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

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