Multiple Myeloma: Has Crowd Control Ever Been As Important?
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on May 26, 2021.
Multiple Myeloma: A Crowded House
If you or a loved one has been diagnosed with multiple myeloma, you will no doubt have many questions about this form of cancer.
So what is multiple myeloma? Multiple myeloma forms when cancerous plasma cells, a white blood cell normally found in the bone marrow, crowd out healthy plasma cells and form 'multiple' tumors -- hence the name 'multiple' myeloma. The tumors usually affect the bones, but may infrequently occur in other areas, too.
Multiple myeloma is a rare type of blood cancer, but that doesn't mean it can't take a toll. The American Cancer Society estimates that roughly 34,920 new cases of multiple myeloma will be diagnosed in 2021 (19,320 in men and 15,600 in women), with about 12,410 deaths (6,840 in men and 5,570 in women).
A rare disease -- also called an orphan disease in the US -- typically occurs in less than 200,000 people nationwide.
Am I At Risk for Multiple Myeloma?
Remember, multiple myeloma is a very uncommon cancer.
To put some numbers to it, the US lifetime risk of getting multiple myeloma is 1 in 132; about a 0.76% chance, according to the latest 2021 figures put out by the American Cancer Society.
But some factors that may increase your risk of being diagnosed with multiple myeloma are:
- Older age, 60 to 70's
- Men are more at risk than women
- Blacks more at risk than whites
- Family history
- Monoclonal gammopathy of undetermined significance (MGUS)
- Exposure to radiation, benzene, or pesticides
Symptoms of Multiple Myeloma
Early in the disease process, multiple myeloma may not cause any symptoms, and even after diagnosis, treatment may not be needed immediately.
But as it progresses, symptoms of multiple myeloma can include:
- Bone pain, often in the back and ribs
- Extreme fatigue
- Easy bruising due to low platelets
- Anemia: cancerous plasma cells crowd out normal red blood cells
- Loss of appetite
- Stomach problems like nausea and vomiting
- Mental changes like confusion
- A greater risk for infections, bone fractures, dehydration, and kidney problems can also occur.
How Is Multiple Myeloma Diagnosed?
Usually multiple myeloma isn't caught early because the symptoms don't appear until a more advanced stage of disease. However, in some cases, your doctor might suspect multiple myeloma based on a blood or urine test or your symptoms, such as bone pain or easy bleeding.
To diagnosis multiple myeloma, your doctor might use these tests or procedures:
- Blood tests (CBC) to look for blood cell counts and certain proteins
- Urine tests to also look for proteins
- Bone marrow biopsy to look for myeloma cells
- Imaging tests such as X-rays, MRI, CT or positron emission tomography (PET)
Staging Multiple Myeloma
Staging is the process of finding out how far the cancer has advanced. Your multiple myeloma will be staged into Standard (Stage I), Intermediate (Stage II) or High (Stage III) risk disease to help direct initial treatment.
The stage is determined by evaluating several factors, including lab results, protein levels, and bone lesions. Staging can also help to give your doctor the expected outcome over time (prognosis) for your myeloma and what to expect from treatment. Your doctor will be able to share this information with you.
New treatments are rapidly expanding a patient's options.
Broad Treatment Options for Multiple Myeloma
Multiple Myeloma: Treatments by Stage
Some patients with early disease may not have symptoms and can do well for years without treatment. This is called smoldering myeloma (SMM) and can be closely monitored for progression without treatment. However, some patients may need to have treatment based on the stage of the disease and symptoms. Presence of high calcium levels, kidney disease, blood cell counts, bone lesions, and symptoms all help to direct your treatment.
Drug treatment typically involves targeted therapy or chemotherapy, use of corticosteroids, and a possible stem cell transplant (autologous hematopoietic cell transplantation [HCT]), if the patient is deemed eligible.
Patients with high risk disease should discuss treatment options with their doctor. They may want to consider enrolling into a clinical trial with an investigational agent or use newly approved treatments, as standard treatments are often not as effective.
What Is a Stem Cell Transplant?
A stem cell transplant is a procedure to replace your diseased bone marrow cells with healthy bone marrow cells.
If you and your doctor have decided that a stem cell transplant is the right option to treat your multiple myeloma, you will receive high doses of chemotherapy to kill the cancer cells before the transplant. Then you receive a transfusion of stem cells taken from your blood or bone marrow (autologous) before you receive drug treatment, or from a donor (allogenic).
The transplanted stem cells develop into healthy new blood cells. Targeted drug therapy, chemotherapy, and stem cell transplants are not a cure, but these therapies may control your multiple myeloma for years.
To learn more about stem cells, review this article from Mayo Clinic.
Multiple Myeloma: Drug Therapy Options
If you have a stem cell transplant, you'll most likely receive specific types of drugs afterwards -- called targeted drug therapy or biological therapy -- to help prevent a recurrence of myeloma.
If a stem cell transplant is not in your regimen, your initial therapy may include chemotherapy, corticosteroids, targeted therapy or biological therapy.
There may be other complications from multiple myeloma that need treatment, too, including:
- bone pain or bone fractures
- kidney disease
- vaccines to prevent infections
Bisphosphonates are also used in the treatment of multiple myeloma. Extensive invasion of bone by tumor cells can lead to high blood calcium levels, bone pain or bone fractures.
- Zoledronic acid (Zometa)
- Pamidronate (Aredia)
Xgeva (denosumab) is a monoclonal antibody (a RANKL inhibitor) used to prevent bone fractures and other skeletal conditions in people with multiple myeloma.
Medications for anemia may be used to increase your red blood cell count.
Specific Drugs Used in Multiple Myeloma
Treatment choice will depend upon if you are newly diagnosed with multiple myeloma and your stage at diagnosis, or if you are experiencing a recurrence of the disease.
Treatments are often combined for greater success and to help lower side effects. Your doctor may select from the following drugs:
- Proteasome inhibitors - Bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomid (Ninlaro)
- Immunomodulators/Antiangiogenics - Lenalidomide (Revlimid), pomalidomide (Pomalyst) and thalidomide (Thalomid)
- Histone deacetylase inhibitors - panobinostat (Farydak)
- Corticosteroids - dexamethasone, prednisone
- Alkylating agents - cyclophosphamide, carmustine (BiCNU, Gliadel), melphalan (Alkeran, Evomela)
Pepaxto (melphalan flufenamide) was first approved in March 2021 as a peptide-drug conjugate used with dexamethasone in adults for the treatment of r/r multiple myeloma. Pepaxto is an alkylating agent used in patients who have received at least four prior lines of therapy.
Additional agents are also outlined on further slides.
Common Treatment Regimens
Drug treatment regimens for multiple myeloma typically involve a combination of medications, given over a period of time (a cycle, from 21 to 28 days), usually for 2 to 4 cycles. Your treatment may be different based on:
- your risk profile
- tumor targets
- drug availability
- your doctors preference
- whether or not you are having a stem cell transplant.
Lenalidomide (Revlimid), bortezomib (Velcade), and thalidomide (Thalomid) may be used in initial treatments of multiple myeloma.
For recurrent myeloma, lenalidomide (Revlimid), panobinostat (Farydak), pomalidomide (Pomalyst), bortezomib (Velcade), and carfilzomib (Kyprolis) may be options. These agents are often combined with corticosteroid agents like dexamethasone or prednisone to enhance therapy.
Some patients continue maintenance therapy with agents like lenalidomide to extend survival time. Chemotherapy drugs that stop cancer growth like cyclophosphamide, doxorubicin, or melphalan may also be combined with targeted treatments.
Another option for r/r myeloma is belantamab mafodotin-blmf (Blenrep) from GSK. Blenrep was approved in August 2020 as the first anti-BCMA (B-cell maturation antigen) therapy and is used in adults who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulatory agent.
Can Side Effects Be Controlled?
Palliative care, or preventing and controlling side effects during treatment, will be a major goal of your health care team.
If there is a chance of infection, some patients may receive antibiotic or antiviral medications, if needed. If treatments increase the risk of a blood clot, a blood thinning agent might be used to prevent a heart attack or stroke.
More Palliative Care
Bisphosphonates, for example:
can increase bone density, reduce bone pain, and lower the risk of fractures.
Doses may be lowered in patients with liver or kidney disease and to help prevent side effects like peripheral neuropathy, a type of nerve damage that may cause weakness, numbness and pain.
Hair loss, a worry for many patients, is not common with all treatments, so be sure to ask your doctor about your specific regimen. And remember, if you do lose your hair, it usually grows back after treatment ends.
First-Line Use for Revlimid
In February 2015, Revlimid (lenalidomide) plus dexamethasone was given another approved use for patients newly diagnosed with multiple myeloma and can now be used as first-line treatment. Lenalidomide is a derivative of thalidomide, another drug treatment used in multiple myeloma.
Median progression-free survival (PFS), the length of time a patient lives from starting a study to disease progression or death was the primary endpoint of a study evaluating Revlimid. PFS for patients receiving Revlimid plus dexamethasone was about 25 months compared to 21 months in those receiving melphalan, prednisone and thalidomide.
Common side effects include fatigue, low white blood cell count, constipation, and diarrhea, among others.
Farydak by Novartis
In February 2015, FDA approved Farydak (panobinostat) for multiple myeloma. Farydak, a histone deacetylase (HDAC) inhibitor, slows or kills the excess development of the cancerous plasma cells in the bone marrow.
Farydak is used in those who have received at least two previous regimens. In studies, people who received Farydak, plus bortezomib and dexamethasone, saw a delay in disease progression of about 10.6 months, compared with 5.8 months among people who received bortezomib and dexamethasone alone.
Common side effects include diarrhea (which can be severe), tiredness, nausea, swelling in the arms or legs, decreased appetite, fever, vomiting and weakness.
Empliciti by Bristol-Myers Squibb and AbbVie
Originally approved in November 2015, Empliciti (elotuzumab) injection is a Signaling Lymphocyte Activation Molecule (SLAMF7)-directed immunostimulatory antibody. It activates the body’s immune system to attack and kill multiple myeloma cells.
In studies, patients experienced a delay in the amount of time before their disease worsened (19.4 months) compared to participants taking only Revlimid and dexamethasone (14.9 months).
In November 2018, the FDA approved Empliciti in combination with pomalidomide and dexamethasone (EPd for short) for adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
- In the ELOQUENT-3 trial, EPd demonstrated benefit in patients with relapsed or refractory multiple myeloma, doubling both median progression-free survival (PFS) and overall response rate (ORR) when compared to treatment with pomalidomide and dexamethasone.
- PFS is the length of time a patient lives from starting a study to disease progression or death.
Common side effects may include: fatigue, diarrhea, fever (pyrexia), constipation, cough, nerve damage/peripheral neuropathy, upper respiratory tract infection, and decreased appetite and pneumonia.
Ninlaro by Takeda
Takeda’s Ninlaro (ixazomib), an oral proteasome inhibitor used in combination with Revlimid (lenalidomide) and dexamethasone was approved in November 2015 for use in patients with multiple myeloma who have received at least one prior therapy.
In clinical trials, participants in the Ninlaro treatment group lived longer without their disease worsening (average 21 months) compared to the group taking placebo plus lenalidomide and dexamethasone (15 months).
In studies, common side effects of Ninlaro included:
- low blood platelet count (thrombocytopenia)
- peripheral neuropathy
- peripheral edema
- vomiting and back pain.
Darzalex by Janssen Biotech
Darzalex (daratumumab), first approved in November 2015, is an injectable human anti-CD38 monoclonal antibody for patients given at least 3 prior treatments including a proteasome inhibitor and an immunomodulatory agent.
Since 2015, Darzalex has been approved for multiple uses and combinations treatments in multiple myeloma. It can be used alone for with other agents for the treatment of multiple myeloma. See the various approvals for Darzalex here.
A new subcutaneous formulation of Darzalex -- Darzalex Faspro (daratumumab and hyaluronidase-fihj) -- was approved in May 2020. Darzalex Faspro can lower administration time from several hours for the IV solution down to about 5 minutes for the subcutaneous route.
Common side effects in studies have included: allergic-like reactions, infusion reactions, diarrhea, upper respiratory tract infections, fatigue, nausea, back pain, fever and cough.
Evomela, from Spectrum Pharmaceuticals, is approved for these uses:
- as a high-dose conditioning treatment prior to stem cell transplantation in patients with multiple myeloma
- for the palliative treatment (providing relief from the symptoms and pain of the disease) of patients for whom oral therapy is not appropriate.
Approved in March 2016, Evomela's new melphalan formulation does not contain propylene glycol and is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution. Propylene glycol as a co-solvent in melphalan can be associated with kidney and heart rhythm problems.
Common side effects include diarrhea, hair loss, nausea, and vomiting.
Xpovio: A First-In-Class Agent
In July 2019, the FDA approved Xpovio (selinexor), a Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist and the first drug with this unique mechanism of action. Xpovio is from Karyopharm Therapeutics.
In the initial approval, Xpovio was approved for use in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma (RRMM). In studies, 122 patients received Xpovio with dexamethasone on Days 1 and 3 of every week. The Overall Response Rate (ORR) was 25.3% in a subgroup of 83 patients previously refractory to at least 5 agents, with a median duration of response of 3.8 months.
In addition, in Dec. 2020, Xpovio was approved for use in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
The most common side effects (incidence ≥20%) are thrombocytopenia (low platelet count), fatigue, nausea, anemia, and diarrhea among others. The rate of fatal adverse reactions in studies was 8.9%.
Sarclisa for RRMM
In March 2020, the FDA firt approved Sanofi’s Sarclisa (isatuximab-irfc) used in combination with pomalidomide and dexamethasone (pom-dex) for the treatment of adults with relapsed refractory multiple myeloma (RRMM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
- Sarclisa is a monoclonal antibody that binds to the CD38 receptor on multiple myeloma cells. Sarclisa is given as an intravenous (IV) infusion in combination with pom-dex every week for four weeks and then every two weeks, until disease progression or unacceptable toxicity.
- In studies, Sarclisa added to pom-dex prolonged survival without disease progression (PFS) of 11.53 months compared to 6.47 months with pom-dex alone.
In March 2021, Sarclisa was also cleared by the FDA to be used in combination with carfilzomib and dexamethasone (Kd), for the treatment of adults with RRMM who have received one to three prior lines of therapy.
The most common side effects (> 20%) include neutropenia (96%), infusion-related reactions (39%), pneumonia (31%), upper respiratory tract infection (57%) and diarrhea (26%).
Abecma First CAR-T Cell Therapy for Multiple Myeloma
In March 2021, the FDA approved Abecma (idecabtagene vicleucel), the first B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell immunotherapy. CAR-T cell therapy is made from a patient’s white blood cells that are genetically modified. Abecma is approved as a one-time infusion given in a certified healthcare facility.
Abecma is used in adults with multiple myeloma who have not responded to, or whose disease has returned after, four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
- Abecma recognizes and binds to BCMA, a protein that is expressed on most cancer cells in multiple myeloma, leading to the death of BCMA-expressing cells.
- In a Phase 2 study of 100 evaluable patients, 72% of patients partially or completely responded, with 28% showing a complete response (disappearance of all signs of multiple myeloma).
- Common, serious and fatal side effects can occur with Abecma. Cytokine release syndrome (CRS), neurologic toxicity, and other serious and possibly fatal toxicities are outlined in the Boxed Warning.
The Path Forward
It is important to work with your healthcare team and maintain a network of local support as you move through the initial stages of multiple myeloma treatment. Newly approved medications are helping patients to live longer and with a better quality of life.
Plus, don't be afraid to ask questions of your doctor, get second opinions, and lean on your family and loved-ones when you need a lift.
Consider joining the Drugs.com Multiple Myeloma Support Group, too. Here, you can keep up with the latest news, read about new medications, and ask questions and express concerns to others who know exactly how you feel.
Finished: Multiple Myeloma: Has Crowd Control Ever Been As Important?
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- Sonneveld P, Avet-Loiseau H, Lonial S. et al. Treatment of Multiple Myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016 Mar 21. pii: blood-2016-01-631200. [Epub ahead of print]. Accessed May 30, 2020 at doi: 10.1182/blood-2016-01-631200
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