What is the threshold for achieving minimal residual disease (MRD) negativity after treatment?
MRD measurement aims to detect any myeloma cells that remain in the body after a complete response is achieved following treatment. MRD tests can detect at least 1 myeloma cell in 100,000 healthy bone marrow cells (a threshold of 1 × 10-5) and other tests can detect 1 cell in a million (a threshold of 1 × 10-6). As an example, when you collect 100,000 bone marrow cells and you don’t find any myeloma cells with testing, you are considered MRD negative (this is a threshold of 10-5) and similarly if you don’t find any myeloma cells within one million bone marrow cells (this is a threshold of 10-6). Currently, a threshold of 10-5 is used to define MRD negativity in clinical studies and the FDA drug development process. Deeper thresholds like 10-6 are being used and reported in clinical studies, but in practice it might be difficult to get the one million bone marrow cells needed to test at this threshold.
Sometimes patients may receive a result that is difficult to tell whether they are MRD positive or not. These results are considered below the level of detection and even though the result may not be zero, it is still a very good result. Regardless of your MRD status, it is always best to discuss your MRD test results and what they mean with your doctor.
Are MRD results being used to guide treatment decisions?
MRD testing is far from an experimental test. Testing has been well-validated based on extensive data from clinical studies. However, basing treatment decisions on MRD test results is not routinely done, especially outside of the academic medical center setting. For example, it is unclear whether patients who are MRD positive should get more treatment, whether patients who go from MRD negative to MRD positive should get treatment before development of clinical symptoms, and whether patients who are MRD negative no longer need maintenance therapy. Several clinical studies are ongoing to determine how MRD results might be used to guide treatment in the future. However, MRD testing results do provide some level of information for the patient and the doctor about the trajectory of the disease. What this means is that MRD test results help to inform doctors if and how the number of myeloma cells has changed since a patient’s last MRD test (that is, did the number of cells go up, go down, or remain the same?). This information will help patients and their doctors understand how the amount of myeloma in a patient’s body may be changing over time. Be sure to ask your doctor to put your MRD test results, over time, into context for you and where you are in your myeloma journey.
Is MRD testing covered by insurance?
MRD measured by flow cytometry is usually covered by insurance because it is typically part of bone marrow biopsy testing. MRD measured by next-generation sequencing (that is, the ClonoSEQ assay developed by Adaptive Biotechnologies) is FDA-approved and is widely covered for patients on Medicare. Medicare covers clonoSEQ at 100% for multiple myeloma, and 90% of all patients pay $0 out of pocket. Patients will only receive a bill for unmet deductibles or coinsurance after the test is covered by insurance. Call the Adaptive Patient Support team at 1-855-236-9230 or visit Adaptive-Assist.com for 5-minute enrollment and rapid verification.
How often should blood tests and PET scans be performed following a response to treatment?
Once patients have completed their induction therapy and a stem cell transplant (if they were eligible for one) and begin maintenance therapy, blood tests are usually performed once a month. After about a year of maintenance therapy, the frequency of testing goes down to once every three months. Patients who have high-risk myeloma (for example, those who have the chromosome 17 deletion or other high-risk features) will be checked more frequently.
PET scans are not performed routinely after a response to initial treatment. PET scans are performed only when there is a change in lab values (such as M protein values begin to rise). At this time a PET scan will be conducted to see if the rise in M protein represents a significant relapse (that is, new lytic lesions in the bones can be visualized).
How common is a partial response versus a complete response to treatment?
One of the most exciting things about myeloma therapy in 2023 is that, more than ever before, patients are achieving a very good partial response or better (a reduction of M protein in the blood by 90% or more) with treatment! The reason for these incredible responses is due to the availability of a variety of drugs that can be combined into three- and four-drug regimens. Ultimately, the type of response a patient achieves will depend on which regimen is given, but the use of these regimens can lead to a very good partial response and complete response in approximately 70% to 80% of patients. Furthermore, with the use of minimal residual disease (MRD) testing (that is, a test that can determine the number of multiple myeloma cells or DNA sequences still present in bone marrow after treatment), patients are reaching a deeper level of response called MRD negativity (no multiple myeloma cells or DNA sequences can be detected in the bone marrow). Patients who are MRD negative following treatment have been shown to live longer than those who remain MRD positive.
How can myeloma patients reduce the pain and stress of a bone marrow biopsy?
Undergoing the procedure of a bone marrow biopsy is one of the most stressful tests myeloma patients have to endure during their journey. The reason it is stressful is that the procedure, unfortunately, is associated with pain and anxiety. Many institutions have the means to reduce pain and anxiety in their patients, so if you are concerned, you need to have an upfront discussion with your care team in order to meet your needs. Luckily, there are many ways, both with and without medication, to prevent pain and anxiety during a bone marrow biopsy. Some examples are listed below.
To find the right solution for you that your institution offers, please discuss your options for pain control with your care team.
The 2023 American Society of Clinical Oncology (ASCO) annual meeting was held from June 2 to 6 in Chicago! Clinicians and researchers gathered to present and discuss several updates in multiple myeloma relating to:
Let us break down the key findings for you…
New data on both Carvykti and Abecma, which are FDA approved CAR T-cell therapies that target BCMA on myeloma cells, was reported.
Carvykti is approved for patients with multiple myeloma (MM) after at least four previous treatments. Given the success of CAR T-cell therapy in patients who have failed many different treatments and have relapsed/refractory MM (RRMM), there is an interest in testing CAR T-cell therapy for patients who have received fewer prior therapies.
In a late-breaking abstract presentation, Dr. Binod Dhakal and colleagues reported their findings from CARTITUDE-4, the first randomized phase 3 study evaluating the efficacy and safety of Carvykti in 419 patients with RRMM that no longer responded to treatment with Revlimid (ABSTRACT LBA106). Findings from CARTITUDE-4 were simultaneously published in the New England Journal of Medicine. The study compared Carvykti with standard of care treatments (Pomalyst, Velcade, and dexamethasone [PVd] or Darzalex, Pomalyst, and dexamethasone [DPd]) in Revlimid-refractory patients who received one to three prior lines of therapy, including a proteasome inhibitor and an IMiD. The results showed:
These findings demonstrate the dramatic benefit of Carvykti over the standard of care in 1 to 3 prior lines of therapy and highlight the potential for Carvykti to be a promising new treatment option for patients in this setting.
In a separate presentation, Dr. Yi Lin and colleagues from the Mayo Clinic reported final results from CARTITUDE-1, which was a phase 1/2 study of Carvykti in heavily pretreated patients with RRMM—in individuals who received 3 prior lines of therapy or were double refractory to a proteasome inhibitor (PI) such as Velcade, Kyprolis or NInlaro and immunomodulatory drug (IMiD) such as Revlimid or Pomalyst; and had received prior PI, IMiD, and anti-CD38 antibody therapy (ie, Darzalex or Sarclisa). (ABSTRACT 8009). A previous publication by Dr. Thomas Martin and researchers from the University of California, San Francisco reported an overall response rate (ORR) of 98%. These updated results, including analyses of high-risk patient subgroups, showed heavily pretreated patients with RRMM were able to live an average of 35 months before their myeloma progressed.
A longer median progression free survival (PFS)—that is, the length of time during and after treatment in which a patient is living with a disease that does not get worse—was observed after a single infusion of Carvykti than any previously reported therapy in heavily pretreated patients with RRMM. Patients continue to be followed for safety and survival in the CARTITUDE long-term study.
A pair of presentations highlighting recent findings on Abecma, the first CAR T-cell therapy approved for RRMM, were presented. Researchers presented patient-reported outcomes on health-related quality of life from the phase 3 KarMMa-3 trial (ABSTRACT 8032). Health-related quality of life captures information on the physical and mental health status of individuals, and on the impact of disease and treatment on a patient’s quality of life. The results from the patient-reported outcomes showed statistically significant and clinically meaningful improvements in health-related quality of life including cognitive functioning, fatigue, and pain reduction for patients with RRMM who received Abecma compared with standard treatment regimens.
Adam Sperling and colleagues from Dana-Farber Cancer Institute reported updated results from a phase 1 study of BCMA-targeting CAR T PHE885 (ABSTRACT 8004), which uses a new development process that shortens the manufacturing time from several weeks to less than two days. The results showed an ORR of 100% in patients who received the highest dosage of PHE885 and 98% in all 49 patients. CRS was observed in 96% of patients, which is a similar rate seen in patients receiving CAR T-cell therapy. Only 28% of patients required bridging chemotherapy. A phase 2 study is underway in patients with RRMM, and evaluation in earlier lines of therapy is about to begin.
Tecvayli was the first approved off-the-shelf BCMA-directed bispecific antibody for the treatment of patients with RRMM. The approval was based on data from the pivotal phase 1/2 MajesTEC-1 study, which showed an ORR of 63% in patients who received Tecvayli. In this presentation, Dr Niels van de Donk and colleagues from the Netherlands presented updated findings. Patients had a median of 5 prior treatments (92% Darzalex exposed; 78% triple-class refractory; 81% Darzalex-refractory).The results showed:
These long-term follow-up data support Tecvayli as a safe and effective off-the-shelf BCMA bispecific therapy for patients with RRMM.
Dr. Yael Cohen and researchers from Israel reported initial results from the phase 1 RedirecTT-1 trial that examined the combination of Tecvayli with talquetamab, an investigational bispecific antibody targeting GPRC5D, an immunotherapeutic target like BCMA on myeloma cells (ABSTRACT 8002). This trial is the first to test the combination of two bispecific antibodies with two different myeloma cell targets (that is, BCMA and GPRC5D) with the hope of overcoming resistance to single agent bispecific antibody therapy. The goals of this study were to evaluate safety and identify an optimal dosage of the combination of bispecific antibodies. The results showed:
Combining BCMA-targeted Tecvayli with GPRC5D-targeted talquetamab yielded high response rates in patients with RRMM and support the continued evaluation of this combination therapy.
Dr. Bhagirathbhai Dholaria and colleagues from Vanderbilt University Medical Center reported findings from the phase 2 TRiMM-2 study in patients with heavily pretreated RRMM who received investigational talquetamab in combination with Darzalex (ABSTRACT 8003). The study included some patients who were previously exposed to anti-CD38 (88%) inhibitors like Darzalex or Sarclisa, BCMA-targeted therapy (54%), and CAR-T therapy (17%). Patients in the TRiMM-2 study were treated with talquetamab at a dose of either 0.8 mg/kg every two weeks or 0.4 mg/kg weekly in addition to Darzalex. The ORR was 84% for patients who received the higher dose of talquetamab and 71% for those who were treated with the lower dose. Ongoing studies will continue to examine the clinical potential of this combination of therapy.
Dr. Carolina Schinke from University of Arkansas for Medical Sciences presented updated findings from the phase 1/2 MonumenTAL-1 study of talquetamab in patients with RRMM (ABSTRACT 8036). Patients were treated with talquetamab at the recommended phase 2 dose (RP2D) of 0.8 mg/kg biweekly or 0.4 mg/kg weekly with step-up doses. The results showed:
Elranatamab is an investigational off-the-shelf BCMA-directed bispecific antibody in the same class as Tecvayli, being evaluated as monotherapy in patients with RRMM. In this presentation, Dr. Mohamad Mohty and colleagues from France reported findings from the MagnetisMM-3 study that showed 61% patients who have not been exposed to a prior BCMA-directed therapy achieved a response to elranatamab monotherapy (ABSTRACT 8039). The most common side effects were CRS (66%) and low red blood cell counts (59%).
In a separate presentation, Dr. Ajay Nooka and colleagues from Emory University reported their findings from a pooled analysis of patients treated with prior BCMA-directed therapies enrolled in the MagnetisMM program (ABSTRACT 8008). The results showed:
These results support elranatamab monotherapy as a treatment option for patients with RRMM who have been pre-treated with another BCMA-targeting agent.
Linvoseltamab is another investigational BCMA-targeting bispecific antibody for patients with RRMM who previously received 3 or more prior treatments. Dr Hans Lee and researchers presented findings from the phase 2 LINKER-MM1 trial that tested 50 mg and 200mg dosages of linvoseltamab (ABSTRACT 8006). The results showed an overall response rate of 71% for patients who received the 200 mg dose and 50% for those who were treated with 50 mg of linvoseltamab. Cytokine release syndrome was the most common side effect observed in patients receiving either dosage. A phase 3 trial, LINKER-MM3, will be initiated in patients with RRMM.
In patients with newly diagnosed multiple myeloma (NDMM), triplet or quadruplet induction regimens, high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) remain a standard of care. Empliciti is approved in combination with other medications such as Revlimid or Pomalyst and dexamethasone for patients with RRMM, but its role in NDMM has not been studied. In this clinical trial (ABSTRACT 8000), Dr. Stefan Krop and researchers from Germany compared Empliciti plus Kyprolis, Revlimid, and dexamethasone (KRd) to KRd in transplant-eligible NDMM patients up to 70 years. The results showed the addition of Empliciti to KRd significantly improved the rate of early, deep minimal residual disease (MRD)-negative remission (50% Empliciti-KRd vs 35% KRd) in transplant-eligible NDMM. Future studies will explore the potential role of Empliciti in NDMM.
While maintenance or continuous therapy with Revlimid is the current standard of care for patients with standard-risk myeloma following induction therapy and ASCT, current data suggest those with high-risk myeloma should receive a proteasome inhibitor such as Velcade, either as a single agent or combined with Revlimid, or even a triplet like Velcade, Revlimid, and dexamethasone (VRd).
Dr. Ajay Nooka and colleagues from Emory reported their findings of a phase 2 trial that assessed KPd as maintenance therapy patients with high-risk myeloma (ABSTRACT 8001). More than half of patients (59%) enrolled in the single arm trial were Black. High-risk myeloma was defined by the presence of certain changes in a patient’s DNA such as translocation of (4;14) or (14;16), deletion of 17p, gain of 1q, or greater than 20% circulating tumor cells. Double-hit myeloma (as defined by the presence of 2 or more high-risk genetic mutations was seen in 59% of patients in this study. The results showed:
In patients with high-risk myeloma, KPd maintenance deepened responses and may be able to fill an unmet treatment need in this patient population. Be sure to hear what myeloma experts have to say about the meeting’s presentations here.
When is a clinical study the best option for a patient with high-risk smoldering multiple myeloma (SMM)?
A clinical study is the only option to gain access to treatment of high-risk SMM at this time. If you have a multiple myeloma precursor condition (monoclonal gammopathy of undetermined significance [MGUS] or SMM), the standard of care is watchful waiting—that is, monitoring you closely to determine if you progress to myeloma and treating you only when progression occurs. The reason patients with MGUS or SMM are not treated is that neither condition is associated with organ damage or any of the symptoms commonly associated with myeloma. Furthermore, no more than half of SMM patients progress to myeloma within the first 5 years after diagnosis, and the number is even smaller for patients with MGUS. Additionally, administering treatments (typically the same drugs used to treat myeloma) to patients who have precursor conditions that may or may not advance to multiple myeloma could lead to unwanted side effects while also yielding no benefit.
High-risk SMM may warrant treatment rather than watchful waiting and may yield the benefits of delaying the onset of active myeloma and increasing life expectancy. Treatment, if recommended at this stage, should take place only in the context of a clinical study.
It is also important to note that not every clinical study focuses on therapeutic intervention for precursor conditions. There are several observational studies and research studies for patients with MGUS or SMM that involves the collection of bone marrow and blood samples to help clinicians better characterize the conditions and to better predict which patients are at the highest risk of progression to myeloma. Additionally, non-pharmacologic interventional studies, such as diet and lifestyle modification, are also available to determine whether these types of interventions modify the diseases at all.
Search for a clinical trial in your area access the MMRF’s Clinical Trial Finder
(themmrf.org/diagnosis-and-treatment/clinical-trials-and-emerging-therapies/clinical-trial-finder/) or let an MMRF patient navigator help guide you through the process (1-888-841-6673 or [email protected]).
How can I join a clinical study if my doctor has not brought up the possibility of joining one?
As with any aspect of clinical care for a patient with multiple myeloma or one of its precursor conditions, open communication with the care team is important. You (and your caregivers) should always feel comfortable asking your doctors about alternative options for your care including whether or not a clinical study should be considered. All clinicians expect these questions and they want their patients to be happy with their care. You should not worry about your clinician’s feelings if you wish to seek care with a different doctor or to enroll on a clinical study.
Is there a negative impact on a patient’s relationship with their care team if he or she eventually withdraws from a clinical study due to life events or some other reason?
A withdrawal from a clinical study is never held against a patient! Of course, most clinicians would like patients to stay on a clinical study for the integrity of the data, but patients always have the right to discontinue participation for any reason. Patients will still receive quality care and respectful treatment and will in no way be punished for deciding not to participate. Clinicians understand that circumstances can change in a patient’s life that may make it difficult to continue participating.
What determines if patients with monoclonal gammopathy of undetermined significance (MGUS) will eventually advance to active multiple myeloma or something else like Waldenström’s macroglobulinemia and can anything be done to try and prevent this progression?
MGUS almost always occurs before a person develops myeloma or another malignant plasma cell disease (such as Waldenström’s macroglobulinemia or lymphoma). MGUS is associated with a risk of progression of approximately 1% per year. Therefore, the longer you have MGUS the higher the risk is that you will progress. For example, if a patient has had MGUS for 10 years there is a 10% risk and for 30 years the risk is 30%. Overall, the risk of progression is continuous and unfortunately, there are no data to definitively identify patients who have had MGUS for 10 to 15 years or longer that will never develop myeloma. The reason for this is that an MGUS cell clone might be stable during this time, but the longer one has this clone the more likely the clone will evolve to myeloma or another malignant plasma cell disease.
Immune regulation is thought to prevent the switch from MGUS to myeloma. Some data suggest that a patient’s immune system keeps the potentially malignant clone in check. For instance, MGUS that is diffuse (that is, spread out) in the bone marrow has a much lower risk of progression than clustered MGUS. Clustering excludes a patient’s immune cells from controlling the clone. Clusters of MGUS cells make it harder for the immune cells to get to the cells in the center of the cluster allowing the clone then to evolve and change and that is what we get into trouble with.
For now, doctors are unable to predict which MGUS patients will progress and as a result patients should be monitored continuously.
What does the hazard ratio mean when clinical trial data are reported?
The hazard ratio (HR) is a value calculated by statistical analysis that estimates survival endpoints such as overall survival or progression-free survival between two treatment groups over the entire duration of a randomized clinical trial (that is, a study that compares two different treatment groups: the experimental treatment versus the control treatment). The HR value (usually a number greater than or less than 1) indicates how much one treatment is better or worse than the other. For example, if the experimental treatment is better than the control treatment then the HR is less than 1 and if it is worse than the control treatment then the HR is greater than 1. A HR that is equal to 1 means equal efficacy between the two treatment groups.
What new data from myeloma precursor conditions should patients be aware of?
Several interventional trials are under way using newer immunotherapies in smoldering multiple myeloma patients who have the highest risk of developing myeloma within 1 to 2 years. The objective is to determine if immunotherapy has curative potential in these patients. Using immunotherapies earlier in the disease may be more beneficial than using them at relapse since a patient’s immune system is healthier at that stage. However, it is important to note that immunotherapy approaches come with a risk of infections. Infection risk for smoldering multiple myeloma patients may be quite significant considering they are asymptomatic to begin with. Also, it is not yet known whether targeting B-cell maturation antigen (BCMA) with a CAR T cell or bispecific antibody may wipe out the regulatory immune microenvironment that is necessary to control the malignant clone.
After receiving Tecvayli and achieving a complete response, how long should treatment continue and is risk of infection present as long as treatment continues?
Bispecific antibody therapy is administered to myeloma patients until their disease progresses or side effects of the treatment become intolerable. Prolonged treatment like this is similar to how most other myeloma treatments are administered with the exception of CAR T-cell therapy. Ongoing studies with bispecific antibody therapy are investigating different approaches to shortening the duration of administration. For example, some studies are investigating a fixed duration of treatment, that is, treatment is administered for a set period of time and then stopped. Other studies are investigating a guided therapy approach in which treatment is stopped only in patients who achieve a complete response and minimal residual disease (MRD) negativity and maintain that response for a period of time.
And, yes, the risk of infection continues for as long as a patient is on treatment.
What are the effects of missing doses of bispecific antibody treatment and infection risk?
Unlike traditional chemotherapy (for example, Cytoxan) where a patient’s white blood cell counts are immediately reduced and then bounce back to normal levels within weeks, the effects of bispecific antibody therapy on the immune system are long-lasting. As a result, patients may take longer to clear an infection (like COVID-19). Therefore, if a myeloma patient has an active infection, doctors will stop the administration of bispecific antibody therapy so as to not further diminish a patient’s ability to fight an infection. Some myeloma patients have been able to maintain their response to bispecific antibody therapy even after being off treatment.
Is risk of infection higher with bispecific antibody therapy than with CAR T-cell therapy?
Both CAR T-cell therapy and bispecific antibody therapy are associated with a high risk of infection. Infection may be easier to manage in a patient receiving CAR T-cells because they are administered as a fixed duration—it is a “one and done” infusion and a patient’s immune system can eventually recover within a year after infusion. With bispecific antibody therapy, the effect on the immune system lasts for the entire time a patient is on treatment—keeping them at risk of infection during that time.
What is a second primary malignancy (SPM) and what is a myeloma patient’s risk for developing one while on Revlimid maintenance therapy?
SPM is another cancer that occurs after the diagnosis of multiple myeloma. Myeloma patients may be at risk of developing a SPM with long-term use of Revlimid such as its use as maintenance therapy (which is a standard of care for newly diagnosed patients). A recent clinical study (called the Myeloma XI study) showed the impact of Revlimid (as induction and maintenance) on the development of SPM, since Revlimid was used in both transplant-eligible and -ineligible newly diagnosed patients. The results of the study showed that patients who received Revlimid as induction and maintenance (double-exposure) had a higher incidence of SPMs; this observation was more marked in transplant-ineligible patients. And although deaths due to SPMs were increased with Revlimid maintenance, deaths due to myeloma were lower. Therefore, patients should be carefully monitored while receiving Revlimid maintenance so that possible early intervention for SPMs can occur.
What is a frailty score for patients with myeloma and what does this score measure?
In addition to age, a variety of factors influence fitness and frailty in older patients with MM. For example, older MM patients can have multiple comorbidities and a range of activity levels that affect their response to, adherence to, and tolerance of MM treatment approaches. Therefore, treatment decisions for every patient should consider not only age but also clinical and functional status. Physicians use a frailty score assessment that is designed to help predict prognosis of patients with MM and help guide them on what therapy to offer. The link here (www.myelomafrailtyscorecalculator.net/) shows the different categories that are used to calculate a frailty score specific for myeloma patients. It evaluates comorbidities and how functional a patient is to determine how frail a patient is. It is important to note that frailty can improve or decline with time, so continuous assessment of patient fitness is important to providing the best possible care.
