18. For maintenance therapy, the NCCN recommends lenalidomide (category 1)
Bortezomib may also be used.
Relapse
For Multiple Myeloma that relapses after more than 6 months, the regimen used for primary induction therapy can
be repeated. For relapses that occur sooner, regimens that are NCCN category 1 preferred include the following
Carfilzomib (twice weekly)/dexamethasone
Carfilzomib/lenalidomide/dexamethasone
Daratumumab/bortezomib/dexamethasone
Daratumumabm/lenalidomide/dexamethasone
Elotuzumab/lenalidomide/dexamethasone
Ixazomib/lenalidomide/dexamethasone
Isatuximab–pomalidomide–low-dose dexamethasone is recently approved for relapsed and refractory MM in
patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.
Maintenance Therapy and Treatment of Relapse

19. Adjunctive therapy for Multiple Myeloma includes radiation therapy to target areas of pain, impending
pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie,
primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture,
need for surgery, need for radiation). Evidence suggests that it may be effective in treating bone pain and in
decreasing the likelihood of lesion recurrence.
Adjunctive therapy may also include any of the following, as appropriate:
Erythropoietin
Corticosteroids
Surgical intervention
Plasmapheresis
Bone disease guidelines: Bisphosphonates (eg, zoledronic acid, pamidronate) or denosumab for prevention
of skeletal related events (SREs) should be considered for all patients with MM receiving first-line
antimyeloma therapy, regardless of presence of osteolytic bone lesions.
Adjunctive therapy for Multiple Myeloma

20. Using the patient’s own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more
intense therapy for MM. After harvesting the stem cells from the patient, physicians can use otherwise
lethal doses of total body irradiation and chemotherapy and then “rescue” the patient by reinfusing the
harvested cells. This process of myeloablative therapy, followed by the reinfusion of stem cells, is termed
autologous stem cell transplantation.
The advantage of this approach over autologous transplantation is that the patient is not at risk of being
reinfused with MM cells. In addition, the donor’s immune system may fight the recipient’s cancer (ie, graft
vs myeloma effect). Unfortunately, the donor’s immune system may also attack the recipient’s body (ie,
graft vs host effect).
Physicians use allogeneic transplantation less often than autologous transplantation in MM patients, for
several reasons. First, the risks of complications and death from allogeneic transplantation increase with
age, and most patients with MM are older than the ideal age for allogeneic transplantation.
Second, the transplantation-related mortality rate is quite high in patients with MM who undergo
allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to 56% in
different case series.
Third, although some survivors experience long-term disease-free results after allogeneic
transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation
showed a median survival of 34 months for the autologous transplantation group and 18 months for the
allogeneic group.
Transplantation

21. Intense research has focused on the use of interferon alfa to treat Multiple Myeloma. This drug does
not appear to be effective for inducing remission, and a randomized controlled trial showed that
patients do not benefit from the addition of interferon to melphalan and prednisone.
Interferon alfa does appear to prolong remission in selected patients with Multiple Myeloma. For
this use, it may be administered after conventional chemotherapy or bone marrow (ie, stem cell)
transplantation has been completed.
The toxicity of interferon and the availability of alternate interventions have significantly limited the
role of interferon alfa.
Interferon Alfa Therapy

22. Multiple Myeloma is extremely sensitive to radiation. Physicians use radiation to treat symptomatic
lesions and to stabilize bones at risk for fracture. Physicians also use radiation to treat spinal cord
compression. Low-dose, double-hemibody irradiation has been studied as systemic therapy for
refractory or relapsed MM, but without dramatic success.
If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated.
Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing
should be limited for the first 4-6 weeks.
Radiation Therapy

23. Surgical therapy for Multiple Myeloma is limited to adjunctive therapy. It consists
of prophylactic fixation of pending fractures, decompression of the spinal cord
when indicated, and treatment of pathologic fractures.
Surgical Care

24. Bisphosphonates
Bisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone resorption. They also
have a role in the secondary prevention of bony complications in Multiple Myeloma, including hypercalcemia,
pathologic fracture, and spinal cord compression.
Intravenous (IV) pamidronate (Aredia) has been shown to be effective in preventing skeletal complications;
zoledronic acid (Zometa) may be significantly more potent than pamidronate. It has been found that the early use
of zoledronic acid was superior to clodronic acid in preventing skeletal-related events among patients with newly
diagnosed MM, irrespective of bone disease status at baseline.
Denosumab
In January 2018, denosumab was approved by the FDA for prevention of skeletal-related events (SREs) in patients
with Multiple Myeloma. It was originally indicated for SREs in patients with solid tumors. Denosumab is a human
monoclonal antibody targeting and binding to receptor activator of nuclear factor kappa-Β ligand (RANKL).
Osteoclast-activating factors, such as RANKL, are implicated in an increased risk for SREs with Multiple Myeloma.
Therapy for Skeletal-Related Events

25. In 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with MM who have received at
least two prior therapies including bortezomib and an immunomodulatory agent, and have demonstrated
disease progression on or within 60 days of therapy completion.
The approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with relapsed
multiple myeloma with other therapies. The study assessed for overall response rate (ORR), which was 22.9%
over a median duration of 7.8 months.
Drug of Interest

26. Mechanism of Action
 Tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S
proteasome, the proteolytic core particle within the 26S proteasome; has antiproliferative and proapoptotic activities in vitro in solid and
hematologic tumor cells
 Administered IV over 10 or 30 minutes depending on the dose regimen
Absorption
 Peak plasma concentration: 4232 ng/mL (27 mg/m²); 2079 ng/mL (56 mg/m²)
 AUC: 379 ng·hr/mL (27 mg/m²); 948 ng•hr/mL (56 mg/m²)
Distribution
 Protein bound: 97%
 Vd: 28 L
Metabolism
 Rapidly and extensively metabolized
 Principal pathways of metabolism: peptidase cleavage and epoxide hydrolysis
 The metabolites have no known biologic activity
Elimination
 Half-life: ≤1 hr (Day 1 of Cycle 1)
 Clearance: 151-263 L/hr
 Excretion: Urine, metabolites (~25%)
 Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose)
Carfilzomib - Pharmacology

27. THANK YOU 