Staging and Treatment: Multiple Myeloma
What is staging for cancer?
Staging is the process of learning how much cancer is in your body and where it is. Tests like blood work (CBC, or complete blood count), urine tests, biopsy, X-ray, CT, and bone marrow biopsy may be done to help stage your cancer. Your providers need to know about your cancer and your health so that they can plan the best treatment for you.
Multiple myeloma (MM) is staged using the Revised International Staging System (RISS) based on:
- How much albumin, beta-2-microglobulin, and LDH is in the blood.
- Certain gene changes (cytogenetics) of the cancer.
How is multiple myeloma staged?
Using the results of blood tests, urines tests, biopsies, and imaging tests, your myeloma will be given a stage. This will help guide your treatments. Below is a summary of the staging system. Talk to your provider about the stage of your cancer.
- RISS Stage Group I: Serum beta-2 microglobulin is less than 3.5 (mg/L), albumin level is 3.5 (g/dL) or greater, cytogenetics are considered “not high-risk” (meaning there are not certain changes to chromosomes 17, 4, 14, or 16), and LDH levels are normal.
- RISS Stage Group II: Not stage I or III.
- RISS Stage Group III: Serum beta-2 microglobulin is 5.5 (mg/L) or greater, cytogenetics are considered “high-risk” (meaning there is at least one kind of change to chromosomes 17, 4, 14, or 16), and LDH levels are high.
How is multiple myeloma treated?
Treatment for multiple myeloma depends on many things, like your cancer stage, age, overall health, and test results.
Treatment also depends on which type of MM you are diagnosed with—smoldering (asymptomatic) myeloma or active (symptomatic) myeloma. The differences between smoldering myeloma and active myeloma are:
- Smoldering multiple myeloma: This is an early form of MM. There will be no symptoms yet (asymptomatic). For the most part, your blood counts, kidney function, calcium levels, and bones/organs will be normal, but you may have other signs of myeloma in your body, such as:
- Too many plasma cells in your bone marrow.
- A high level of monoclonal immunoglobulin in your blood.
- A high level of light chains (also called Bence Jones protein) in your urine.
- Active multiple myeloma: This form of MM will cause symptoms. These may include:
- Bone problems (pain, weakness, broken bones).
- Low blood counts (low red blood cells/anemia, low white blood cells/leukopenia, low platelets/thrombocytopenia).
- High levels of calcium in the blood.
- Changes to your nervous system, like numbness, weakness, and tingling. If you have sudden back pain, numbness in your legs, or muscle weakness, call 911 or go to the Emergency Room right away. These are signs of a serious problem called spinal cord compression.
- Thickened blood in your body, which can cause confusion and symptoms of a stroke. Call your provider right away if you have these symptoms.
- Kidney problems.
Patients with smoldering (asymptomatic) myeloma (stage I) should be followed closely, without treatment. Research studies have found that treating asymptomatic myeloma does not improve long-term survival.
There have been many advances in the treatment of active myeloma. Most patients respond to initial therapy and can live with myeloma as a chronic cancer for many years. Your treatment for active myeloma may include some or all of the following:
- Chemotherapy and other medications.
- Stem Cell Transplant.
- CAR T-Cell Therapy.
- Clinical Trials.
Chemotherapy and Other Medications
Chemotherapy is a type of medication that goes throughout your whole body to kill cancer cells. The ones used to treat multiple myeloma are cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin, melphalan, and bendamustine. Often, one of these drugs is given with another type of drug (like corticosteroids and immuno-modulating medication). Corticosteroids include dexamethasone and prednisone. An immune-modulating medication is one that changes your immune response to fight the cancer cells. Immuno-modulating medications include thalidomide, lenalidomide, and pomalidomide.
Other kinds of medication that can be used to treat MM include proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib. Medications called monoclonal antibodies can also be used, including daratumumab, daratumumab and hyaluronidase, isatuximab, and elotuzumab. Belantamab mafodotin-blmf is an antibody-drug conjugate, meaning a monoclonal antibody is attached to a chemotherapy drug.
Your provider will likely combine 2 or 3 different medications to treat your MM.
High-Dose Chemotherapy with Stem Cell Transplant
High-dose chemotherapy and autologous stem cell transplant (using your own stem cells) have proven to be good treatment options for multiple myeloma. This may be used as the first-line therapy or after the myeloma has progressed while on other therapies. However, patients who are older (over 65) or with many other health issues may not be candidates for a transplant. This treatment is not a good option for some high-risk patients with certain DNA abnormalities.
There are three phases of stem cell transplant therapy:
- Induction therapy: The goal of initial chemotherapy ("induction chemotherapy") is to kill as many myeloma cells as possible without hurting the stem cells. You are given several cycles of chemotherapy that often include bortezomib with dexamethasone and another agent (or agents) that may include thalidomide, carfilzomib, ixazomib, lenalidomide, doxorubicin, daratumumab, cisplatin, etoposide and/or cyclophosphamide. Your providers will talk with you about your specific regimen of medications.
- Stem cell transplant: After induction therapy, you will start the process of collecting your stem cells so that they can be given back to you later. Stem cells can be collected from your blood instead of directly from your bone marrow. The next part of the transplant is often done in the hospital. You will be given high doses of chemotherapy to kill as much of the myeloma as possible. This round of chemotherapy aims to also damage or kill the stem cells in your body. A day or two after this chemotherapy, your previously collected stem cells are thawed and given back to you through a catheter. These cells replace the stem cells that were damaged during the high-dose chemotherapy, allowing your body to recover from this chemotherapy.
- Maintenance therapy: After transplant, if remission is achieved, you may need treatment with "maintenance" chemotherapy. It is not clear whether maintenance therapy is needed in all patients at this time. Your care team may instead choose observation without maintenance chemotherapy. This is often a less intense chemotherapy regimen and its goal is to prolong the period of remission. Maintenance therapy may include lenalidomide, ixazomib, or bortezomib. These medications may be used alone or in combination.
Some studies are looking at the benefit of a second transplant (called tandem transplant) for patients who do not reach full remission after the first transplant. With this therapy, a second transplant is done within six months of the first. Up to half of the patients treated with tandem transplants may have a complete response, but this is still being studied.
Allogeneic Stem Cell Transplant
While autologous transplants use stem cells from the person with multiple myeloma, allogeneic transplants use stem cells that are harvested (collected) from a donor who has been matched with the person with multiple myeloma. This match must be as close to the patient with MM as possible, such as from a sister or brother, or someone else who matches their cell type closely. The role of allogeneic transplant in the treatment of MM is still being studied and they are only used right now in clinical trials. These transplants have more risks but may be better at fighting the cancer cells because of something called the graft vs. tumor effect.
Talk with your provider about whether an allogeneic stem cell transplant is an option for you.
CAR T-Cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy helps your body use its own immune system to fight cancer cells. Immune cells, called T cells, are taken from your blood (called leukapheresis). These removed T cells are frozen, sent to a lab, and genetically changed to have certain receptors on their surface. These receptors help your T cells find and attach to proteins on the cancer cells. The lab will make many of these T cells. When these T cells are ready, you will receive chemotherapy to kill some of the cancer. The CAR T cells are then given back to you through your blood. These T cells find remaining cancer cells, attach to them, and start to attack them. Idecabtagene vicleucel and ciltacabtagene autoleucel are CAR T-cell therapies that target the BCMA protein that is found on myeloma cells.
Many patients who have been treated for MM relapse at some point. Treatment for relapse depends on the treatment you have already had, how long you were in remission, any side effects of treatments, and other health issues. Most often chemotherapy or immunotherapy medication is used.
Patients who have kidney failure when diagnosed with MM need treatment quickly to improve the chances of restoring kidney function. Both bortezomib and lenalidomide have been found to help reverse kidney damage. Plasmapheresis, a process that separates myeloma cells from the blood, has not been shown to be helpful in treatment.
When there are signs and symptoms of spinal cord compression, dexamethasone should be started right away, followed by urgent imaging of the spine. A neurosurgeon and/or radiation oncologist should be consulted to consider surgical decompression of the spine or radiation therapy to the spine.
Patients who have bone pain caused by myeloma may be treated with low-dose radiation (10-30 Gy) to the bones to relieve pain, which hopefully improves the quality of life. If myeloma involves the bones in the spine (the vertebrae) and a vertebral compression fracture happens, vertebroplasty or kyphoplasty is recommended. Both procedures involve injecting bone cement into the vertebral body; kyphoplasty also uses a balloon to restore normal height of the bone.
Bisphosphonates are commonly used in patients with myeloma to strengthen bones, prevent fractures, and lower calcium levels. Bisphosphonates (pamidronate, zoledronate) inhibit bone breakdown and promote the formation of new bone, opposing the effects of multiple myeloma on bones. Long-term use of bisphosphonates is associated with a small risk of osteonecrosis of the jaw (death of the jaw bone), atrial fibrillation, unusual fractures, and esophageal cancer. You should have a baseline dental exam before starting bisphosphonate therapy. often, the benefits of bisphosphonates outweigh the risks, but it is important to discuss risks and benefits with your care team. Another treatment for bone disease is the use of denosumab.
Patients with a solitary plasmacytoma (a solid tumor made of myeloma cells) are best treated with radiation therapy as an initial (and potentially curative) treatment. Sometimes, surgery is needed after radiation therapy.
Important Side Effects of Multiple Myeloma and Its Treatments
Myeloma increases your risk of developing a blood clot in the legs, known as a deep vein thrombosis (DVT). The risk of developing a DVT is even more when taking thalidomide or lenalidomide. DVT only happens in 1-3% of people on these medications. However, when used in combination with dexamethasone, this can increase to 10-15%, and if used in combination with dexamethasone and doxorubicin, this number can increase to 25%. DVT in the leg is concerning because the blood clot in the leg can travel to the lungs, causing a serious condition called a pulmonary embolus. A pulmonary embolus can cause cough, chest pain, shortness of breath, and even death.
Due to the risk of DVT and pulmonary embolism, all patients taking lenalidomide with dexamethasone or any thalidomide-containing therapy should receive anticoagulation (blood thinners) to prevent the formation of a blood clot. Thalidomide and lenalidomide also cause severe life-threatening birth defects. You should not become pregnant or father a child while taking these medications. Bortezomib can increase one's risk of developing herpes zoster (shingles), so a shingles vaccine is recommended before bortezomib therapy. Other side effects of chemotherapy medications include low blood counts,fatigue, constipation, diarrhea, and neuropathy (nerve damage, often numbness in the fingers and toes).
You may be offered a clinical trial as part of your treatment plan. To find out more about current clinical trials, visit the OncoLink Clinical Trials Matching Services.
Making Treatment Decisions
Your care team will make sure you are included in choosing your treatment plan. This can be overwhelming as you may be given a few options to choose from. It feels like an emergency, but you can take a few weeks to meet with different providers and think about your options and what is best for you. This is a personal decision. Friends and family can help you talk through the options and the pros and cons of each, but they cannot make the decision for you. You need to be comfortable with your decision – this will help you move on to the next steps. If you ever have any questions or concerns, be sure to call your team.
American Cancer Society, Multiple Myeloma, http://www.cancer.org/cancer/multiplemyeloma/
NCCN Guidelines: Multiple Myeloma (registration required) http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
SEER Stastistics: Multiple Myeloma, http://seer.cancer.gov/statfacts/html/mulmy.html
Attal, M., Lauwers-Cances, V., Marit, G., Caillot, D., Moreau, P., Facon, T., ... & Decaux, O. (2012). Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. New England Journal of Medicine, 366(19), 1782-1791.
Bataille, R., Annweiler, C., & Beauchet, O. (2013). Multiple myeloma international staging system:"Staging" or simply "aging" system?. Clinical Lymphoma Myeloma and Leukemia, 13(6), 635-637.
Cook, G., Williams, C., Brown, J. M., Cairns, D. A., Cavenagh, J., Snowden, J. A., ... & Cavet, J. (2014). High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. The Lancet Oncology, 15(8), 874-885.
Cooper, D. L., Stewart, A. K., Rajkumar, S. V., & Dimopoulos, M. A. (2015). Treatment of relapsed multiple myeloma. The New England Journal of Medicine, 372(18), 1774-1774.
Colson, K. (2015). Treatment-related symptom management in patients with multiple myeloma: a review. Supportive Care in Cancer, 23(5), 1431-1445.
Dimopoulos, M. A., Sonneveld, P., Leung, N., Merlini, G., Ludwig, H., Kastritis, E., ... & Vesole, D. H. (2016). International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. Journal of Clinical Oncology, JCO650044.
Dolloff, N. G., & Talamo, G. (2013). Targeted therapy of multiple myeloma. In Impact of Genetic Targets on Cancer Therapy (pp. 197-221). Springer New York.
Durie, B. G., Hoering, A., Abidi, M. H., Rajkumar, S. V., Epstein, J., Kahanic, S. P., ... & Orlowski, R. Z. (2017). Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. The Lancet, 389(10068), 519-527.
Findlay, M., & Isles, C. (2015). Myeloma and the Kidney. In Clinical Companion in Nephrology (pp. 71-75). Springer International Publishing.
Kumar, S. K., Lee, J. H., Lahuerta, J. J., Morgan, G., Richardson, P. G., Crowley, J., ... & LeLeu, X. (2012). Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia, 26(1), 149-157.
Lonial, S., Dimopoulos, M., Palumbo, A., White, D., Grosicki, S., Spicka, I., ... & Belch, A. (2015). Elotuzumab therapy for relapsed or refractory multiple myeloma. New England Journal of Medicine, 373(7), 621-631.
Ludwig, H., Miguel, J. S., Dimopoulos, M. A., Palumbo, A., Sanz, R. G., Powles, R., ... & Romeril, K. (2014). International Myeloma Working Group recommendations for global myeloma care. Leukemia, 28(5), 981-992.
Manier, S., Salem, K. Z., Park, J., Landau, D. A., Getz, G., & Ghobrial, I. M. (2017). Genomic complexity of multiple myeloma and its clinical implications. Nature Reviews Clinical Oncology, 14(2), 100.
Mhaskar, R., Redzepovic, J., Wheatley, K., Clark, O. A., Miladinovic, B., Glasmacher, A., ... & Djulbegovic, B. (2012). Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev, 5(CD003188).
Mikhael, J., Noonan, K. R., Faiman, B., Gleason, C., Nooka, A. K., Costa, L. J., ... & Lentzch, S. (2020). Consensus Recommendations for the Clinical Management of Patients With Multiple Myeloma Treated With Selinexor. Clinical Lymphoma Myeloma and Leukemia.
Nooka, A. K., Kaufman, J. L., Hofmeister, C. C., Joseph, N. S., Heffner, T. L., Gupta, V. A., ... & Lonial, S. (2019). Daratumumab in multiple myeloma. Cancer, 125(14), 2364-2382.
Paiva, B., van Dongen, J. J., & Orfao, A. (2015). New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood, 125(20), 3059-3068.
Palumbo, A., Avet-Loiseau, H., Oliva, S., Lokhorst, H. M., Goldschmidt, H., Rosinol, L., ... & Bringhen, S. (2015). Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. Journal of Clinical Oncology, JCO-2015.
Palumbo, A., Hajek, R., Delforge, M., Kropff, M., Petrucci, M. T., Catalano, J., ... & Cascavilla, N. (2012). Continuous lenalidomide treatment for newly diagnosed multiple myeloma. New England Journal of Medicine, 366(19), 1759-1769.
Palumbo, A., Rajkumar, S. V., San Miguel, J. F., Larocca, A., Niesvizky, R., Morgan, G., ... & Dimopoulos, M. A. (2014). International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. Journal of Clinical Oncology, 32(6), 587-600.
Podar, K., Shah, J., Chari, A., Richardson, P. G., & Jagannath, S. (2020). Selinexor for the treatment of multiple myeloma. Expert Opinion on Pharmacotherapy, 21(4), 399-408.
Rawstron, A. C., Gregory, W. M., de Tute, R. M., Davies, F. E., Bell, S. E., Drayson, M. T., ... & Owen, R. G. (2015). Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood, 125(12), 1932-1935.
Raje, N. S., Yee, A. J., & Roodman, G. D. (2014). Advances in supportive care for multiple myeloma. Journal of the National Comprehensive Cancer Network, 12(4), 502-511.
Rajkumar, S. V., Dimopoulos, M. A., Palumbo, A., Blade, J., Merlini, G., Mateos, M. V., ... & Landgren, O. (2014). International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology, 15(12), e538-e548.
Sonneveld, P., Schmidt-Wolf, I. G., van der Holt, B., el Jarari, L., Bertsch, U., Salwender, H., ... & Weisel, K. C. (2012). Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. Journal of Clinical Oncology, 30(24), 2946-2955.
Stewart, A. K., Rajkumar, S. V., Dimopoulos, M. A., Masszi, T., Špika, I., Oriol, A., ... & Goranova-Marinova, V. (2015). Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 372(2), 142-152.