Table of Contents
- Key Points
- What Is This Summary About?
- What Is Multiple Myeloma?
- What Is Relapsed or Refractory Multiple Myeloma?
- How Is Multiple Myeloma Treated?
- What Is Isatuximab?
- What Is Carfilzomib and Dexamethasone (Kd) Treatment?
- What Was the Goal of the IKEMA Study?
- Who Took Part in the Study?
- How Was the IKEMA Study Done?
- What Were the Main Results?
- What Were the Most Common Adverse Events?
- Conclusions and Key Messages
- Limitations of the Study
- What This Means for Patients
- Frequently Asked Questions
- Source Information
Key Points
- In the IKEMA study of 302 people with relapsed and/or refractory multiple myeloma, the median time to death was 50.6 months with Kd and was not reached with Isa-Kd.
- A computer prediction estimated Isa-Kd could extend life by nearly 13 months compared with Kd, but this difference was not statistically significant, so chance could not be ruled out.
- People receiving Isa-Kd lived 47.2 months before their cancer got worse after starting their next treatment, versus 32.4 months for Kd.
- The most common side effects were infusion-related reactions, upper respiratory tract infections, diarrhea, and high blood pressure; 95% of side effects with Isa-Kd were mild or moderate.
- Stopping treatment due to side effects was similar between groups (14% with Isa-Kd versus 18% with Kd), even though people on Isa-Kd stayed on treatment about 1.5 times longer.
What Is This Summary About?
This article summarizes a publication about the IKEMA clinical trial. The publication appeared in The Lancet Haematology in July 2024.
The IKEMA trial tested whether a combination of cancer drugs called Isa-Kd would help people with relapsed or refractory multiple myeloma live longer. Isa-Kd is made up of three medicines: isatuximab (Isa), carfilzomib (K), and dexamethasone (d).
The researchers compared Isa-Kd with a combination of carfilzomib and dexamethasone alone, called Kd for short. At the time of the study, Kd was the standard treatment for people with relapsed and/or refractory multiple myeloma.
The IKEMA trial included participants who had already been treated for their multiple myeloma with other cancer medicines before joining the study.
The purpose of this plain language summary is to help you understand the findings from this research. Isatuximab is approved to treat the condition discussed in this summary. Approval varies by country, so please check with your local healthcare provider for more details.
This summary may help people with relapsed and/or refractory multiple myeloma, their caregivers, patient advocates, payers, and healthcare professionals.
What Is Multiple Myeloma?
Multiple myeloma is a type of blood cancer. There are many different types of blood cancer, depending on which type of blood cell they affect.
Multiple myeloma is a blood cancer that occurs in plasma cells. Plasma cells are a type of white blood cell made in the bone marrow. In multiple myeloma, abnormal plasma cells (also called myeloma cells) grow uncontrollably and build up in the bone marrow. This buildup prevents the bone marrow from making a normal number of healthy blood cells.
Myeloma cells also make abnormal antibodies that do not work properly and cannot fight against infections. These abnormal cells can weaken the bone and spread throughout the rest of the body.
People with multiple myeloma may have symptoms such as:
- Damage to their kidneys or other organs
- Bone pain
- Tiredness
- Infections
- Low numbers of blood cells
The areas of the body most commonly affected by multiple myeloma are the bones, kidneys, and blood.
What Is Relapsed or Refractory Multiple Myeloma?
Relapsed multiple myeloma is when initial treatment seems to reduce the signs and symptoms of multiple myeloma, but after some time, those signs or symptoms come back.
Refractory multiple myeloma is when the cancer does not respond to treatment at all.
Together, relapsed and/or refractory multiple myeloma is abbreviated as RRMM.
How Is Multiple Myeloma Treated?
There are many different medicines to treat relapsed or refractory multiple myeloma. These medicines are often given in combinations of 2 to 5 different treatments.
The main types of treatments include:
- Steroids help decrease swelling and inflammation. Steroids work together with other medications to increase their effect. In high doses, steroids can kill cancer cells.
- Proteasome inhibitors block the action of proteasomes. Proteasomes control the concentration of proteins in cells and dispose of proteins that are damaged or no longer needed.
- Immunomodulatory agents can increase the immune response as well as the effect of targeted treatments.
- Targeted treatments stop a specific gene or protein found on the surface of, or within, myeloma cells from working. These may also include a type of drug called bispecific antibodies, which target 2 different proteins on myeloma cells.
- CAR-T therapy uses T cells (a type of immune system cell) from a patient. These T cells are changed in the laboratory and customized to attack cancer cells. T cells are taken from a patient's blood.
The choice of treatments for relapsed and/or refractory multiple myeloma is influenced by many factors. These factors include:
- How old people are
- What stage their myeloma disease is
- Their cytogenetic risk
- What previous treatment a patient has received
Stages of multiple myeloma are measured using the International Staging System (ISS). The ISS uses blood test results to classify patients' multiple myeloma as stages 1, 2, or 3. Stage 1 is the least severe stage of multiple myeloma. Stage 3 is the most severe stage.
Cytogenetic risk refers to changes in the genes of cancer cells. Genes contain the instructions for how a cell develops and functions. Some gene changes lead to a more high-risk disease. People with high-risk multiple myeloma have more aggressive and difficult-to-treat disease than multiple myeloma that is not high-risk (called standard risk).
What Is Isatuximab?
Isatuximab is a targeted medicine for multiple myeloma. Isatuximab is a protein called a monoclonal antibody. It recognizes and binds to the CD38 molecule found on the outside surface of myeloma cancer cells and immune cells. There is much more CD38 on myeloma cells than on healthy cells.
When isatuximab binds to CD38 on the surface of myeloma cells, it triggers a chemical process in the myeloma cells that kills them. Isatuximab also signals to the immune system to kill the myeloma cancer cells.
In summary, isatuximab targets myeloma cells by binding to CD38 on their cell surface. Isatuximab also works with the body's immune system to stop cancer cells from growing.
What Is Carfilzomib and Dexamethasone (Kd) Treatment?
Kd is the name of a commonly used combination of medicines for treatment of multiple myeloma. It is made up of:
- Carfilzomib (K), which is a proteasome inhibitor drug that prevents myeloma cancer cells from working properly
- Dexamethasone (d), which is a type of steroid that has been shown to improve how well other antimyeloma drugs work
The combination of isatuximab (Isa) with Kd is known as Isa-Kd.
What Was the Goal of the IKEMA Study?
In the IKEMA study, the overall goal was to find out how well Isa-Kd treatment worked compared with Kd on its own. At the time the study was done, Kd was the standard treatment for people with relapsed and/or refractory multiple myeloma.
In the broader IKEMA study, researchers were looking at 3 things:
- How long each person lived before their cancer got worse, known as progression-free survival. This was the primary endpoint (main result) of the study. These results have already been reported. The first publication showed that progression-free survival was on average 16.5 months longer with Isa-Kd than with Kd.
- Whether levels of myeloma protein decreased over time.
- The total amount of time that people in the study lived, even if their disease got worse during that time. This is known as overall survival.
Of these 3, this paper only reports the overall survival results of the IKEMA study.
This paper also reports a secondary measure called second progression-free survival. Second progression-free survival is the measure of how long people lived before their cancer got worse. This measure applies once people stopped taking the IKEMA study treatments and started taking a new multiple myeloma treatment.
Who Took Part in the Study?
In total, 302 people from 69 centers across 16 countries were included in the IKEMA study.
These people met the following criteria:
- They were at least 18 years old.
- They had relapsed and/or refractory multiple myeloma.
- They had received between 1 and 3 other prior treatment combinations for their multiple myeloma before joining the IKEMA study.
Most people were in their 60s, were White, had Stage 1 multiple myeloma at the start of the study, and had a standard cytogenetic risk. People had taken an average of 2 treatment combinations for their myeloma disease before starting the study.
The table below shows the characteristics of participants in each treatment group:
- Isa-Kd group: 179 participants
- Kd group: 123 participants
Median age: 65 years in the Isa-Kd group and 63 years in the Kd group.
Age range: 37 to 86 years in the Isa-Kd group and 33 to 90 years in the Kd group.
Sex of participants: In the Isa-Kd group, 44% were women and 56% were men. In the Kd group, 45% were women and 55% were men.
Race: In the Isa-Kd group, 2% were multiple race, 20% were Asian, 73% were White, and 3% were Black or African American. In the Kd group, 67% were White, 15% were Asian, and 3% were Black or African American.
International Staging System stage at study entry: In the Isa-Kd group, 50% had stage 1 myeloma, 35% had stage 2 myeloma, and 15% had stage 3 myeloma. In the Kd group, 58% had stage 1 myeloma, 25% had stage 2 myeloma, and 16% had stage 3 myeloma.
Cytogenetic risk: In the Isa-Kd group, 64% had standard risk and 23% had high risk. In the Kd group, 63% had standard risk and 25% had high risk.
Average number of prior combinations for multiple myeloma: 2 in both groups.
Percentage of patients whose last treatment did not work: 50% in the Isa-Kd group and 59% in the Kd group.
How Was the IKEMA Study Done?
The IKEMA study began in November 2017, and the last person joined in March 2019.
As of February 2023, when these data were analyzed, the median time that people had been in this study was about 4.5 years.
After people started the study, they were given either Isa-Kd or Kd alone. The decision on which treatment to give each patient was made by a computer program. For every 3 people assigned to Isa-Kd, 2 were assigned to Kd.
Cancer treatment often happens in "cycles" where treatments are taken on specific days, and then each cycle is repeated a certain number of times. Each treatment cycle in this study was 4 weeks long.
People received study treatment until either their disease got worse, or they had to stop treatment due to unacceptable side effects, or they chose to leave the trial.
Almost 60% of people received Isa-Kd and the rest received Kd.
Here is how each treatment was given:
- Isatuximab (Isa): Given as an injection into a vein (also called an infusion). It was given on the 1st day of each week for 4 weeks, then after that on the 1st day of every other week. In cycle 1, it was given 4 times. In subsequent cycles, it was given 2 times.
- Carfilzomib (K): Given as an infusion. It was given on the 1st and 2nd day of each week for 3 weeks. It was given 6 times in cycle 1 and 8 times in subsequent cycles.
- Dexamethasone (d): Given as a tablet to be swallowed. It was taken on the 1st and 2nd day of each week. It was taken 8 times in each 4-week cycle.
What Were the Main Results?
Overall survival was a key secondary endpoint in this study, meaning it was not the main result. When the researchers planned the study, they did not expect that the study would have enough participants to see a difference in overall survival between the Isa-Kd and Kd treatments.
Researchers measured the median time to death and the 2-year survival probability. Both of these were ways to see if Isa-Kd resulted in a benefit to survival compared with Kd.
- Median time to death was the length of time from the date when people entered the study until only half of them were still alive. More than half of the people in the Isa-Kd group were still alive at the time of this analysis. Because of this, a computer program predicted how long it would take to reach the median time to death in the Isa-Kd group.
- The 2-year survival probability was the probability that a patient was still alive at 2 years after starting the study.
After 4.5 years (or 56.6 months):
- Median time to death: In the Isa-Kd group, this was "not reached," meaning that more than half of patients were alive at 56.6 months. In the Kd group, 50% of patients remained alive longer than 50.6 months.
- Computer-predicted median time to death: The computer predicted that 50% of patients who received Isa-Kd would still be alive 63 months longer than when the data were analyzed. This value was not calculated for the Kd group because the median had already been reached.
- Probability of being alive at 2 years: 60% in the Isa-Kd group and 52% in the Kd group.
The computer-predicted median time to death for Isa-Kd (63 months) and the median time to death for Kd (50.6 months) were not statistically significantly different. This means that the researchers could not rule out that the difference between the Isa-Kd and Kd groups was due to chance.
It is important to understand the difference between "statistically significant" and "clinically meaningful." A treatment that shows a statistically significant difference has an effect that is considered unlikely to be due to chance. A treatment that has a clinically meaningful effect has an impact on well-being or survival that is noticeable and appreciated.
Median second progression-free survival (PFS2)
The researchers also measured how long people lived before their cancer got worse, once they stopped taking the IKEMA study treatments and started taking a new multiple myeloma treatment. This was a way to assess the benefit of Isa-Kd compared with Kd in helping to keep the multiple myeloma from getting worse after people started their next treatment.
Patients in the Isa-Kd group went 47.2 months without progressing in their next treatment of the disease. Patients in the Kd group went 32.4 months without progressing. This means that even when people took their next treatment after the IKEMA study, people in the Isa-Kd group lived longer without progressing or dying. People in the Isa-Kd group lived longer without progressing or dying than those in the Kd group.
What Were the Most Common Adverse Events?
Researchers monitored adverse events in all participants to see if any differences were seen between Isa-Kd and Kd treatments. An adverse event is a side effect of the medicine or other illness that occurs while taking the study medicines. Adverse events may or may not be caused by the study medicines.
The researchers looked at all adverse events reported in the study, whether or not they were related to the treatments that people had during the study.
The median time that people took their study treatment was longer in people treated with Isa-Kd than those treated with Kd. The median time taking study treatment was 94.0 weeks in the Isa-Kd group and 61.9 weeks in the Kd group.
The percentage of people who had adverse events was similar in both the Isa-Kd and Kd groups:
- Had an adverse event during treatment: 99% in the Isa-Kd group and 98% in the Kd group.
- Had to take a lower dose of their medicines because of an adverse event: 81% in the Isa-Kd group and 80% in the Kd group.
- Had to stop taking their medicines because of an adverse event: 14% in the Isa-Kd group and 18% in the Kd group.
- Died due to an adverse event during the treatment period: 7% in the Isa-Kd group and 5% in the Kd group.
The most common adverse events were infusion-related reactions, upper respiratory tract infection, diarrhea, and hypertension. Most adverse events were mild or moderate in severity.
Infusion-related reactions occurred in 46% of people in the Isa-Kd group and 3% in the Kd group. All occurrences except one were mild or moderate in severity.
Here is a breakdown of the most common adverse events:
- Any event: 99% in the Isa-Kd group and 98% in the Kd group.
- Infusion-related reaction: 46% in the Isa-Kd group and 3% in the Kd group.
- Upper respiratory tract infection: 40% in the Isa-Kd group and 28% in the Kd group.
- Diarrhea: 40% in the Isa-Kd group and 32% in the Kd group.
- Hypertension: 39% in the Isa-Kd group and 35% in the Kd group.
An infusion-related reaction is a reaction that may occur when isatuximab is administered intravenously. This might look like an allergic reaction. An upper respiratory tract infection is an infection in your upper airway. This might look like a cough with no symptoms of pneumonia. Hypertension is high blood pressure.
Adverse events are divided into different grades, with increasing grades being more severe. They range from 1, which is a mild adverse event, to 5, which is an adverse event that results in a patient's death.
- Grade 1 (mild): Side effects include those in which a participant has awareness of symptoms that are easily tolerated, causing minimal discomfort and not interfering with everyday activities.
- Grade 2 (moderate): Side effects include those where sufficient discomfort is present to cause interference with normal activity.
- Grade 3 (severe but not life-threatening): Side effects include those that cause extreme distress and significantly disrupt normal everyday activities.
- Grade 4 (life-threatening): Side effects can be disabling and have life-threatening consequences.
- Grade 5 (death): Death is related to the side effect.
Here is how adverse events were graded in each group:
- Mild to moderate (grade 1-2): 95% in the Isa-Kd group and 95% in the Kd group.
- Severe (grade 3): 80% in the Isa-Kd group and 68% in the Kd group.
- Life threatening (grade 4): 15% in the Isa-Kd group and 16% in the Kd group.
- Death (grade 5): 7% in the Isa-Kd group and 5% in the Kd group.
The most common adverse events that were severe or worse were hypertension and pneumonia. Their incidence was similar in both groups.
Twelve people in the Isa-Kd group and 6 people in the Kd group died because of an adverse event. Only 2 of these deaths were due to multiple myeloma getting worse, 1 in each treatment group.
Some people developed another cancer in addition to the multiple myeloma. This is known as a secondary primary malignancy. This is not due to the multiple myeloma treatment but is a new cancer that occurs in a person who has had cancer in the past.
Skin cancers happened in 13 (7%) people receiving Isa-Kd and 4 (3%) people receiving Kd. The incidence of secondary primary malignancies except skin was similar in both treatment groups. Two patients in each treatment group died because of a secondary primary malignancy.
Conclusions and Key Messages
In this study, people with relapsed and refractory multiple myeloma who received Isa-Kd continued to benefit from therapy after more than 4 years of monitoring.
- The median time to death was 50.6 months in the Kd group but was not reached in the Isa-Kd group. A computer program was run to predict the median time to death in the Isa-Kd group with an additional 12 months of monitoring. Treatment with Isa-Kd was predicted to increase how long people lived by nearly 13 months compared with the standard treatment at the time of the study. However, this finding was not statistically significant.
- When people took their next treatment after the IKEMA study, those who received Isa-Kd lived longer without the disease progressing or dying than those in the Kd group.
- Most of the adverse events were considered either mild or moderate (95% with Isa-Kd), meaning that they were easily treated or did not last long. The adverse events were as expected. There were no new adverse events in this study that the doctors did not already know about from earlier studies.
- Adding isatuximab to the Kd combination did not increase how many people stopped treatment during the study. This was true even though people who received Isa-Kd were on treatment for 1.5 times longer than people who received Kd.
The findings of this study provide evidence to support doctors using Isa-Kd in people with relapsed and/or refractory multiple myeloma.
Limitations of the Study
The study had several important limitations that patients should understand.
First, the overall survival difference between Isa-Kd and Kd was not statistically significant. This means the researchers could not rule out that the difference was due to chance. When the researchers planned the study, they did not expect the study to have enough participants to detect a difference in overall survival.
Second, more than half of the people in the Isa-Kd group were still alive at the time of the analysis. Because of this, the median time to death for Isa-Kd was not reached. The researchers used a computer program to predict what the median time to death would be with an additional 12 months of monitoring. This prediction is an estimate, not a direct measurement.
Third, the study was open-label, meaning that people knew which treatment they were given. This can sometimes influence how people report their symptoms and side effects.
Fourth, the study included a specific group of patients. These patients were at least 18 years old, had relapsed and/or refractory multiple myeloma, and had received between 1 and 3 prior treatment combinations. The results may not apply to patients with different characteristics.
What This Means for Patients
If you or a loved one has relapsed and/or refractory multiple myeloma, this study provides important information to discuss with your healthcare team.
- Ask about Isa-Kd as a treatment option. The study showed that adding isatuximab to carfilzomib and dexamethasone helped people live longer without their cancer getting worse, both during the study and after starting their next treatment.
- Understand the survival results. People who received Isa-Kd were predicted to live about 13 months longer than those who received Kd. However, this difference was not statistically significant, meaning it could have been due to chance.
- Discuss side effects. The most common side effects were infusion-related reactions, upper respiratory tract infections, diarrhea, and high blood pressure. Most side effects were mild or moderate. Infusion-related reactions were more common with Isa-Kd (46% versus 3%), so ask your healthcare team how these are managed.
- Know that Isa-Kd did not increase treatment discontinuation. People who received Isa-Kd were on treatment for 1.5 times longer. Even so, the percentage of people who stopped treatment due to side effects was similar between the two groups. This percentage was 14% with Isa-Kd versus 18% with Kd.
- Check approval in your country. Isatuximab is approved to treat the condition discussed in this summary, but approval varies by country. Please check with your local healthcare provider for more details.
Remember that every patient is different. The choice of treatment for relapsed and/or refractory multiple myeloma depends on many factors. These factors include your age, the stage of your disease, your cytogenetic risk, and what treatments you have received before. Talk with your healthcare team about whether Isa-Kd is right for you.
Frequently Asked Questions
Who was eligible to take part in the IKEMA study?
The IKEMA study included 302 people aged 18 or older with relapsed and/or refractory multiple myeloma. They had received between 1 and 3 prior treatment combinations. Most were in their 60s, had Stage 1 disease, and standard cytogenetic risk. People with different characteristics may not have the same results, so ask your healthcare team whether the findings apply to you.
What does it mean that the median time to death was 'not reached' in the Isa-Kd group?
It means that at the time of the analysis, more than half of the people who received Isa-Kd were still alive. Because the midpoint had not been reached, researchers used a computer prediction to estimate it. In the Kd group, half of the people lived longer than 50.6 months. The difference between groups was not statistically significant.
What were the most common side effects of Isa-Kd?
The most common side effects were infusion-related reactions, upper respiratory tract infections, diarrhea, and high blood pressure. Infusion-related reactions occurred in 46% of people receiving Isa-Kd versus 3% receiving Kd, and nearly all were mild or moderate. Overall, 95% of side effects in the Isa-Kd group were mild or moderate. No new safety concerns appeared.
Did adding isatuximab increase how many people stopped treatment because of side effects?
No. In the IKEMA study, 14% of people receiving Isa-Kd stopped treatment because of side effects, compared with 18% receiving Kd. This was similar even though people on Isa-Kd stayed on treatment about 1.5 times longer. The median time on treatment was 94.0 weeks for Isa-Kd and 61.9 weeks for Kd.
What does 'not statistically significant' mean for the survival difference?
It means researchers could not rule out that the difference in survival between Isa-Kd and Kd was due to chance. A computer predicted Isa-Kd could extend life by nearly 13 months compared with Kd, but this finding was not statistically significant. The study was not designed with enough participants to detect a survival difference.
How long did people live before their cancer got worse after starting their next treatment?
In the IKEMA study, people who received Isa-Kd lived 47.2 months before their cancer got worse after starting their next treatment, compared with 32.4 months for those who received Kd. This measure is called second progression-free survival. It suggests Isa-Kd helped keep the disease from getting worse even after the study treatments ended.
What should I discuss with my healthcare team about Isa-Kd?
Ask whether Isa-Kd is a suitable option for you. Discuss the survival results, including that the difference was not statistically significant, and the side effects, especially infusion-related reactions. Also check whether isatuximab is approved in your country. Treatment choice depends on your age, disease stage, cytogenetic risk, and previous treatments, so every patient is different.
When should a patient with relapsed or refractory multiple myeloma seek a second opinion about treatment with Isa-Kd?
A second opinion can help when weighing Isa-Kd against carfilzomib and dexamethasone alone. In the IKEMA study, the median time to death was 50.6 months with Kd and was not reached with Isa-Kd; a computer prediction estimated nearly 13 months longer survival, but this difference was not statistically significant, so chance could not be ruled out. Second progression-free survival was 47.2 versus 32.4 months. Because treatment choice depends on age, disease stage, cytogenetic risk, and prior treatments, an independent review can clarify whether Isa-Kd fits your situation. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Plain language summary of publication of how long people with relapsed multiple myeloma lived after treatment in the IKEMA study: Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone.
Authors: Yong K, Martin T, Dimopoulos MA, Mikhael J, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Moreau P.
Publication: The Lancet Haematology. 2024;11(10):e741-e750.
DOI: 10.1016/S2352-3026(24)00148-0
Clinical trial information: More information about this study can be found at https://clinicaltrials.gov/study/NCT03275285
Sponsor: This study was sponsored by Sanofi. A sponsor is a company or organization that oversees and pays for a clinical research study. The sponsor also collects and analyzes the information that was generated during the study.
Note: This patient-friendly article is based on peer-reviewed research. The original article can be accessed for a fee at the link provided above.
