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Multiple myeloma Treatment in Israel
What is Multiple Myeloma?
Multiple myeloma is a disease that originates from mature B-type white blood cells that have differentiated into plasma cells. The disease is characterized by the clonal proliferation of plasma cells in the bone marrow that secrete a monoclonal antibody found in the blood and urine. The disease affects the bone marrow, bones, kidneys, and immune system.
Epidemiology
Multiple myeloma is the second most common hematologic malignancy (10 percent of all diseases of this type). In Western countries, the incidence of the disease is 4–5 new cases per 100,000 people per year. There is an increase in the incidence of multiple myeloma, probably due to early detection and the increase in the age of the population. There is a sharp increase in the incidence of the disease over the age of 50 and most patients are over the age of 70 (the average age at diagnosis is 62 years). The disease is slightly more common in men than in women.
Etiology
The etiology of the disease is unknown, the prevailing belief is that multiple myeloma develops in most cases from a premalignant state (MGUS, Monoclonal Gammopathy of Undetermined Significant) which develops into a dormant myeloma (Smoldering Multiple Myeloma, SMM) and finally into symptomatic myeloma (Figure 1). Multi-step genetic changes and changes in the local environment of the plasma cells cause the premalignant plasma cells to transition from a premalignant state to a malignant state.
Among the reasons proposed as increasing the risk of developing the disease are:
- Exposure to ionizing radiation (higher incidence in Hiroshima and Nagasaki survivors)
- Exposure to pesticides
- Exposure to benzene and metals in industry
The disease is not genetic but there is an increased incidence in families. (A first-degree relative has an increased risk of developing MM\MGUS or another hematological disease).
Clinical Presentation
The disease is often manifested by bone pain (80 percent of patients), anemia (70 percent of patients), kidney failure (20-40 percent of patients), increased calcium levels in the blood (Hypercalcemia) (uncommon) and recurrent infections.
There are asymptomatic patients who are discovered incidentally in blood tests. These patients usually have a dormant disease or a premalignant state (MGUS, SMM). MGUS is a premalignant state that is not defined as a disease and usually does not develop into a malignant state. There is a one percent risk per year of transition from this state to active multiple myeloma. Most of the transition to myeloma occurs in the first three to five years after diagnosis.
Recommended Tests for Suspected Myeloma
- Blood and urine tests:
CBC, complete blood count including LDH (Lactate Dehydrogenase), Total protein, Albumin, Globulin, kidney function, Plasma protein electrophoresis, Immune fixation, blood antibody levels, blood free light chains, 24-hour urine collection for protein and Bence Jones and Beta 2 Microglobulin
- Imaging:
Any patient with suspected MGUS/myeloma should undergo skeletal imaging: usually whole body CT scan or PET-CT. When there is localized pain and/or suspicion of plasmacytoma, a magnetic resonance imaging (MRI) directed at that area or PET-CT should be completed
- Additional tests:
- Bone marrow biopsy + immunohistochemical staining
- Fine needle aspiration and chromosome analysis with FISH (Fluorescence In Situ Hybridization)
- FLOW CYTOMETRY of the bone marrow for MRD testing
Staging of Multiple Myeloma
- Stage I – Beta 2 Microglobulin below 3.5, Albumin above, LDH normal, no high-risk cytogenetic abnormalities
- Stage II – Beta 2 Microglobulin above 3.5 or Albumin below 3.5
- Stage III – Beta 2 Microglobulin above 5.5 or elevated LDH + high-risk cytogenetic abnormality (t(4;14), t(14;16),t(14;20), TP53/del17p, Amp 1q)
There are cellular genetic changes (Cytogenetics) that affect the behavior of the disease and the response to treatment. Disorders such as: translocation (t(11;14) and hyperploidy are associated with a lower risk. While disorders such as: chromosomal translocations of (4;14), (14;16), (14;20), disruption of the tumor suppressor protein p53 and deletion of chromosome 17 are associated with a higher risk.
Diagnosis
The diagnosis of myeloma is made by a combination of blood tests, skeletal radiographs and/or imaging, and bone marrow biopsy.
To diagnose myeloma, three conditions are required:
- A bone marrow biopsy showing a proliferation of monoclonal plasma cells, over 10 percent or over one plasmacytoma
- A monoclonal protein in the blood or urine (over 500 mg of Bence Jones protein)\or a disorder in the ratio and absolute number of free light chains in the blood
- There is damage to one of the target organs manifested as SLIM -CRAB: HyperCalcemia, Renal failure, Anemia, lytic Bone lesions, Clonal Plasma Cells≥60%, FLC ratio≥100, more than one lytic bone lesion on MRI
Patients who meet sections 2+1, but without one of the characteristics in section 3: SLIM -CRAB are not defined as active myeloma but as smoldering myeloma and do not need, according to the usual definitions, to start immediate treatment. Patients as mentioned above with smoldering myeloma SMOLDERING MYELOMA need monitoring Close. In certain cases of high-risk creeping myeloma, we will consider starting treatment or suggesting that the patient enter a clinical trial. There are studies that examine whether early treatment in a state of dormant myeloma with high-risk signs and in the era of new drugs is effective and justified. There is no answer to this question, so the international guidelines remain as they were in the past.
Treatment Options
The treatment is intended only for patients who meet the definition of active multiple myeloma (SLIM-CRAB).
Since about 2004, the treatment of myeloma has undergone a fundamental change, with the advent of new drugs that have significantly improved disease-free survival and overall survival of myeloma patients compared to treatments given before the era of new drugs. The progress achieved is mainly attributed to the development of new drugs, monoclonal antibodies, as well as bispecific antibodies and therapy using CART technology.
Proteasome Inhibitors
Bortezomib
First-line treatment usually includes Bortezomib (Velcade), which is a targeted therapy that inhibits the proteasome (the cellular particle responsible for breaking down abnormal proteins in the cell). Velcade is given by subcutaneous injection. The treatment is given once or twice a week (in cases where a rapid response is required). A treatment cycle contains four doses of Velcade. The main side effects of Velcade are weakness, neuropathy (damage to the nerve endings, manifested as numbness or tingling, in the palms of the hands and feet), fluid retention, and thrombocytopenia (decreased platelet count). The drug requires prophylactic treatment with acyclovir.
Carfilzomib
Carfilzomib (Kyprolis) – belongs to the proteasome inhibitor family, is an irreversible inhibitor of the proteasome and is more effective than Bortezomib and also works in patients who have not responded in the past or have progressed during treatment with Bortezomib.
Ixazomib
Ixazomib (Ninlaro) – an oral proteasome inhibitor. Given once a week. Efficacy and activity are similar to that of Bortezomib.
Immunomodulatory Drugs
Lenalidomide
Lenalidomide (Revlimid) is a biological drug that also belongs to the family of immune response modulators, works through the cerebellum protein, is administered orally and has a lower rate of side effects than Thalidomide. The drug does not cause neuropathy, but may cause a significant decrease in blood counts (panctopenia) and therefore immunosuppression. The drug increases the risk of excessive clotting, so prophylactic treatment with aspirin should be given. Patients at high risk of DVT should be given Clexane/NOACs prophylactically, especially in the initial months of treatment. In addition, the dose of the drug should be adjusted in patients with impaired renal function.
Pomalidomide
Pomalidomide (Imnovid) is a new generation of immune response modulators, which has also shown efficacy in patients who are resistant to lenalidomide. It can be combined with Bortezomib, the PVD protocol (the protocol is in the second-line basket) or with other drugs. Patients at high risk for DVT should be given prophylactic Clexane/NOACs, especially in the initial months of treatment.
Selinexor
Selinexor (Xpovio) was approved by the FDA in December 2020 for treatment-resistant or relapsed multiple myeloma.
Belongs to a family of substances that are selective inhibitors of nuclear export proteins (SINE family, abbreviation for Selective Inhibitor of Nuclear Export). Selinexor works by blocking a protein called XPO1, also called CRM1 = ‘Exportin 1’.
This is an oral drug that is given once a week at a dose of 40–80 mg, usually until the disease progresses or toxicity develops. The drug is given in combination with Velcade / Amenovid and in combination with steroids.
Main side effects: nausea, fatigue, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infections, weight loss, vomiting, cataracts, low blood platelet levels (thrombocytopenia), low white blood cell levels (lymphopenia), anemia (low iron levels), low phosphorus levels (hypophosphatemia), hyponatremia in the blood and a decrease in the number of neutrophils in the blood (neutropenia).
Monoclonal Antibodies
Daratumumab
Daratumumab (Darzalex) is an antibody Monoclonal antibody against CD38- which is found on the surface of myeloma cells. It is given by subcutaneous injection once a week for two months (8 doses) then once every two weeks for 4 months (8 doses) and then once a month. The drug is given in various combinations in combination with Bortezomib and/or Thalidomide\ Lenalidomide\ Pomalidomide\ Carfilzomib and has shown excellent results. It is already given in the first line of treatment. Requires prophylactic treatment with acyclovir.
Belantamab Mafodotin
Belantamab Mafodotin is a monoclonal antibody that binds to a receptor called BCMA (abbreviation of B Cell Maturation Antigen) found on myeloma cells, and carries a toxin (mafodotin) that penetrates the myeloma cells through this connection and causes their destruction. The drug is given by intravenous infusion lasting about half an hour as a day hospital. The infusion is given once every three weeks/month. Approved in August 2020 by the FDA as an advanced treatment for patients with relapsed or refractory disease, after exhausting four previous drugs.
Isatuximab
Isatuximab (Sarclisa) is a monoclonal antibody against CD38 similar to Daratumumab, in advanced stages of research.
Bispecific Antibodies (BITs)
- A site on the surface of the malignant cell (myeloma).
- A site of the immune system that activates it, so that the immune system can act against myeloma cells
Teclistamab
Tecvayli is a bispecific antibody that targets BCMA (B Cell Maturation Antigen) – which is located on the surface of the myeloma cell (a protein that plays a role in the survival of myeloma cells) and at the same time also binds to the CD3 protein on T cells of the immune system. In this combined activity – the antibody activates the immune system against myeloma cells similar to CART. The drug has been proven effective in the treatment of multiple myeloma resistant to existing treatments. It is given by subcutaneous injection until the disease progresses. Usually, the first treatment is given in hospital and after a few days, if there are no side effects, you can be discharged and receive the continuation of treatment on an outpatient basis.
Approved in October 2022 by the FDA for the treatment of multiple myeloma resistant to treatments / or relapsed in the fourth line.
The treatment involves infections, and rarely a cytokine storm phenomenon similar to CART but less turbulent.
Talcetamab
Talquetamab is a bi-primary antibody against GPRC5, which is found on the surface of myeloma cells.
Yeloma + and like Teclistamab also binds to the T cells of the immune system (CD 3). This activates the immune system cells against myeloma cells. It is in advanced stages of research (phase 2–3 of research) with promising results.
Elranatamab
Elranatamab is a bivalent antibody against BCMA that is found on the surface of the myeloma cell and also binds to the CD3 protein on the T cells of the immune system. In this combined activity – the antibody activates the immune system against myeloma cells similar to CART. It is in advanced stages of research with promising results.
CAR-T Cell Therapy
The patient’s immune system T cells are extracted from the patient’s body (cell collection) and transferred outside the patient’s body, using genetic engineering methods, a process in which a protein is introduced that has the ability to recognize and bind to myeloma cells. The cells are returned to the body by intravenous infusion and after identifying the myeloma cells, the immune system is activated against them.
The first such treatment approved by the FDA is idecabtagene vicleucel.
Treatment Options
Classically, it is customary to administer an induction treatment of about 4–6 cycles of treatment in one of the above combinations: DARA-VTD, DARA-VD, DARA-RD, DARA-VRD In patients under the age of 65–70, who do not suffer from serious underlying diseases, the patients were candidates for stem cell collection and autologous bone marrow transplantation. About 60 days after transplantation, it is customary to repeat the induction treatment for about 2 (consolidation) and then maintenance treatment (LENALIDOMIDE\VELCADE\DARA).
Older patients or patients suffering from serious underlying diseases continue induction treatment for about 10–12 months and then move on to the maintenance phase (LENALIDOMIDE\VELCADE\DARA).
The need for autologous bone marrow transplantation is controversial and patients who are not at high risk and who respond well to induction treatment can choose to postpone the transplantation to a later date if necessary and continue Induction for 10–12 months and then move on to maintenance therapy.
Several studies have shown an advantage in providing maintenance therapy after consolidation, with Lenalidomide in pills or alternatively with Velcade, a dose once every two weeks, until disease progression. There are studies examining maintenance therapy with Daratumumab +\- Lenalidomide.
Patients who experience a relapse of the disease are usually treated with different treatment combinations depending on the previous treatments they received, such as: PVD (pomalidomide-Velcade-Dexa), KPD (Cerfilzomib-pomalidomide-Dexa), KRD. Treatment of patients in third and fourth relapse includes monoclonal antibodies such as Belantamab or bivalent antibodies (Ticlestamab, Elranatamab) or CART therapy.
Since the beginning of the 2000s, there has been a significant improvement in the quality of life and life expectancy of multiple myeloma patients. Due to the accelerated development of new drugs, life expectancy is expected to continue to increase. Multiple myeloma is a chronic disease. Some believe that the combination of new drugs and new technologies currently in advanced research may not only slow the progression of the disease but also lead to a cure.
Take the First Step Toward Expert Myeloma Care
Contact our private clinic in Tel Aviv to schedule a consultation with a leading hematologist. We offer state-of-the-art treatments for multiple myeloma, including CAR-T therapy, monoclonal antibodies, and comprehensive diagnostics in central Israel.
“Patients who choose to undergo treatment in Israel benefit from cutting-edge technologies, short waiting times, English-speaking specialists, and access to innovative clinical trials.”
