Refractory Multiple Myeloma: Tailoring Treatment to Patient Characteristics
Several abstracts addressing challenging-to-treat, refractory multiple myeloma were presented at the Virtual Edition of the 25th EHA Annual Congress. Subgroups of interest included heavily pretreated patients, those with renal impairment, and those who were refractory to agents in more than 1 class of therapy.
Following the presentation, our featured expert, S. Vincent Rajkumar, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Rajkumar’s clinical perspectives on these abstracts are presented here.
Edward W. and Betty Knight Scripps Professor of Medicine
“Carfilzomib is a very effective therapy, and it should be considered in almost all patients with multiple myeloma at some point in their disease course, but the optimal timing of its introduction will depend on a number of factors.”
Outcomes such as health-related quality of life (HRQOL) can reflect both the burden of disease and the effects of treatment. In abstract EP1028, Meletios Dimopoulos, MD, presented the results of a post-hoc analysis of the ICARIA-MM trial in which HRQOL was assessed in 2 difficult-to-treat subgroups. As an investigator for the ICARIA-MM trial, I am quite familiar with this study, in which isatuximab plus pomalidomide and dexamethasone was compared with pomalidomide and dexamethasone, showing that isatuximab is a CD38-directed antibody that is very effective in the relapsed and refractory population. Now, this EHA25 Virtual abstract reports that HRQOL was improved or maintained with isatuximab plus pomalidomide and dexamethasone, which was gratifying to see, and this was shown in both heavily pretreated and renally impaired patients.
It was not surprising to me that HRQOL was maintained, as isatuximab is an effective targeted therapy against CD38-positive cells, pomalidomide is very well tolerated, and clinicians have become adept at using dexamethasone in most combinations for multiple myeloma. Teasing out changes in HRQOL can be challenging because you have the competing effects of the disease and its treatment. Although, if well tolerated, a more effective regimen may improve HRQOL by treating the multiple myeloma, QOL can suffer due to tolerability issues associated with the treatment; however, isatuximab is so well tolerated that the reduction in disease activity results in an improvement in HRQOL. On the other hand, you see some worsening of disease control with pomalidomide and dexamethasone, resulting in worsening of HRQOL.
In addition to renal impairment and heavy pretreatment, comorbidities such as cardiovascular disease may be relevant when planning therapy. Carfilzomib is a very effective therapy, and it should be considered in almost all patients with multiple myeloma at some point in their disease course, but the optimal timing of its introduction will depend on a number of factors. Results of the phase 3 ENDURANCE trial (carfilzomib, lenalidomide, and dexamethasone [KRd] vs bortezomib, lenalidomide, and dexamethasone [VRd]) in newly diagnosed patients with standard- to intermediate-risk multiple myeloma showed that the incorporation of carfilzomib into the backbone had no significant benefit and was associated with additional vascular toxicity. However, toxicity profiles are viewed in a very different light in the relapsed/refractory setting, where the options are more limited. In these situations, carfilzomib may be an option, although the risks and benefits must be weighed carefully in at-risk populations. Patient characteristics such as age and the presence of comorbidities help guide decisions about when carfilzomib might be used (eg, in the first, second, or third relapse), and one may be inclined to delay its use in at-risk patients. In general, we try to use triplets at every relapse with at least 2 new agents, where individual agents in the triplet are selected based on which agent(s) the patient has already become refractory to. At some point, one needs to consider carfilzomib, even when the patient is older or has cardiac or pulmonary issues. Abstract PB2027 reported that 16% of patients in the series had cardiac and/or renal toxicity attributable to carfilzomib, and only 2 patients showed evidence of thrombotic microangiopathy. Other studies have reported lower cardiac and/or renal toxicity rates. Thus, the risk is seen in only a small percentage of patients, and, at some point, the gravity of the myeloma becomes more critical than the risk of adverse events.
As a final note, triple-class refractory disease represents a distinct challenge and a great unmet need in the treatment of multiple myeloma. Studies in this population, such as the one described in abstract EP1032, are particularly useful in demonstrating the need for accelerated approval of new agents. I think that we will see more studies like this one, showing that patients who are refractory to 4 or 5 classes of drugs could benefit from a new therapeutic class.
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.
Chen JH, Lenihan DJ, Phillips SE, Harrell SL, Cornell RF. Cardiac events during treatment with proteasome inhibitor therapy for multiple myeloma. Cardiooncology. 2017;3:4.
Dimopoulos M, Campana F, Bury DP, 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. Accessed June 13, 2020. https://library.ehaweb.org/eha/2020/eha25th/293518/meletios.dimopoulos.health-related.quality.of.life.in.heavily.pre-treated.and.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dep1028
Guidez S, Joly F, Nsiala L, et al. Renal and cardiac toxicity associated with carfilzomib treatment in RRMM. Accessed June 13, 2020. https://library.ehaweb.org/eha/2020/eha25th/297943/stphanie.guidez.renal.and.cardiac.toxicity.associated.with.carfilzomib.html?f=listing=0%2Abrowseby=8%2Asortby=1%2Asearch=pb2027
Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial [abstract LBA3]. J Clin Oncol. 2020;38(18 suppl):LBA3. Accessed June 13, 2020. https://meetinglibrary.asco.org/record/186906/abstract
Mehra M, Vogel M, Valluri S, et al. Patient characteristics, treatment patterns and outcomes in patients with triple class refractory multiple myeloma. Accessed June 13, 2020. https://library.ehaweb.org/eha/2020/eha25th/293522/maneesha.mehra.patient.characteristics.treatment.patterns.and.outcomes.in.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Drefractory+myeloma
Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548‐567.
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