Sequencing of myeloma therapy: Finding the right path among many standards

In the last decade, major changes have occurred in the diagnostic criteria, staging system, and response criteria for multiple myeloma (MM).1, 2 These changes have been accompanied by several advances in treatment of the MM, including many new drugs (carfilzomib, pomalidomide, daratumumab, elotuzumab, panobinostat, ixazomib, selinexor, isatuximab, and belantamab). Numerous clinical trials provide data on best practices along the spectrum of the disease. The purpose of this article is to describe the complexity of MM therapy in a landscape where many parallel standards exist for the same indications, and to provide an outline selecting the first line and subsequent sequencing of therapy according to dynamic changes in the disease and patient features. Approach to initial therapy in myeloma is affected by host factors (age, performance status, renal function), eligibility for stem cell transplantation, and presence or absence of high risk features. High-risk MM is defined by the presence of t(4;14), t(14;16), t(14;20), deletion 17p, gain 1q, or p53 mutation.3 Double-hit MM refers to the presence of any two or more high-risk abnormalities. Triple-hit MM refers to the presence of three or more high-risk abnormalities. Although minimal residual disease (MRD) negative status is associated with improved progression-free survival (PFS) and overall survival (OS), there are no data from randomized trials that modifying therapy in MRD positive patients in an attempt to make them MRD negative will lead to better outcomes. The current algorithms for the treatment of symptomatic newly diagnosed MM is shown in Figure 1. Patients who candidates for autologous stem cell transplantation (ASCT) are treated with three to four cycles of induction therapy followed by stem cell harvest. After stem cell harvest, the standard of care has been ASCT followed by maintenance. However, in selected patients who have standard risk MM, ASCT can be delayed until relapse, and randomized trials show no detrimental effect on OS with such an approach. Approach to the treatment of newly diagnosed myeloma in transplant eligible (A) and transplant ineligible (B) patients. ASCT, autologous stem cell transplantation; Dara-VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone. Modified from Rajkumar and Kumar2 The preferred initial therapy is bortezomib, lenalidomide, and dexamethasone (VRd).4 The 4-year OS rate with VRd is greater than 80% with or without early ASCT.5 An important alternative to VRd in newly diagnosed MM is daratumumab, lenalidomide, and dexamethasone (DRd). DRd has shown significant efficacy in a randomized trial conducted in transplant ineligible patients, with improved PFS compared with Rd.6 However, there are important differences between the two approaches, particularly in transplant ineligible patients where VRd consists of triplet therapy for 6 months followed by maintenance, while DRd requires continuous triplet therapy until disease progression. Thus due to overall cost, and strength of long-term data, I prefer VRd over DRd for most patients.7 However, DRd is a suitable alternative for patients with preexisting neuropathy or for patients who have intolerance to VRd. In high-risk transplant eligible patients with double hit MM or triple hit MM, I recommend addition of daratumumab to the standard VRd regimen (Dara-VRd), or the daratumumab, bortezomib, thalidomide, and dexamethasone (Dara-VTd) regimen.8 There is no significant benefit with carfilzomib, lenalidomide, and dexamethasone (KRd) over VRd in newly diagnosed MM.9 KRd is more expensive, and is associated with a higher risk of serious cardiac, renal, and pulmonary toxicity than VRd. In certain settings, the treatment regimens for newly diagnosed MM must be modified. Thus, bortezomib, cyclophosphamide, and dexamethasone (VCd) is the preferred regimen in patients presenting with acute renal failure due to light chain cast nephropathy. In patients with primary plasma-cell leukemia multiagent combination chemotherapy such as bortezomib/dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide (VDT-PACE) is usually needed initially to achieve rapid disease control. In elderly frail patients who are unable to travel to receive parenteral therapy, the all oral regimen of ixazomib, lenalidomide, and dexamethasone (Ixa-Rd) is a reasonable alternative to VRd and DRd. Melphalan-based regimens are no longer recommended for newly diagnosed MM due to concerns about stem cell damage, secondary myelodysplastic syndrome, and acute leukemia. One of the main controversies in initial therapy is concerning the sequencing of ASCT. Older randomized trials have found similar OS with early ASCT (immediately following four cycles of induction therapy) versus delayed ASCT (at the time of relapse as salvage therapy). More recently, the Intergroupe Francophone du Myelome (IFM) trial found no significant OS difference between early versus delayed ASCT in patients treated with VRd as initial therapy and lenalidomide maintenance.10 No difference has emerged even after 8 years of follow-up. There is a significant improvement in PFS as expected with early ASCT, and there are other logistical benefits to ASCT. In general, early ASCT is preferred, but based on the IFM results it is reasonable to consider a delayed ASCT in patients with standard-risk multiple MM who prefer such an approach for personal reasons. The role of consolidation therapy and tandem (double) ASCT is limited. Results of randomized trials are contradictory and likely reflect the availability of new treatment options in the salvage setting. In the United States, where multiple options for salvage therapy are available, there seems to be no benefit with tandem ASCT. At present, outside of a clinical trial setting, we consider tandem ASCT only in selected young patients with del 17p. The standard of care following initial therapy MM is lenalidomide maintenance. In high-risk patients, bortezomib plus lenalidomide, or VRd maintenance is preferable. There are limited data on optimal duration of maintenance. Many patients can benefit from a drug-free interval, and trials are examining if the duration of maintenance can be modified based on MRD results. MM is characterized by multiple remissions and relapses. The sequencing of therapies appropriately is critical in achieving the best long-term survival. Many patients with MM receive five or more lines of therapy in a sequential manner over several years. The choice of treatment at each relapse is affected by the Timing of the relapse, Response to prior therapy, Aggressiveness of the relapse, and Performance status. Patients are eligible for ASCT should be considered for transplantation if they had elected to delay the procedure, or if they achieved excellent remission duration with the first ASCT, defined as a remission of 36 months or longer with maintenance. In order to provide the best sequential therapy, we need to select the most active regimen early on. A triplet regimen is preferred at first relapse. At each subsequent relapse, a triplet, quadruplet, or multidrug regimen that contains at least two new drugs that the patient is not refractory to should be used. The algorithm for the treatment of relapsed MM is given in Figure 2. Approach to the treatment of relapsed multiple myeloma in first relapse (A) and second or higher relapse (B). DKd, daratumumab, carfilzomib, and dexamethasone; DPd, daratumumab, pomalidomide, and dexamethasone; DRd, daratumumab, lenalidomide, and dexamethasone; DVd, daratumumab, bortezomib, and dexamethasone; ERd, elotuzumab, lenalidomide, and dexamethasone; IPd, ixazomib, pomalidomide, and dexamethasone; IRd, ixazomib, lenalidomide, and dexamethasone; KPd, carfilzomib, pomalidomide, and dexamethasone; KRd, carfilozomib, lenalidomide, and dexamethasone; VCd, bortezomib, cyclophosphamide. Modified from Rajkumar and Kumar2 Treatment is typically continued until disease progression. However, based on tolerability and response, increasing the interval between cycles, as well as treatment-free intervals should be considered. At first relapse, my preferred option is DRd for patients who are not refractory to lenalidomide. If patients are refractory to lenalidomide, the choices are daratumumab, bortezomib dexamethasone (DVd), daratumumab pomalidomide, dexamethasone, or isatuximab, pomalidomide, dexamethasone. In patients who are refractory to daratumumab at first relapse, carfilzomib-based regimens such as KRd or carfilzomib, pomalidomide, dexamethasone (KPd) are excellent options. For patients who are frail, Ixa-Rd would be a reasonable first choice for relapse. There are numerous other alternatives, and these can be used in second and subsequent relapses. They include elotuzumab, pomalidomide, dexamethasone (EPd), bortezomib, cyclophosphamide, dexamethasone (VCd), bortezomib, pomalidomide, dexamethasone (VPd), and daratumumab, carfilzomib, and dexamethasone (DKd). Unfortunately, none of the triplet regimens used in relapsed MM have been compared head-to-head in randomized trials. When sequencing therapy, there are a few other important considerations. At each relapse, any of the regimens that were mentioned for use in first relapse can be considered, with the goal of having at least two new drugs that the patient is not refractory two, and preferably from a different drug class. In many instances, this may mean the necessity of adding a monoclonal antibody to one of the triplets to create a quadruplet regimen. Although it is in the same drug class, pomalidomide has clinical activity in patients who are refractory to lenalidomide. Similarly, carfilzomib has activity in patients who are refractory to bortezomib. Carfilzomib is typically administered twice-weekly at a dose of 27 mg/m2, but a once-weekly schedule of 56–70 mg/m2 may be equally effective and safe, and more convenient.11 Carfilzomib has a lower risk of neurotoxicity than bortezomib, but approximately 5% of patients can experience serious cardiac side effects. There are several additional options for patients with MM refractory to immunomodulatory drugs, proteasome inhibitors, alkylators, CD38 antibodies, and elotuzumab. One option is to add panobinostat to a proteasome-inhibitor containing regimen. A second option is to use a selinexor-containing regimen such as selinexor, bortezomib, dexamethasone (SVd). A third options is treatment with belantamab mafodotin, a humanized anti-BCMA antibody that is conjugated to monomethyl auristatin-F, a microtubule disrupting agent.12 Other options for refractory disease include bendamustine-containing regimens or anthracycline-containing regimens. Venetoclax is not approved for use in MM, but has single-agent activity in patients with t(11;14) subtype of MM.13 A recent randomized trial found significantly higher mortality with venetoclax in relapsed MM despite producing deeper responses and better PFS.14 Therefore, venetoclax is considered investigational, and its use should be restricted to patients with t(11;14) who have relapsed disease. With careful analysis of the various options and combinations possible, we can induce remissions multiple times with creative strategies. At each step opportunities for clinical trials may open up and should be considered. One of the most exciting options being studied is chimeric antigen receptor T cells targeting B cell maturation antigen such as bb2121.15 In studies so far, more than 80% of patients appear to respond, with median response duration of approximately 12 months. Another promising new strategy is the use of bispecific T-cell engager, such as AMG 701, talquetamab, or cevostamab. Iberdomide and other cereblon inhibitors are also showing promise. This study was supported in part by grants CA 107476, CA 168762, and CA186781 from the National Cancer Institute, Rockville, MD, USA. The author declares that there is no conflict of interest.