When multiple myeloma returns after treatment, patients and their medical teams face new challenges and important decisions. The focus shifts to controlling the disease, managing symptoms, and maintaining quality of life through specialized treatment approaches tailored to each person’s unique situation.

Finding the Right Path When Myeloma Returns

Multiple myeloma is a cancer that affects plasma cells, which are specialized white blood cells normally responsible for making antibodies to fight infections. When this cancer comes back after treatment, it creates a situation that requires careful consideration and personalized care. The return of myeloma, known as relapse, is unfortunately common because the disease is considered chronic in nature^[1].

The main goals when treating relapsed myeloma are to keep the disease under control so it is not actively causing problems, reduce or eliminate symptoms that affect daily life, and help people maintain their ability to do the things that matter to them. Treatment decisions depend heavily on how long the myeloma stayed quiet after the last treatment, which specific treatments were used before, how well those treatments worked, and the patient’s overall health and personal preferences^[7].

Throughout the course of this disease, many people will experience several cycles of remission and relapse. A remission is when there are no signs of active myeloma in the body. When the disease becomes active again, patients need more treatment. This pattern means that managing relapsed myeloma becomes a long-term journey requiring ongoing partnership between patients and their healthcare teams^[10].

Standard Treatment Approaches for Relapsed Myeloma

When myeloma returns for the first time after initial treatment, doctors usually prescribe combinations of medicines rather than single drugs. These combinations work together to attack the cancer cells in different ways. The choice of which combination to use depends greatly on what was used during first-line treatment and how long the remission lasted^[10].

If someone’s myeloma stayed in remission for longer than 18 months, their doctor might consider using the same combination of drugs that worked before. However, it is more common to switch to a different combination to avoid the cancer cells becoming resistant to the same treatments. The goal is to find an approach that the myeloma cells have not yet learned to evade^[10].

First Relapse Treatment Options

For the first relapse, several standard treatment combinations are available through regular healthcare systems. One common option combines bortezomib with dexamethasone. Bortezomib is a type of targeted drug called a proteasome inhibitor, which works by blocking protein breakdown inside myeloma cells, ultimately causing the cancer cells to die. Dexamethasone is a steroid that reduces inflammation and also has direct effects against myeloma cells^[10].

Another widely used combination includes lenalidomide and dexamethasone. Lenalidomide belongs to a class of drugs called immunomodulatory agents, which work by changing how the immune system responds to cancer cells and by directly affecting the cancer cells themselves. This combination has proven effective for many people whose myeloma has returned^[10].

More recently, doctors have been adding newer targeted antibodies to these combinations. For example, daratumumab can be combined with bortezomib and dexamethasone. Daratumumab is a monoclonal antibody that targets a protein called CD38 found on the surface of myeloma cells. By attaching to this protein, daratumumab helps the immune system recognize and destroy the cancer cells^[6].

Carfilzomib represents another proteasome inhibitor that can be used, either with dexamethasone alone or in combination with lenalidomide and dexamethasone. This drug works similarly to bortezomib but has some differences in how it is given and its side effect profile. Some patients might have another stem cell transplant if they are healthy enough and if their first transplant resulted in a long remission^[10].

Treatment After First Relapse

When myeloma returns a second, third, or additional times, treatment options continue to evolve. At these stages, doctors might use ixazomib, which is an oral proteasome inhibitor, combined with lenalidomide and dexamethasone. Having an oral option can make treatment more convenient for some patients^[10].

Daratumumab can be used on its own after patients have already received multiple other treatments. Isatuximab is another monoclonal antibody targeting CD38, used in combination with pomalidomide and dexamethasone. Pomalidomide is a newer immunomodulatory drug that can be effective even when lenalidomide no longer works^[10].

Panobinostat combined with bortezomib and dexamethasone offers yet another approach. Panobinostat is a histone deacetylase inhibitor, which affects how genes are expressed in cancer cells, leading to their death. Selinexor with dexamethasone is an option for patients who have received multiple prior treatments. Selinexor works by blocking proteins that help cancer cells export important molecules out of their nucleus, causing harmful substances to build up inside the cancer cells^[10].

Duration and Delivery of Treatment

Most people with relapsed myeloma receive treatment as outpatients, meaning they visit a clinic or hospital for their medications and tests but return home the same day. Treatment is usually given in cycles, with periods of receiving medicine followed by rest periods to allow the body to recover. For example, some combinations might be given for three weeks followed by one week off^[10].

The duration of treatment varies greatly depending on how well the myeloma responds. Some patients might take combinations continuously as maintenance therapy as long as the treatment is working and side effects remain manageable. Others might complete a set number of cycles. Regular monitoring through blood tests and sometimes bone marrow examinations helps doctors assess whether treatment is working^[8].

Managing Treatment Side Effects

Understanding potential side effects is an essential part of treatment planning. Proteasome inhibitors like bortezomib and carfilzomib can cause peripheral neuropathy, which is numbness, tingling, or pain in the hands and feet. This happens because these drugs can affect nerve cells. The severity varies from person to person, and doctors can adjust doses or switch medications if neuropathy becomes too bothersome^[17].

Immunomodulatory drugs like lenalidomide and pomalidomide can lower blood cell counts, increasing the risk of infections, bleeding, or fatigue from anemia. They can also increase the risk of blood clots, so doctors often prescribe blood thinners alongside these medications. Some people experience digestive problems like constipation or diarrhea^[7].

Steroids such as dexamethasone can cause increased appetite and weight gain, mood changes including irritability or anxiety, trouble sleeping, elevated blood sugar levels, and weakening of bones with long-term use. These side effects can significantly impact quality of life, but doctors can often adjust steroid doses or prescribe additional medications to help manage these problems^[17].

Monoclonal antibodies like daratumumab and isatuximab are generally well tolerated, but they can cause infusion reactions during or shortly after the medicine is given. These reactions might include fever, chills, difficulty breathing, or changes in blood pressure. Healthcare teams carefully monitor patients during infusions and can give medicines beforehand to prevent or reduce these reactions^[6].

Emerging Treatments in Clinical Trials

Clinical trials are research studies that test new treatments or new ways of using existing treatments. For people with relapsed or refractory myeloma, especially those whose disease has stopped responding to multiple standard treatments, clinical trials offer access to innovative therapies that might not otherwise be available^[7].

Participating in a clinical trial means being part of advancing medical knowledge while potentially benefiting from cutting-edge treatments. Trials are carefully designed with safety as the top priority and include multiple phases. Phase I trials primarily evaluate safety and determine the right dose of a new treatment. Phase II trials assess whether the treatment works against the cancer and continue to monitor safety. Phase III trials compare the new treatment to current standard treatments to see if it works better or has fewer side effects^[7].

CAR T-Cell Therapy

One of the most exciting advances in treating relapsed myeloma is CAR T-cell therapy, a type of immunotherapy that uses a patient’s own immune cells. In this approach, doctors collect T cells, which are infection-fighting white blood cells, from the patient’s blood. These cells are sent to a specialized laboratory where they are genetically modified to produce special receptors on their surface called chimeric antigen receptors, or CARs^[6].

The CAR allows the T cells to recognize and attach to a specific protein on myeloma cells. After the T cells are modified, they are grown in large numbers in the laboratory and then infused back into the patient. Once in the body, these CAR T cells seek out and destroy myeloma cells. Two CAR T-cell therapies have been approved for certain patients with advanced multiple myeloma who have already received multiple treatments^[6].

Idecabtagene vicleucel, also known by its brand name Abecma, targets a protein called BCMA that is found on the surface of myeloma cells. It has been approved for patients who have received at least four prior treatments including a proteasome inhibitor, an immunomodulatory drug, and a monoclonal antibody. Ciltacabtagene autoleucel, known as Carvykti, also targets BCMA and is approved for similar patient populations^[6].

Clinical trials have shown that these CAR T-cell therapies can produce deep responses in patients whose myeloma had stopped responding to other treatments. Many patients experienced significant reductions in their myeloma burden, and some achieved complete remissions. However, CAR T-cell therapy can also cause serious side effects. Cytokine release syndrome occurs when the activated T cells release large amounts of inflammatory molecules, potentially causing fever, low blood pressure, and difficulty breathing. Most cases can be managed with supportive care and specific medications. Some patients also experience neurological side effects like confusion or difficulty speaking, which usually improve over time^[6].

Bispecific T-Cell Engagers

Another innovative approach being studied involves bispecific antibodies, which are specially designed proteins that can attach to two different targets at once. In the case of myeloma, these antibodies connect to both a protein on myeloma cells and a protein called CD3 on T cells. By physically linking cancer cells and T cells together, these antibodies help the immune system recognize and attack the myeloma^[6].

Teclistamab, marketed as Tecvayli, is a bispecific antibody that targets BCMA on myeloma cells and CD3 on T cells. It has been approved for patients with relapsed or refractory multiple myeloma who have received at least four prior therapies. Clinical trials showed that teclistamab could produce responses in heavily pretreated patients whose disease had become resistant to many other drugs. The treatment is given as an injection under the skin, which is more convenient than intravenous infusions^[6].

Elranatamab is another bispecific antibody with a similar mechanism, targeting BCMA and CD3. It has also received approval for heavily pretreated patients with relapsed or refractory myeloma. Like other immune-engaging therapies, these bispecific antibodies can cause cytokine release syndrome and other immune-related side effects, but healthcare teams have developed strategies to manage these problems^[10].

Clinical trials are ongoing to test these therapies earlier in the disease course and in combination with other treatments. Researchers are also studying bispecific antibodies targeting different proteins on myeloma cells, which might help patients whose disease does not respond to BCMA-targeting therapies^[6].

Antibody-Drug Conjugates

Antibody-drug conjugates represent another innovative strategy that combines the targeting ability of antibodies with the cancer-killing power of chemotherapy. These medicines consist of an antibody attached to a toxic drug. The antibody finds and attaches to myeloma cells, and then the toxic drug is released specifically inside those cancer cells, limiting damage to healthy cells^[6].

Several antibody-drug conjugates targeting BCMA and other proteins on myeloma cells are being tested in clinical trials. Early results have shown promising response rates in patients with heavily pretreated disease. Researchers continue to study the optimal doses, schedules, and combinations with other drugs to maximize benefit while minimizing side effects. Common side effects can include low blood counts, fatigue, and effects on the eyes or nerves, depending on which toxic drug is attached to the antibody^[6].

Other Investigational Approaches

Clinical trials are exploring many other innovative approaches for relapsed and refractory myeloma. Some studies are testing combinations of approved drugs in new ways, while others are evaluating completely novel mechanisms of attacking myeloma cells. For example, some trials are studying drugs that work by blocking proteins that help myeloma cells survive or by interfering with the bone marrow environment that supports cancer cell growth^[7].

Researchers are also investigating ways to overcome drug resistance. Some drugs work by targeting the specific genetic changes found in a person’s myeloma cells, an approach called precision medicine. Other studies are looking at combining different types of immunotherapy to create stronger anti-myeloma immune responses. These might include combinations of CAR T cells with checkpoint inhibitors or bispecific antibodies with immunomodulatory drugs^[9].

What Clinical Trials Have Shown

Early results from many clinical trials of new therapies have been encouraging. For CAR T-cell therapies targeting BCMA, studies showed that a substantial proportion of heavily pretreated patients achieved significant responses, with some experiencing complete remissions where no myeloma could be detected using standard tests. Response durations varied, with some patients maintaining responses for extended periods^[6].

Bispecific antibody trials have similarly shown that these agents can produce responses in patients whose disease had progressed after multiple prior lines of therapy. The ability to administer these treatments in outpatient settings makes them more accessible than CAR T-cell therapy, which requires specialized facilities and in-patient monitoring, especially during the initial treatment period^[6].

Safety profiles from clinical trials have generally been manageable with appropriate monitoring and supportive care. While immune-based therapies can cause serious side effects, healthcare teams have become increasingly experienced in recognizing and managing these complications early. Ongoing research focuses on identifying which patients are most likely to benefit from specific treatments and how to minimize side effects while maintaining effectiveness^[9].

Most Common Treatment Methods

• Proteasome Inhibitors
  • Bortezomib combined with dexamethasone for first relapse treatment
  • Carfilzomib with dexamethasone or with lenalidomide and dexamethasone
  • Ixazomib as an oral option combined with lenalidomide and dexamethasone
  • Panobinostat combined with bortezomib and dexamethasone
• Immunomodulatory Agents
  • Lenalidomide with dexamethasone as a standard combination for relapsed disease
  • Pomalidomide with dexamethasone for heavily pretreated patients
  • Often combined with proteasome inhibitors or monoclonal antibodies
• Monoclonal Antibodies
  • Daratumumab targeting CD38, used alone or in combinations with other drugs
  • Isatuximab targeting CD38, combined with pomalidomide and dexamethasone
  • Elotuzumab targeting SLAMF7, combined with lenalidomide and dexamethasone
• CAR T-Cell Therapy
  • Idecabtagene vicleucel (Abecma) targeting BCMA for patients with advanced disease
  • Ciltacabtagene autoleucel (Carvykti) targeting BCMA for heavily pretreated patients
  • Involves collecting, modifying, and reinfusing patient’s own T cells
• Bispecific T-Cell Engagers
  • Teclistamab targeting BCMA and CD3, approved for heavily pretreated patients
  • Elranatamab targeting BCMA and CD3 for relapsed or refractory disease
  • Connect cancer cells to immune cells to trigger immune attack
• Other Targeted Therapies
  • Selinexor with dexamethasone, blocking protein export from cancer cell nucleus
  • Various antibody-drug conjugates being tested in clinical trials
  • Novel combinations and mechanisms being explored in research studies