Review of Recent Approvals for Relapsed/Refractory Multiple Myeloma
Pomalidomide-based combinations and anti-CD38–directed therapies are among those that have been shown to be effective in patients with relapsed and refractory multiple myeloma. Such individuals have many more options for treatment today than in the past.
How have recent drug approvals impacted the relapsed/refractory treatment landscape?
Kraft Family Professor of Medicine
“We are extremely blessed in multiple myeloma right now because of all of the currently available treatment options. We can usually match the appropriate therapy to the individual patient characteristics, and we can achieve high response rates and durable responses, even in far-advanced disease."
When patients have relapsed multiple myeloma, a number of factors guide us in selecting the best treatment option for each person. These factors include frailty status, comorbidities, risk status by the Revised International Staging System, and, in particular, the presence of high-risk genetics. We also consider the patient’s goals for treatment and their history of treatment. We are extremely blessed in multiple myeloma right now because of all of the currently available treatment options. We can usually match the appropriate therapy to the individual patient characteristics, and we can achieve high response rates and durable responses, even in far-advanced disease.
Lenalidomide-dexamethasone–based treatments are active in bortezomib-refractory multiple myeloma. Lenalidomide-dexamethasone has been compared in randomized trials with lenalidomide-dexamethasone plus elotuzumab, ixazomib, carfilzomib, or daratumumab. All of those trials, conducted primarily in bortezomib-refractory multiple myeloma, led to US Food and Drug Administration (FDA) approvals. Similarly, options for patients who have lenalidomide-refractory multiple myeloma have been developed. There is a whole series of regimens that are bortezomib-dexamethasone based, including bortezomib-dexamethasone with pomalidomide or bortezomib-dexamethasone with daratumumab. However, most patients seen in the clinic nowadays have received both lenalidomide and bortezomib as part of their initial treatment. And, if these patients are truly refractory to both drugs, then we will often treat with a second-generation proteasome inhibitor (PI) and a second-generation immunomodulatory drug (IMiD; eg, carfilzomib, pomalidomide, and dexamethasone), or we may treat with a monoclonal antibody in a regimen such as daratumumab, pomalidomide, and dexamethasone. Even for triple-class–refractory multiple myeloma, we now have selinexor and belantamab mafodotin as options.
While we are fortunate to have all of these newer options, if you think about what the patient has had previously, the amount of options actually comes down to a relatively small number. Additionally, the paradigm is very much in flux. For example, daratumumab is being moved into the front line with lenalidomide, bortezomib, and dexamethasone, which might impact our ability to use anti-CD38 therapy at relapse.
Chair and Professor
“In triple-class–refractory disease, once you get past the ability to use the PIs, IMiDs, and anti-CD38 antibodies, there are essentially 3 options right now—4 if you include what is being evaluated in clinical trials.”
In the context of a first relapse, a key question is whether the patient is daratumumab resistant from earlier exposure. If the answer is no, which is likely true for most patients in their first relapse right now, daratumumab essentially becomes the backbone, and you add either an IMiD or a PI to it. Our group here at the Winship Cancer Institute favors the IMiD–anti-CD38 combination, but there are also some compelling data for a PI–anti-CD38 combination.
In triple-class–refractory disease, once you get past the ability to use the PIs, IMiDs, and anti-CD38 antibodies, there are essentially 3 options right now—4 if you include what is being evaluated in clinical trials. There are pros and cons for each of these options. We can use combinations of chemotherapy, which are fraught with potential side effects. There are 2 FDA-approved approaches (ie, selinexor and belantamab mafodotin) or one can opt for a clinical trial. Belamaf (belantamab mafadotin) requires partnering with an ophthalmologist before each dose, but it can be safely given. And, from a patient convenience perspective, it typically requires 1 office visit every 3 weeks, which is relatively straightforward if you do not encounter significant ocular toxicity. Selinexor plus dexamethasone in refractory multiple myeloma can be challenging to administer twice per week and may be associated with tolerability issues. As Dr Anderson alluded to, in the STORM trial, selinexor-recruited penta-class–refractory patients (ie, patients who were resistant to 2 PIs, 2 IMiDs, and an anti-CD38 monoclonal antibody) were treated with selinexor plus dexamethasone twice per week.
Edward W. and Betty Knight Scripps Professor of Medicine
“I agree that, in the first relapse, the main issues are going to be what the patient has received previously and what they are refractory to.”
I agree that, in the first relapse, the main issues are going to be what the patient has received previously and what they are refractory to. If patients are refractory to lenalidomide, daratumumab, or bortezomib, as single agents, then we just omit that agent and proceed with a triplet that we can use in the first relapse. The challenge arises when a patient has been on, say, daratumumab-lenalidomide-dexamethasone or is progressing on RVd (lenalidomide-bortezomib-dexamethasone). This is a bit more complicated, but I would still go with the principle of using at least 2 new agents that the patient is not refractory to.
With regard to the sequencing of all of these options, there are so many variables that it is difficult to recommend a particular sequence for all patients (eg, “use belantamab first, then venetoclax, then alkylators, then selinexor”). It really varies, depending on the patient and what they have previously received. But, clearly, we have multiple options on- and off-study. Belantamab is really a great new option that is not cross-reactive with most of the other agents that we have been discussing. I agree with my colleagues, however, in that, while it is comforting that we have so many options and that there is no end to the options, in truth, the options can become very limited—especially when you consider that 3 of these agents are PIs, another 3 are IMiDs, and many are anti-CD38– or B-cell maturation antigen–directed therapies.
In terms of drug development, I would encourage industry to conduct more trials that are aligned with patient presentations that we see right now in clinical practice with drugs that patients are not already refractory to. I realize that this is, in part, due to the regulatory framework, but the problem is that, when I am reaching for selinexor, the chances that the patient is already not refractory to a PI are vanishingly small, so we need to know about other combinations.
Attal M, Richardson PG, Rajkumar SV, et al; ICARIA-MM Study Group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study [published correction appears in Lancet. 2019;394(10214):2072]. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5
Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981. doi:10.1182/blood-2017-05-785246
Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455
ClinicalTrials.gov. Belantamab mafodotin plus pomalidomide and dexamethasone (Pd) versus bortezomib plus Pd in relapsed/refractory multiple myeloma (DREAMM 8). Accessed March 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04484623
Dimopoulos MA, Campana F, Bury D, et al. Health-related quality of life in heavily pre-treated and renally impaired patients with relapsed/refractory multiple myeloma receiving isatuximab plus pomalidomide and dexamethasone: ICARIA-MM study [abstract 3438]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
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Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. doi:10.1002/ajh.25791
Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020;34(12):3286-3297. doi:10.1038/s41375-020-0813-1