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Medical Director, AMyC
Co-Chair Myeloma Committee, SWOG
Chairman, International Myeloma Foundation
Specialist in Multiple Myeloma and Related Disorders
Cedars-Sinai Outpatient Cancer Center
Los Angeles, California
Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda and fees from non-CME/CE services from Amgen.
Department of Hematology
Shaji Kumar, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Janssen, MedImmune, Oncopeptides, Takeda, and TeneoBio and consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Oncopeptides, and Takeda.
Clinical Professor of Medicine
Associate Director, Myeloma Program
University of California, San Francisco Medical Center
San Francisco, California
Thomas G. Martin, MD, has disclosed that he has received consulting fees from GlaxoSmithKline and funds for research support from Amgen, Janssen, and Sanofi.
Professor of Clinical Hematology
Head, Hematology Department
University Hospital Hôtel-Dieu
Philippe Moreau, MD, has disclosed that he has received consulting fees from AbbVie, Amgen, Celgene, Janssen, and Sanofi.
Edward W. and Betty Knight Scripps Professor of Medicine
S. Vincent Rajkumar, MD, has no relevant conflicts of interest to disclose.
Director of Clinical and Translational Medicine
Universidad de Navarra
Jesús F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Roche, Sanofi, and Takeda.
In this commentary, myeloma experts Brian G.M. Durie, MD; Shaji Kumar, MD; Thomas G. Martin, MD; Philippe Moreau, MD; S. Vincent Rajkumar, MD; and Jesús F. San-Miguel, MD, PhD, answer questions on the management of myeloma posed by the audience during a live CCO Webinar in December 2020.
Diagnosis and How to Manage Smoldering Multiple Myeloma (MM)
When using the International Myeloma Working Group (IMWG) 20/2/20 risk stratification model, how do you determine when to treat vs when to watch and wait patients with smoldering MM?
S. Vincent Rajkumar, MD: The threshold at which we need to intervene for patients with smoldering MM starts when they have > 50% risk of progression to active disease, which occurs when at least 2 of the 3 characteristics of the 20/2/20 model are present: free light chain (FLC) ratio of > 20, serum M-protein of > 2 g/dL, or > 20% bone marrow plasma cells. The IMWG risk stratification model is similar, but incorporates M-protein, FLC ratio, bone marrow plasma cells, and FISH abnormalities to assign a risk score from 0-17, with any score > 12 having a > 70% risk of progression and a score from 9-12 having approximately 50% risk of progression. Although no one can predict exactly who will and who will not progress, if we follow this rule, we will be more often right than wrong.
In those patients with > 50% risk of progression, the E3A06 and QuiRedex trials showed that even a mild therapy such as lenalidomide or lenalidomide plus dexamethasone will reduce the risk of end organ damage and delay disease progression. Therefore, in my clinical practice, I prefer treatment to watching and waiting for my patients with high-risk smoldering MM.
Jesús F. San-Miguel, MD, PhD: I agree. For those who feel uncomfortable starting treatment for high-risk smoldering MM, careful consideration and ongoing monitoring for any accumulation of risk factors is essential and therapy should be initiated immediately once a patient progresses to active disease or shows evolving biomarkers associated with active disease.
How should I proceed if a patient’s risk scores do not match when using multiple classification models?
S. Vincent Rajkumar, MD: If any method you use determines that the patient has a > 50% risk of progression, that is enough. You do not need agreement across each method; they complement each other. Use all available tools to ascertain if your patient is high risk for progression or not. Currently, the pendulum has swung such that it is imperative to be sure the patient is not high risk, rather than the other way around.
Brian G.M. Durie, MD: Absolutely. I agree.
Jesús F. San-Miguel, MD, PhD: I agree, and another point that I want to raise on the 20/2/20 risk stratification model and the IMWG scoring system is that you can also identify low-risk patients who will not need treatment. Therefore, I think this kind of risk classification has 2 advantages: simplicity and the ability to discriminate between the high-risk and the very low–risk patients.
How would you treat a patient with high-risk smoldering MM?
S. Vincent Rajkumar, MD: When selecting therapy, a clinical trial would be the best choice. Thankfully, we have many available trials for high-risk patients. At a minimum, I would recommend therapy with lenalidomide plus dexamethasone.
Brian G.M. Durie, MD: I agree. Particularly for a patient with an IMWG score > 12, enrollment on a clinical trial that does not contain a placebo arm, either a single-arm trial or a comparison between 2 levels of therapy, is ideal.
Shaji Kumar, MD: That is quite true. Most of the ongoing randomized clinical trials consist of an intervention in both arms, comparing MM therapy vs less intense therapy. For a patient with IMWG score > 12, I might choose a single-arm trial, where I already know what therapy the patient will receive, or standard treatment for active MM outside of a clinical trial would be appropriate as well.
What is the goal for therapy in patients with smoldering MM? Is achieving a PR to treatment enough?
Shaji Kumar, MD: I think that is an important question. At present, the goal is to give an intervention that will reduce the risk of progression. I do not think we are at a point where we are saying that if somebody with smoldering MM gets an intervention and they only get a PR, we should change therapy.
I think we should focus on giving 2 years of treatment to a patient with high-risk smoldering MM, and regardless of response, we stop there and monitor the disease. We all have patients in our practice who might have a PR after treatment of MM and then go several years without progression.
Frontline Treatment Selection
How do you choose between a quadruplet and a triplet regimen for newly diagnosed patients who are eligible for more intense therapy?
Shaji Kumar, MD: Currently, clinical trials are ongoing to address this important question. I think we need to wait for a more mature data from the phase III trials before incorporating the quadruplet regimens into our routine practice, as we do not yet know which patients will benefit more from the quadruplet regimens, and cost is a concern. I think the only way we will be able to make the quadruplet regimens cost-effective is by limiting the duration of therapy to a defined interval.
In light of the STaMINA trial, where there was an impact of continued lenalidomide maintenance on progression, should we be more focused on continuing lenalidomide maintenance until progression?
Philippe Moreau, MD: That is a very important question. The phase III STaMINA trial assessed whether additional consolidation following autologous stem cell transplant (ASCT) or tandem ASCT, followed by lenalidomide maintenance therapy, improved outcomes for newly diagnosed MM, and an updated analysis presented at ASCO 2020 also assessed the impact of the duration of maintenance therapy. These data showed that patients who discontinued lenalidomide maintenance had a higher risk for progression at 5 years vs those who continued lenalidomide maintenance (PFS: 86.3% vs 66.7%; P < .001), suggesting that continued lenalidomide maintenance therapy provides some disease control. However, there was no significant difference in OS in patients who continued or discontinued lenalidomide maintenance (P = .353).
We also know from a meta-analysis published by McCarthy and colleagues in 2017 that the median duration of lenalidomide maintenance after ASCT in patients with newly diagnosed MM was 2.3 years and many patients discontinued either for progressive disease or toxicity. Currently, I think that the optimal duration of lenalidomide maintenance is 3 years, which potentially balances efficacy vs safety. In France, we are recommending 2-3 years of maintenance with lenalidomide. I also think it is important for patients to have a fixed duration, so that they have some treatment-free interval after maintenance.
For patients with newly diagnosed MM who are ineligible for ASCT, how do you choose between lenalidomide/bortezomib/dexamethasone (VRd) and daratumumab/lenalidomide/dexamethasone (DRd)?
S. Vincent Rajkumar, MD: I think it is important for experts to be clear that we do not have randomized data comparing VRd vs DRd in this population. In the MAIA trial, the median PFS with DRd has not been reached and the 48-month PFS rate is 60% and the HR vs lenalidomide/dexamethasone (Rd) was 0.54 (95% CI: 0.43-0.67). In the SWOG S0777 trial, the median PFS for VRd was 41 months and the HR vs Rd was 0.742 (95% CI: 0.594-0.928).
When evaluating these available data, it is important to note the differences in treatment duration in these trials: DRd treatment was given as a triplet therapy until progressive disease, whereas VRd was given for eight 21-day cycles and then followed by doublet therapy with Rd maintenance until progressive disease. It should not be surprising that the longer duration of triplet therapy has led to a longer PFS, but we do not have head-to-head comparison data of these regimens administered for the same duration.
Moreover, we have to understand what is realistic in terms of cost. Daratumumab is comparatively expensive. If you are going to give it month after month for many years, you need evidence that doing so will improve OS. That is why I would say you could choose either VRd or DRd but do not give preference to the latter.
Philippe Moreau, MD: I agree. However, in addition to the differences in PFS that you mentioned, we also must consider the tolerability of the treatments, as well as what will be available to use as salvage regimens after first-line therapy.
Jesús F. San-Miguel, MD, PhD: To follow up on that, because it is a challenge to treat patients who are refractory to lenalidomide, I would also consider the regimen from the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone as a potential frontline therapy.
What treatment would you choose for a patient with disease progression following daratumumab-based induction therapy followed by lenalidomide maintenance?
S. Vincent Rajkumar, MD: In general, when a patient is refractory to lenalidomide, the 2 best options in my mind are daratumumab/bortezomib/dexamethasone (DVd) and daratumumab/pomalidomide/dexamethasone. It is difficult to choose between a daratumumab/PI-based regimen and a daratumumab/pomalidomide-based regimen because both are effective regimens and there is no head-to-head randomized trial comparing them.
For a patient who has previously received bortezomib and presumably tolerated it well but is relapsing on or after lenalidomide, particularly patients with t(4;14) or other cytogenetic abnormalities, I would recommend DVd followed by carfilzomib/pomalidomide/dexamethasone (KPd) at the next progression, since the patient had no previous carfilzomib or pomalidomide. I would prioritize KPd over an anti-BCMA bispecific antibody or CAR T-cell therapy, particularly the investigational therapies that have not yet demonstrated phase III efficacy.
Given that many of us are moving to daratumumab-VRd in first-line setting, I think carfilzomib is most useful in the first relapse setting, such as in combination with pomalidomide and dexamethasone. That enables you to give the best treatment at first relapse rather than waiting for the second or third relapse.
Shaji Kumar, MD: Also, for very high–risk patients, due to cytogenetics or any other disease-related factors, I tend to consider different regimens than what we conventionally use and would potentially put these patients on a clinical trial with a newer agent.
Thomas G. Martin, MD: Yes, I would agree. Even with a pomalidomide-based therapy, the response duration may be short for high-risk patients. I would consider a pomalidomide-based regimen with the thought that they should be ready to receive a BCMA-directed therapy next—either belantamab mafodotin or a CAR T-cell clinical trial—at progression.
When treating a patient with triple-class refractory MM, how do you choose among the various options for anti-BCMA–targeted therapy (belantamab mafodotin, CAR T-cell therapy, and bispecific antibodies)?
Thomas G. Martin, MD: Currently, only belantamab mafodotin is approved by the FDA for relapsed/refractory MM (after ≥ 4 previous therapies, including an anti-CD38 mAb, a proteasome inhibitor, and an immunomodulatory drug). Clinical trial data suggest that belantamab is relatively well tolerated, with the most important adverse events to watch for being corneal events/keratopathy and thrombocytopenia. Clinical trial eligibility for anti-BCMA CAR T-cell therapy in relapsed/refractory MM has been relatively broad; it is even broader than for ASCT and I think more people can tolerate CAR T-cell therapy than can tolerate ASCT. But, there are some adverse events such as cytokine-release syndrome and neurotoxicity that can be a concern. In addition, it also requires patients to have access to a center that offers CAR T-cell therapy, which can be a limiting factor. We know from the experience of our colleagues who treat lymphoma, where CAR T-cell therapy has been available longer, that a minority of patients who are eligible are able to actually get to centers to receive therapy. So we have some accessibility barriers to overcome.
But accessibility aside, for a young, fit, and otherwise healthy person, I would recommend enrollment on a clinical trial for CAR T-cell therapy before belantamab mafodotin. The main reason is that we do not currently have data about the feasibility or efficacy of CAR T-cell therapy after patients have received belantamab mafodotin.
For an older patient or someone who is rapidly progressing, I would recommend belantamab mafodotin, with a plan for their next therapy or referral for clinical trial at progression.
Shaji Kumar, MD: Another common challenge in these phase II trials with CAR T-cell therapy is the number of patients who are unable to continue between their initial registration and actual CAR T-cell infusion. We know these trials entail a lengthy screening period and a long gap between apheresis and treatment. Using an “off-the-shelf” anti-BCMA therapy, such as belantamab or a bispecific antibody, may help mitigate this lengthy period without effective therapy.
Philippe Moreau, MD: Of importance, when we are speaking about patients who are triple-class refractory, many may not have received pomalidomide, carfilzomib, or alkylators in previous lines of therapy. Hence, some of these patients will have new options available and we must carefully consider the sequence and the agents that they received before claiming that a patient is totally refractory to all available drugs and is limited to a clinical trial.
S. Vincent Rajkumar, MD: I agree. Realistically, very few patients in the United States can easily receive CAR T-cell therapy or a bispecific antibody. Even belantamab mafodotin is not yet easy to obtain. I think it is important to understand that there are good alkylated base combinations available, including pomalidomide/cyclophosphamide/dexamethasone, carfilzomib/cyclophosphamide/dexamethasone, and bortezomib/cyclophosphamide/dexamethasone, that can lead to 8-10 months of remission. That could buy time until the BCMA-directed therapies are more readily available.
What questions do you have about managing patients with MM into your clinical practice? Please answer the poll and post your thoughts and questions in the discussion box below.