CAR T-cell immunotherapy & Stem Cells for Multiple Myeloma

Myeloma & Multiple myeloma (also known as Kahler’s disease) is a type of cancer that develops in the bone marrow (plasma cells). Plasma cells are part of our immune system and are white blood cells that help make antibodies (also called immunoglobulins) to help the body fight infections. Plasma white blood cells help produce antibodies when a patient develops an infection. The body makes different types of antibodies for various conditions, and these help antibodies find, attack, and kill viruses and bacteria, thus protecting us from getting sick.

There are five immunoglobulin (antibody) types:

1. IgA
2. IgG
3. IgM
4. IgD
5. IgE

About Multiple Myeloma

These plasma cells are considered abnormal for patients with multiple myeloma and have grown out of control. Such uncontrolled growth leads to various symptoms, including bone pain, bone damage (lytic lesions) that differs from osteoarthritis, fractures, and a decrease in healthy blood cells (white and red blood cells). These cancer cells also produce large quantities of abnormal proteins (light chains) that can damage the kidneys and, in some cases, cause kidney failure.^[1]

The treatment options for patients with myeloma & multiple myeloma have become much more effective thanks to recent advances in stem cell therapy, immunomodulation medications, and improved supportive care, leading to much-improved survival rates over the past ten years. Traditionally, the primary options for treatment included targeted (non-chemotherapy) medications that target cancer cells, corticosteroid infusions, standard chemotherapy, and modified bone marrow stem cell transplants ^[2].

Each patient’s needs are unique, and all options should be weighed carefully. Conventional therapies rarely cure cancer completely, so many patients end up having multiple treatment protocols during the overall course of their illness. Stem cell therapy is not appropriate in all cases. It might not be a good option for some patients due to several factors, including other serious health conditions (comorbidities), an advanced stage of cancer, advanced age, or other physical limitations.

Care for your Cancer During Covid-19

COVID-19 or “coronavirus disease 2019.” It is an infection caused by the SARS-CoV-2 virus. This virus was first identified in late 2019 and has since spread rapidly worldwide. Vaccinating for COVID-19 helps lower the risk of severe illness; oncologists recommend getting the COVID-19 vaccination for anyone with active cancer or a history of cancer.

Early Detection, Diagnosis, and Staging

When should treatment for Myeloma start? Myeloma and MM can remain pretty stable in some patients for long periods. Some patients with the onset of myeloma who do not show symptoms are called smoldering myeloma. Patients with this condition are usually monitored closely with regular blood tests and scans instead of starting treatment right away. However, patients at high risk for cancer progression may be offered treatment earlier. The Regeneration Center can discuss your options and help you and your hematologist determine when to start treatment.^[3]

Patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) generally do not need treatment. Long-term monitoring is needed to check for progression to myeloma or a related condition. Only a tiny percentage of patients diagnosed with MGUS eventually develop full-blown myeloma. Once the symptoms of MM cancer develop, immediate treatment with one or multiple options (discussed below) is recommended for nearly all cases.

Traditional treatments for Multiple Myeloma

There are nine main types of treatment for multiple myeloma. The options depend on several factors, including the age of diagnosis, whether the condition has relapsed, the patient’s age, and overall health.

• Newly developed cancer medications – There are currently several (non-chemotherapy) based medications developed recently for treating multiple myeloma. These cancer medications may be good options for recently diagnosed patients and those who have relapsed. Usually, these medications are combined with steroid medications (dexamethasone) or standard chemotherapy agents.
• Proteasome inhibitors – The proteasome breaks down proteins in cells and is very active in multiple myeloma cells due to the excess protein produced. Proteasome inhibitors block the proteasome, so unwanted proteins build up inside the myeloma cells and the cells die. The Proteasome inhibitors can include Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib). Usually, Velcade is given subcutaneously (under the skin), Kyprolis is given by IV infusion, and Ninlaro is generally taken as an oral pill. The side effects of these Proteasome inhibitors can include nerve damage and an increased risk of infections. If Velcade is given via IV, it can result in a much higher risk of developing nerve damage (neuropathy), so it is often not preferred.
• Immunomodulation medications – These medications help the body’s immune system fight the cancerous myeloma cells. They include Revlimid (lenalidomide), Pomalyst (pomalidomide), and Thalomid (thalidomide). However, these medications can cause severe birth defects, so they must not be taken during pregnancy, and patients who could become pregnant must follow a strict pregnancy prevention program while taking them. When Immunomodulation medications are given in combination with steroids, the meds can increase the risk of developing blood clots for some patients.
• Monoclonal antibodies – Monoclonal antibodies (MA) are purified proteins used to target specific cell types in the body. Monoclonal antibodies can treat myeloma by targeting the surface antigens of the cancer cells. Several types of monoclonal antibodies are currently available for use in the treatment of multiple myeloma. The most commonly used Monoclonal antibodies today include Darzalex (daratumumab), Empliciti (elotuzumab), Sarclisa (isatuximab-irfc), and Blenrep (Belantamab mafodotin). All monoclonal antibodies are given intravenously, while Darzalex can be given subcutaneously. Belantamab mafodotin is an antibody linked to a chemotherapy drug. It can damage the cornea (the clear front surface of the eye), so patients need regular eye exams during treatment, and its approval status differs between countries.

• Nuclear export inhibitor – Nuclear export machinery inside a cell transfers proteins from the cell nucleus. Xpovio (selinexor) is a newer medication that blocks this action, so tumor-suppressing proteins build up inside the cell nucleus and the myeloma cells die. Xpovio can also be used in the treatment of multiple relapsed multiple myeloma.
• Chemotherapy – Cancer treatments that use certain medicines to slow or stop the growth of cancer cells. For most patients, chemotherapy can help partially control multiple myeloma, and for some patients, traditional chemotherapy can lead to complete remission of Multiple Myeloma. Chemotherapy medications most often used for patients with multiple myeloma include Alkeran (melphalan), Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and Doxil (liposomal doxorubicin)).
• Stem cell transplants – Stem cell transplants can be performed using the patient’s stem cells (autologous) or stem cells donated by a relative or a matched donor (allogeneic). In multiple myeloma, high-dose chemotherapy followed by an autologous stem cell transplant can help control the disease for longer in eligible patients, although most patients eventually relapse. A transplant can be used as part of the initial treatment (for newly diagnosed patients) or in the case of relapse. For some patients, more than one stem cell transplant session may be needed to control the growth of the disease adequately. An autologous stem cell transplant is given after high-dose chemotherapy (usually melphalan), so its side effects include those of the chemotherapy, such as low blood counts, infections, mouth sores and tiredness.
• Corticosteroids, Corticosteroids (steroids) are anti-inflammatory medications. Prednisone and dexamethasone are two commonly used corticosteroids in the treatment of Multiple Myeloma.
• “CAR-T” cell therapy, CAR-T cell therapy is another type of cell immunotherapy that is approved for some patients with relapsed or refractory multiple myeloma. It involves collecting a patient’s own T cells and genetically modifying them in a laboratory so they carry a receptor that recognizes a protein on myeloma cells, such as BCMA. Gene therapy is also currently being used in clinical trials.

Treating Complications from Multiple Myeloma

Patients treated for Multiple myeloma can display a wide variety of complications, including some that can be life-threatening. Some common complications can include the following:

• Loss or impaired renal function, Up to about half of patients with multiple myeloma develop impaired kidney function at some point, often caused by the abnormal proteins (light chains) made by the myeloma cells, a different process from kidney damage in lupus, diabetic nephropathy or in patients with PKD. Treatment for kidney failure in myeloma centers on prompt myeloma treatment, plenty of fluids, correcting high calcium and, when needed, dialysis, along with medication such as allopurinol to lower uric acid. This waste product is produced when cancer cell turnover increases, damaging the renal system. Patients are encouraged to stay well hydrated to produce about 3 liters of urine daily. Patients should also avoid using any NSAIDs such as Motrin, Advil, or Aleve, as they can cause worsening of kidney function.
• Elevated blood calcium levels: High blood calcium levels occur when bone is lost. Patients with multiple myeloma are advised to remain physically active to help counter the risk of atrophy and bone loss. Treatment of higher-than-normal blood calcium levels usually includes IV fluids, bone-protecting medications such as zoledronic acid or denosumab, and steroids, along with treatment of the myeloma itself. Research on stem cell treatment for osteoporosis is not a recommended treatment for high calcium levels.
• Bone Fractures and pain: Physical Exercise can help promote bone strength for patients with multiple myeloma; however, extreme caution should be taken to avoid injuries, which can complicate treatment options. Bone pain, including tenderness, aching, or other discomforts in the bone, can be controlled with pain-relieving medications, myeloma treatment, and radiation therapy to painful areas. Bone-protecting medications such as zoledronic acid or denosumab are used to lower the risk of further bone damage and fractures, which in myeloma is a different process from spine conditions such as ankylosing spondylitis. Early treatment is recommended for patients showing signs of bone damage on scans.
• Infections: Bacterial and viral infections are common in multiple myeloma and often cause fever, which needs prompt medical attention. Bacterial infections are treated with antibiotics, and some patients are given preventive antibiotics or antivirals during certain treatments. Patients are encouraged to receive the flu and pneumococcal vaccines, which can help reduce the risk of pneumonia in high-risk patients.
• Spinal cord compression: Spinal cord injuries, including compression, require immediate treatment to avoid irreversible damage, including transverse myelopathy and paralysis. Initial treatments can include radiation therapy and dexamethasone to help reduce Spinal cord edema (swelling around the spinal cord). If available therapies fail, surgery might be required to relieve pressure. Patients experiencing new or severe back pain, weakness in the legs, numbness or tingling in the legs, or problems with bladder or bowel control should contact their doctor and seek emergency treatment immediately.
• Patients who receive bone-protecting medications such as bisphosphonates or denosumab have a higher risk of osteonecrosis of the jaw after tooth extractions or other invasive dental work. A dental check-up before starting these medications is recommended, and patients should tell their dentist and hematologist before any dental procedure.
• Hyperviscosity syndrome: Thickening of the blood, also known as hyperviscosity syndrome, is rare and can be treated with plasmapheresis. Plasmapheresis is a type of blood filtration system that removes excess monoclonal proteins, causing thickening.
• Anaemia: Low red blood cell count, also known as Anemia, may require patients to get blood transfusions or treatment with EPO (erythropoietin). Erythropoietin helps to stimulate the rapid production of red blood cells. EPO is most often given via injection several times per week. EPO therapy can help increase levels of hemoglobin protein in red blood cells that carry oxygen. EPO sessions can help improve several symptoms and reduce the requirement for blood transfusions.

Relapsed or Refractory Multiple Myeloma

Most patients with multiple myeloma eventually relapse after treatment, and some do not respond well to initial treatment. The condition is called refractory multiple myeloma when it does not respond to treatment or progresses soon after treatment. Non-responsive myeloma treatments can fail during the initial administration of chemotherapy or sometimes to the chemotherapy that is given after the initial relapse. From a treatment perspective, patients with multiple refractory myelomas are much more challenging to treat.

Anatomy guide

Bone and bone marrow

A cutaway of the upper femur showing compact bone, trabecular bone and marrow.

Patients with refractory myeloma or relapsed status are often treated with a combination of medications from several classes.
The main classes of medications that are used to treat refractory myeloma and relapsed patients are:

• Proteasome inhibitors, including carfilzomib, bortezomib, and ixazomib
• Monoclonal Antibodies targeting myeloma cells, including daratumumab, isatuximab, belantamab mafodotin, and elotuzumab
• Immunomodulatory medications including pomalidomide, lenalidomide, and thalidomide
• Modified Stem Cell Transplants
• Chemotherapy medications, including cyclophosphamide & melphalan
• Glucocorticoids such as dexamethasone
• Nuclear export inhibitors, including selinexor

A combination of these treatments can be used depending on the patient’s diagnosis, and each option has varying side effects. After each relapse, patients can try new protocols for meaningful benefits and improvements. Patients with relapses that occur after one year can also be treated again by repeating the initial chemotherapy regimen that was temporarily successful. A second session will work in most cases; however, the response is usually muted and less potent than the original course. If patients do not respond well to initial treatment, other options may include a different drug combination, a stem cell transplant, “CAR-T” therapy, or a clinical trial.

Stem Cell Transplants for Multiple Myeloma

Patients with Multiple Myeloma often need stem cell transplants to recover from the destructive nature of high-dose chemotherapy, which essentially destroys all the cells in the patient’s bone marrow. In a stem cell transplant for myeloma, the patient’s own blood-forming (hematopoietic) stem cells, collected before chemotherapy, are returned to restore the bone marrow. Umbilical cord mesenchymal stem cells (MSCs) are a different cell type being studied for possible effects on angiogenesis and cell death (apoptosis); they do not form blood cells and do not replace a hematopoietic stem cell transplant. During the early days of stem cell research, the cells mostly came from bone marrow and were referred to as bone marrow stem cell transplants^[4].

CAR T-cell therapy for Multiple Myeloma

Today, the Regeneration Center can modify T-cells and harvest stem cells from multiple sources, including peripheral blood, cord tissue, and cord blood stem cells. Natural Killer “NK” cells and mesenchymal cell therapies for myeloma are being studied in clinical research, and they are not a replacement for standard myeloma treatment. For some patients, a combination multi-stage treatment is needed to reduce the number of circulating myeloma cells & cancer stem cells before new transplants are given.

T-Cells Programmed to Attack Cancer Cells

Autologous vs. Allogeneic Stem Cell Transplants

Autologous stem cell transplants use a person’s stem cells, which can be removed from peripheral blood or bone marrow. After the cells are collected, they are cryogenically stored for future treatment until they are needed. Patients then receive high-dose chemotherapy (usually melphalan) to kill as many myeloma cells as possible. When chemotherapy is complete, the patients’ stored or lab-prepared stem cells are reintroduced intravenously.

Some patients with high-risk disease may be offered 2 autologous stem cell transplants within 6 to 12 months (a tandem transplant). The Regeneration Center uses this approach in some cases, as research has shown that staggering therapy can benefit some patients more than a single transplant.

Allogeneic stem cell transplants are when patients receive stem cells from a donor (i.e., another person). The best treatment outcomes for patients who need allogeneic stem cells result from matching donor cell types to patients. This is often much easier if the donor is closely related to the recipient. In cases with no matched donor, a cord blood transplant or a half-matched family donor might be an option; cord blood needs less strict HLA matching than adult donor cells, but some matching is still required. Cord blood transplants carry higher risks than autologous stem cell transplants. Transplanted (Allogeneic) cells have the advantage of helping destroy myeloma cells through the graft-versus-tumor effect.

Allogeneic stem cell transplants are mainly used for blood cancers such as leukemia and lymphoma and for some inherited blood and immune disorders, and they are not a standard treatment for solid tumors such as kidney cancer, lung cancer, liver cancer, colorectal cancer, cancer in the pancreas, or prostate cancer. Donor mesenchymal stem cells are being studied in clinical research for noncancerous conditions such as alcohol-induced liver cirrhosis, TBI due to hypoxia, lung disease, Crohn’s disease, incomplete spinal injuries, heart disease, Alzheimer’s, and degenerative disc disease, but they are not an established treatment for them.

Side effects of Allogeneic stem cell therapy

Some side effects from stem cell transplants come from the high-dose chemotherapy given before it. These include low blood counts: low white blood cells raise the risk of infection, low platelets raise the risk of bleeding, and low hemoglobin causes tiredness and shortness of breath. One of the main side effects of allogeneic transplants is graft-versus-host disease (GVHD). GVHD occurs when the donor’s immune cells recognize the patient’s tissues as foreign and attack them. Graft-versus-host disease can affect multiple functions and can be life-threatening. For this reason, HLA matching is required to help match both patient and donor cells. If both people share the same HLA type, they are considered a ‘good match. I

If you or a loved one has been diagnosed with Multiple Myeloma, you can ask our team about cell therapy research alongside the standard treatment planned by your hematologist.[5]Take the first step toward treatment by allowing our team of experts in our advanced facility to handle your care. We are here to help. To learn more about your treatment options for Multiple Myeloma and whether cell therapy research may be relevant to you, please contact us today.

Published Clinical Citations

[1] ^Wudhikarn K, Wills B, Lesokhin AM. Monoclonal antibodies in multiple myeloma: Current and emerging targets and mechanisms of action. Best Pract Res Clin Haematol. 2020 Mar;33(1):101143. doi: 10.1016/j.beha.2020.101143. Epub 2020 Jan 11. PMID: 32139009; PMCID: PMC7060936.

[2] ^Tan D, Lee JH, Chen W, Shimizu K, Hou J, Suzuki K, Nawarawong W, Huang SY, Sang Chim C, Kim K, Kumar L, Malhotra P, Chng WJ, Durie B; Asian Myeloma Network. Recent advances in the management of multiple myeloma: clinical impact based on resource-stratification. Consensus statement of the Asian Myeloma Network at the 16th international myeloma workshop. Leuk Lymphoma. 2018 Oct;59(10):2305-2317. doi: 10.1080/10428194.2018.1427858. Epub 2018 Feb 2. PMID: 29390932.

[3] ^ Xu S, De Veirman K, De Becker A, Vanderkerken K, Van Riet I. Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia. 2018 Jul;32(7):1500-1514. doi: 10.1038/s41375-018-0061-9. Epub 2018 Feb 22. PMID: 29535427; PMCID: PMC6035148.

[4] ^Huff CA, Matsui W. Multiple myeloma cancer stem cells. J Clin Oncol. 2008 Jun 10;26(17):2895-900. doi: 10.1200/JCO.2007.15.8428. PMID: 18539970; PMCID: PMC2610256.

[5] ^Giuliani N, Mangoni M, Rizzoli V. Osteogenic differentiation of mesenchymal stem cells in multiple myeloma: identification of potential therapeutic targets. Exp Hematol. 2009 Aug;37(8):879-86. doi: 10.1016/j.exphem.2009.04.004. Epub 2009 May 14. PMID: 19446662.

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