CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit
Released: May 16, 2024
Expiration: May 15, 2025
Multiple Myeloma: Overview
MM is characterized by an over proliferation of abnormal plasma cells.1 As a reminder, normal B-cells turn into plasma cells that produce antibodies, or immunoglobulins (Ig), in response to infection. With MM, abnormal clonal plasma cells secrete excessive amounts of a single immunoglobulin, which is referred to as a monoclonal or M protein. Any class of immunoglobulins can be secreted in myeloma, but are made up of 1 heavy chain, usually IgG, IgA, or IgM, and 1 light chain, either kappa or lambda. IgMs are typically seen with Waldenströms macroglobulinemia, but occasionally there are cases of an IgM myeloma. Less commonly, FLC myeloma or “Bence-Jones myeloma” occurs when abnormal amounts of kappa or lambda light chains with no heavy chains are secreted by the abnormal plasma cells.
Annually, there are just under 36,000 new cases of MM and approximately 12,540 deaths due to myeloma.2 The median age at diagnosis is approximately 69 years, but can vary. Unfortunately, we do see myeloma in much younger patients. The good news is the 5-year survival rate has improved over the last 20 years, and if we look at data from 2014 through 2020 it is approximately 61.1%.
IMWG Criteria for Diagnosis of MM
The International Myeloma Working Group (IMWG) has established set criteria for the diagnosis of MM.3 There are 3 levels of the myeloma disease trajectory. The first is monoclonal gammopathy of undetermined significance, or MGUS. At this stage, monoclonal protein is present at low levels (<3 g/dL) and there is <10% clonal plasma cells in the bone marrow. At this stage, there are no myeloma-defining events or CRAB criteria, which we will discuss in more detail. Of patients with MGUS, approximately 1% a year will develop myeloma. We know that all patients with myeloma started with MGUS, whether we identified it when they were in that phase or not. The second stage is smoldering myeloma. Patients with smoldering myeloma have more disease than those with MGUS but are asymptomatic with no myeloma-defining events. Patients with asymptomatic myeloma have more protein in their urine and more clonal plasma cells in their bone marrow, but it is not causing any organ damage. We monitor patients with MGUS or smoldering myeloma, but they do not receive treatment. Some experts recommend considering therapy with lenalidomide or lenalidomide/dexamethasone for patients with high-risk, smoldering myeloma, but often these patients should be referred for clinical trial. For most patients, we begin treatment once their myeloma is active and/or they have symptoms causing end-organ damage.
Active myeloma is characterized by an underlying plasma cell proliferative disorder and 1 or more SLiM-CRAB feature. We have followed the CRAB criteria for diagnosing myeloma for years, looking at patients who have had a serum calcium elevation, renal insufficiency, anemia, or bone disease. Eventually this was updated to SLiM-CRAB criteria, which considers the burden of disease in the bone marrow as well as the above-mentioned CRAB criteria. The SLiM criteria for diagnosis includes ≥60% clonal plasma cells in the marrow, a serum FLC ratio ≥100 involved kappa or ≤0.01 involved lambda, or >1 focal lesion on MRI greater than 5 mm in size.
Although skeletal survey was standard of care for many years, approximately 30% of bone loss in a lesion is needed before it is detected on an x-ray, so the patient’s disease could progress dramatically before this is seen. As such, the field has moved towards using whole-body CT, whole-body MRI, or PET CT for detecting focal lesions, but this is institution dependent. At Emory, we use PET CT to detect bone lesions.
Defining High Risk
In clinical practice, we differentiate myeloma as being standard risk or high risk as these classifications are used to guide treatment decisions. Risk is determined based on clinical factors, laboratory factors, and cytogenetic abnormalities. High-risk MM is characterized by cytogenetic abnormalities such as t(4;14), t(14;16), t(14;20), del(17p), and gain or amplification of 1q.4,5 Of note, del(17p) can be present at diagnosis or be acquired during the course of the disease. For laboratory tests, high-risk disease commonly has low albumin, a high ß2 microglobulin, and increased LDH at diagnosis.
Clinical features associated with high-risk disease are plasma cell leukemia and extramedullary involvement. Plasma cell leukemia is an aggressive form of myeloma where myeloma cells circulate in the peripheral blood. With extramedullary involvement, myeloma cells escape the bone marrow and form tumors in other parts of the body. Extramedullary involvement is typically detected on imaging.
In some cases, myeloma may be defined as being functional high risk.6,7 With functional high-risk myeloma there is rapid disease progression within 18 months from diagnosis. Functional high-risk myeloma cannot be identified with our standard risk and staging criteria. Even with our best technology and criteria for what high-risk disease looks like, sometimes we have a patient who may not have any of the aforementioned cytogenetic abnormalities or laboratory and clinical features for high-risk disease who has rapid disease progression with initial treatment. These patients are hard to manage and typically have a poor prognosis.
ISS Staging Systems
The International Staging System (ISS) is used for myeloma disease staging and risk stratification, and it has undergone 2 revisions.4,8 Originally, the ISS used serum albumin and ß2 microglobulin to stage disease as I, II, or III with higher stages having increased risk and more advanced disease. In clinical practice, providers were incorporating the chromosomal abnormalities we discussed for risk assessment in conjunction with ISS stage to make treatment decisions. Subsequently, the ISS was revised to reflect what we were doing in clinical practice. More recently, there has been a second revision to the ISS system that is being utilized for NDMM. The R2-ISS defines myeloma as being low-, low-intermediate, intermediate-high, and high-risk based on a scoring system that considers cytogenetic abnormalities, serum LDH, and ISS stage and the influence these factors have on overall survival (OS).8,9
Revised ISS Staging System and Overall Survival
Here we see the relationship between revised ISS stage and OS. Patients with stage III disease have a shorter OS when compared with those with standard-risk disease.4 I will add that with the newer therapies and the depth of response that we are now able to achieve starting at induction, even patients with high-risk disease are living longer.
Proposed Treatment Algorithm for Newly Diagnosed Multiple Myeloma
When a patient with NDMM comes to us, the first steps are to determine whether they are a candidate for transplant and if they have standard-risk or high-risk disease.
For transplant-eligible patients with standard-risk disease, our treatment approach has traditionally included induction with VRd (bortezomib/lenalidomide/dexamethasone) or KRd (carfilzomib/lenalidomide/dexamethasone).8 As a note, carfilzomib and bortezomib are proteasome inhibitors (PIs), lenalidomide is an immunomodulatory drug (IMiD), and dexamethasone is a corticosteroid. At our center, we have been utilizing a quadruple-drug induction regimen for years, adding an anti-CD38 antibody (eg, daratumumab or isatuximab) to the VRd or KRd regimens. We will go through the clinical trial data supporting this later in this module. After induction therapy, stem cells are collected, and patients go on to transplant followed by single-agent lenalidomide maintenance. For patients who are transplant-eligible with high-risk disease, we would also treat with a daratumumab-based quadruplet therapy (eg, Dara-VRd or daratumumab plus bortezomib/thialidomide/dexamethasone) followed by maintenance with lenalidomide with or without a PI. For most patients with myeloma, treatment is continuous and typically there are no breaks in treatment.
Patients who are ineligible for transplant also benefit from a multidrug regimen; we will discuss that in detail later.
Selecting Treatment for MM: General Principles
One important factor for treatment decisions is that they are not solely based on age but also on frailty.8,10 You can have a younger patient with aggressive disease and multiple comorbidities, and you would treat them differently than a patient older than 65 who is in good shape with very few comorbidities. Of course, we also consider disease factors such as burden and stage, and the biology of disease including the cytogenetic abnormalities we discussed earlier, which help to determine standard- vs high-risk disease.
For patients with specific comorbidities, toxicities with each treatment should also be a consideration. Myelosuppression, infections, and neuropathy can occur with myeloma treatments. If a patient is diabetic and has neuropathy, we will need to manage their diabetes closely. With myeloma treatments, there is also a risk of secondary cancers, especially in the maintenance setting.
As we think about selecting treatment for myeloma, we also need to keep individual patient characteristics, including lifestyle and preferences, in mind. Many of our patients are still working, some might have small children, and that may influence their treatment decision. It is important to consider what, if any, social support the patient has as well as treatment-associated costs and how far the patient will need to travel to infusion centers. Some patients must drive hours for treatment, and partnering with a local oncologist can help to ease this burden.
GRIFFIN: VRd ± Dara in Patients With NDMM Eligible for ASCT
Let’s now look at a few of the clinical trials that influence our current guideline recommendations for treating NDMM.
Myeloma is a disease that continues to progress. Patients have periods of response during and after treatment, but then experience relapse or progression. Historically, we were hesitant to give treatments that we may need for later lines of therapy in the first line. More recent clinical trials have shown us that depth of response upfront is critical for survival. We now have a better understanding of the depth of response because we have new testing methods that can measure MRD in the bone marrow to the levels 10-5 or 10-6 myeloma cells.
GRIFFIN was a multicenter open-label, randomized phase II trial.11 This trial looked at whether the response rates and the duration of response with VRd, which was the standard of care at the time, could be improved upon with the addition of daratumumab.
GRIFFIN enrolled 207 transplant-eligible patients with NDMM. The patients received daratumumab plus VRd (Dara-VRd) or VRd induction and then went on to receive an ASCT followed by 2 cycles of consolidation with either Dara-VRd or VRd, followed by maintenance therapy. Patients in the VRd arm received single-agent lenalidomide maintenance at 10 or 15 mg, and patients in the Dara-VRd arm received daratumumab plus lenalidomide for maintenance.
The primary endpoint in the GRIFFIN trial was sCR, and key secondary endpoints included rates of MRD negativity, overall response rate (ORR), very good partial response (VGPR) or better, complete response (CR), PFS, and OS.
GRIFFIN: Response Rates
Patients in the Dara-VRd group had deeper responses than those in the VRd group, with 83% vs 60% achieving a CR or better.11 The take-home message is that adding a CD38 monoclonal antibody as a fourth drug made a good regimen even better.
At Emory, we made changes in treatment based on the GRIFFIN data and we began adding daratumumab to VRd regimen.
GRIFFIN: Progression-Free Survival and Overall Survival
Here we see the final PFS and OS from GRIFFIN. Patients receiving Dara-VRd had improved PFS over those receiving VRd with a 4-year survival of 87.2% vs 70.0%. The OS was similar between the 2 arms of the trial.
GRIFFIN: MRD-Negativity Rates Over Time
In GRIFFIN, MRD negativity measured to the 10-5 or 10-6 threshold with NGS increased over time, but the difference was more pronounced in the Dara-VRd arm. At the end of the study, the 10-5 MRD negativity rate was 64% with Dara-VRd compared to 30% with VRd.
PERSEUS: Primary Analysis of Phase III Trial With VRd ± Daratumumab in Patients With NDMM Eligible for ASCT
At ASH 2023 we saw the results of the PERSEUS trial. This multicenter, open-label, phase III trial also compared Dara-VRd to VRd in a transplant-eligible population. In PERSEUS, 709 patients received upfront VRd ± daratumumab, and then went on to transplant.12,13 After transplant, they completed 2 cycles of consolidation with Dara-VRd or VRd. Patients in the VRd arm received single-agent lenalidomide maintenance like in the GRIFFIN trial. Patients in the Dara-VRd arm received daratumumab with lenalidomide as maintenance. After 24 months, if they were MRD negative, they continued single-agent lenalidomide maintenance. If they were MRD positive, then they continued with daratumumab plus lenalidomide maintenance. This MRD-adapted maintenance strategy is different than what we saw in the GRIFFIN trial.
The primary endpoint in PERSEUS was PFS, and key secondary endpoints were MRD negativity, OS, and responses of CR or better.
PERSEUS: Baseline Characteristics
So these are baseline characteristics of the patients on the PERSEUS trial.12,13 The median age was approximately 60 years old, and this trial enrolled more male patients (approximately 58%) and more White patients (93%), which is an issue on clinical trials. Most patients had a performance status of 0 or 1. The majority of patients had ISS stage I or II disease but a small fraction (15.5%) had high-risk stage III disease.
PERSEUS Primary Analysis: PFS (Primary Endpoint)
Looking at the PFS curves, you can see that patients in the Dara-VRd arm are doing better than those in the VRd arm.12,13 The 4-year PFS rate was 84.3% vs 67.7%, respectively (HR: 0.42; 95% CI: 0.30-0.59; P <.0001).
PERSEUS Primary Analysis: PFS Subgroup Analysis
Looking at the PFS by subgroups, we see that benefit with Dara-VRd was consistent across subgroups including cytogenetics risk, disease stage, and performance status.12,13
PERSEUS Primary Analysis: Safety
The safety profile observed in PERSEUS is as you would expect for a 4-drug regimen, and it was notably characterized by hematologic toxicities.12,13 These regimens are noted for their myelosuppression, and in this trial, we saw neutropenia (69%), thrombocytopenia (48%), and anemia (22%) in the Dara-VRd. There were also some gastrointestinal AEs (ie, diarrhea and constipation) and peripheral sensory neuropathy, which we would expect to see. Any grade infusion-related reactions occurred in approximately 6% of patients in the Dara-VRd arm, but only 0.9% of patients experienced grade 3 or 4 infusion-related reactions. Secondary malignancies occurred in approximately 10.5% (n = 37) of patients in the Dara-VRd arm vs 7.2% (n = 25) in the VRd arm.
Based on the results from the PERSEUS trial, Dara-VRd is now considered a new standard of care for transplant-eligible NDMM.
Dara-VRd vs VRd: Retrospective Analysis of Efficacy of Dara-VRd vs VRd in Transplant-Eligible NDMM
We also saw data from a real-world analysis led by investigators at Emory, at ASH 2023. This retrospective analysis compared outcomes for 1326 transplant-eligible patients with NDMM who received Dara-VRd or VRd induction therapy.14 Patients included in this analysis did not receive consolidation after transplant, and maintenance therapy was risk stratified. Patients with standard-risk disease received lenalidomide maintenance until disease progression; patients with high-risk disease received a PI and IMiD as maintenance for 3 years or until disease progression.
The primary endpoint was the rate of CR or better, and the secondary endpoints were PFS, OS, VGPR or better, and rate of MRD negativity.
Dara-VRd vs VRd: Response Rates Over Time
These are the responses over time. Response rates improved from postinduction to the posttransplant phase regardless of treatment arm.14 The rate of CR or better for Dara-VRd was 21.5% post induction and 42.8% post transplant; for VRd it was 35.9% post induction and 67.5% post transplant. MRD assessment in this trial is ongoing.
Dara-VRd vs VRd: Progression-Free and Overall Survival
At the time of this report, the median PFS with Dara-VRd was not reached and the median PFS with VRd was 67.5 months.14 Similarly, the median OS was not reached in the Dara-VRd arm and was 129 months in the VRd arm. At this point, the 1-year PFS was 98% vs 93% and 2-year PFS was 93% vs 82%. So you can see that difference in PFS is improving over time.
IsKia EMN24: Phase III Trial of IsaKRd vs KRd in Transplant-Eligible Patients With NDMM
KRd (carfilzomib, lenalidomide, and dexamethasone) is another approved upfront induction regimen for transplant-eligible NDMM. The open-label, randomized phase III IsKia EMN24 trial asks the same question as GRIFFIN and PERSEUS: can we make an approved regimen better by adding another agent? In this trial, isatuximab, which is also an anti-CD38 monoclonal antibody, was added to KRd.
IsKia EMN24 enrolled 302 transplant-eligible patients aged 70 years or younger with NDMM.15 Patients received induction therapy with isatuximab plus KRd (IsaKRd) or KRd followed by mobilization using cyclophosphamide for stem cell collection. After mobilization, patients underwent ASCT, and then posttransplant consolidation with IsaKRd or KRd. After 4 cycles of standard consolidation, patients received a light consolidation with lower doses of lenalidomide and dexamethasone. MRD measurements were taken throughout this trial—after induction, after transplant, after consolidation, and ongoing after a light consolidation.
The primary endpoint in IsKia EMN24 was MRD negativity after posttransplant consolidation, and secondary endpoints were MRD negativity after induction, PFS, and sustained MRD negativity.
IsKia EMN24: Baseline Characteristics
The arms in this trial were well balanced with similar median age (approximately 60 years old) and cytogenetic risk.15 In both arms, there was more standard-risk (approximately 82%) vs high-risk (approximately 19%) disease by cytogenetic risk per IMWG. There was also more stage I and II disease than stage III disease when using the revised ISS.
IsKia EMN24: Postconsolidation MRD Negativity (ITT) and Response
When comparing IsaKRd to KRd, MRD negativity rates were higher after each treatment phase.15 Here, we see the increased postconsolidation MRD negativity measured by NGS in the arm that had isatuximab added to KRd—77% vs 67% at 10-5 cutoff (P = .049) and 67% vs 48% at the 10-6 cutoff (P <.001). MRD negativity improved with the addition of isatuximab in all subgroups including high-risk and very high-risk disease.
IsKia EMN24: Safety
With regard to safety, we see the toxicities you would expect, including hematologic toxicities such as anemia, neutropenia, and thrombocytopenia.15 The rate of grade 3/4 neutropenia was higher with IsaKRd vs KRd (36% vs 22%, P = .008). The most common nonhematologic toxicity was infection, which we expect with patients when blood counts are dropping.
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