How I Treat In Brief
The patient did not receive any further therapy . Response is ongoing , and grade 2 neuropathy persists .
Comments : For a patient progressing on Rd as frontline therapy , the logical approach is to switch the class of agent , or to try to increase the doses of lenalidomide and dexamethasone ( in case of a previous dose reduction ), rather than to add a third agent to Rd . Vd is commonly used in this setting , and adding cyclophosphamide ( VCD ) may increase the response rate . However , PN remains the most important side effect of Vd combinations .
Kd could also have been a feasible option for this patient , although the schedule of administration is more demanding than that of Vd . The safety profile includes less PN , but higher rates of hypertension , dyspnea , cardiac failure , and acute renal failure .
Outside of a clinical trial , I would propose Vd plus daratumumab ( DVd ) for this patient . In the CASTOR trial , this triplet combination was associated with improved PFS , compared with Vd alone , across all subgroups of patients , including all characteristics of this patient . Daratumumab did not increase significant toxicity when added to Vd .
Case # 5 : Treatment of Refractory Disease
A 67-year-old woman with standard-risk MM was treated with frontline Rd in 2013 . The initial response was VGPR , but she progressed on therapy during cycle 26 in 2015 . Salvage therapy consisted of Vd . She achieved a PR after two cycles ( which was sustained for three cycles ), but her disease progressed again with bone pain , anemia , and an M-spike of more than 1.5 g / dL . The patient was then treated with pomalidomide-dexamethasone ( pom-dex ), but response to pom-dex lasted for only five months before disease progression . At the end of 2016 , she started daratumumab therapy , which induced a partial response . The patient is still receiving daratumumab as a single agent , with a sustained response , good tolerance , no bone pain , and normal performance status .
Comments : Pom-dex is an approved combination regimen for the treatment of patients with refractory disease or those whose disease relapses after at least two prior lines of therapy , including lenalidomide and bortezomib . For this patient , who is refractory to both Rd and Vd , I would recommend pom-dex with either cyclophosphamide or daratumumab .
Based on recent trials that have suggested that pom-dex plus cyclophosphamide increases PFS , compared with pom-dex alone , this patient could have benefitted from the addition of cyclophosphamide ( PCD ), to which she had not been exposed previously . PCD is one of our standard rescue regimens because it is all-oral , effective , and manageable .
Although daratumumab is rarely used as a single agent in the United States , it represents a breakthrough for the treatment of patients with refractory disease . We anticipate that the agent also will be used earlier in the disease course , in combination with PIs and IMiDs , as investigated in the
Questions about the optimal combinations , durations , and dosing of these agents remain unsolved .
CASTOR and POLLUX trials . The feasibility of retreatment with CD38 monoclonal antibodies remains to be investigated .
The Future of MM Treatment
Many other new drugs and immune therapies are in advanced stages of investigation , including the CD38 monoclonal antibody isatuximab , the nuclear exporter inhibitor selinexor , the oral BCL2 inhibitor venetoclax , and the oral HDAC6 inhibitor ricolinostat , as well as checkpoint inhibitors , bispecific T-cell engager antibodies , and chimeric antigen receptor T-cell therapies that will enrich our therapeutic armamentarium .
Moreover , MM is a heterogeneous disease comprised of different genetic entities that vary from each other in evolution , mode of presentation , response to therapy , and prognosis . Clinical trials seldom target specific genetic subtypes that may benefit most from a new drug . In the future , the use of new agents will probably require the identification of biomarkers to predict response to therapy .
Several questions will need to be answered to further optimize the management of patients with myeloma : Does modifying therapy based on response or MRD detection improve outcome ? Can limited-duration combination therapy regimens be developed that are as effective as continuous therapy ? What is the best triplet regimen to use in the most cost-effective way at relapse ? ●
TABLE 1 . Major Frontline Treatment Regimens for Myeloma Regimen
Bortezomib / melphalan / prednisone ( VMP )
Lenalidomide / low-dose dexamethasone ( Rd )
Melphalan / prednisone / thalidomide ( MPT )
Bortezomib / cyclophosphamide / dexamethasone ( VCD )
Bortezomib / thalidomide / dexamethasone ( VTD )
Bortezomib / lenalidomide / dexamethasone ( VRD )
AHCT = autologous hematopoietic cell transplantation
TABLE 2 . Major Treatment Regimens for Relapsed / Refractory Myeloma
Regimen
Carfilzomib / lenalidomide / dexamethasone ( KRd )
Bortezomib / dexamethasone / panobinostat ( VD-Pano )
Carfilzomib / dexamethasone ( Kd )
Lenalidomide / dexamethasone / elotuzumab ( Rd-Elo )
Lenalidomide / dexamethasone / ixazomib ( IRd )
Bortezomib / dexamethasone / daratumumab ( DVd )
Lenalidomide / dexamethasone / daratumumab ( DRd )
Usual Dosing Schedule bortezomib 1.3 mg / m 2 on days 1 , 8 , 15 , 22 melphalan 9 mg / m 2 on days 1-4 prednisone 60 mg / m 2 on days 1-4 ; repeated every 35 days lenalidomide 25 mg on days 1-21 , every 28 days
dexamethasone 40 mg on days 1 , 8 , 15 , 22 , every 28 days ; repeated every 4 weeks
melphalan 0.25 mg / kg on days 1-4 ( or 0.20 mg / kg in patients > 75 years )
prednisone 2 mg / kg on days 1-4
thalidomide 100-200 mg on days 1-28 ( 100 mg in patients > 75 years ); repeated every 6 weeks
cyclophosphamide 300 mg / m 2 orally on days 1 , 8 , 15 , 22 bortezomib 1.3 mg / m 2 on days 1 , 8 , 15 , 22 dexamethasone 40 mg on days 1 , 8 , 15 , 22 ; repeated every 4 weeks bortezomib 1.3 mg / m 2 intravenously on days 1 , 8 , 15 , 22 thalidomide 100-200 mg on days 1-21
dexamethasone 20 mg on day of and day after bortezomib ( or 40 mg on days 1 , 8 , 15 , 22 ); repeated every 4 weeks and 4 cycles as pre-AHCT induction
bortezomib 1.3 mg / m 2 on days 1 , 8 , 15 lenalidomide 25 mg on days 1-14
dexamethasone 20 mg on day of and day after bortezomib ( or 40 mg on days 1 , 8 , 15 , 22 ); repeated every 3 weeks
Usual Dosing Schedule
carfilzomib 20 mg / m 2 ( cycle 1 ) and 27 mg / m 2 ( subsequent cycles ) intravenously on days 1 , 2 , 8 , 9 , 15 , 16
lenalidomide 25 mg on days 1-21
dexamethasone 20 mg on day of and day after bortezomib ( or 40 mg on days 1 , 8 , 15 , 22 ); repeated every 4 weeks
bortezomib 1.3 mg / m 2 on days 1 , 8 , 15 , 22 dexamethasone 20 mg on day of and day after bortezomib
panobinostat 20 mg on days 1 , 3 , 5 of week 1 and 2 ; repeated every 3 weeks ( cycles 1-8 )
carfilzomib 56 mg / m 2 on days 1 , 2 , 8 , 9 , 15 , 16 ( 20 mg / m 2 on days 1 and 2 , cycle 1 only )
dexamethasone 20 mg on days 1 , 2 , 8 , 9 , 15 , 16 , 22 , 23 in 28-day cycles
lenalidomide 25 mg on days 1-21 dexamethasone 40 mg weekly
elotuzumab 10 mg / kg weekly ( cycles 1 and 2 ) and every other week ( cycles 3 +); repeated every 28 days
lenalidomide 25 mg on days 1-21 dexamethasone 40 mg on days 1 , 8 , 15 , 22 ixazomib 4 mg on days 1 , 8 , 15 ; repeated every 28 days bortezomib 1.3 mg / m 2 on days 1 , 4 , 8 , 11 ( cycles 1-8 ) dexamethasone 20 mg on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , 12 ( cycles 1-8 )
daratumumab 16 mg / kg every week ( cycles 1-3 ); every 3 weeks ( cycles 4-8 ), every 4 weeks ( cycles 9 +)
lenalidomide 25 mg on days 1-21 dexamethasone 40 mg orally weekly
daratumumab 16 mg / kg ; weekly ( cycles 1-2 ), every other week ( cycles 3-6 ), and every 4 weeks ( cycles 7 +)
100 ASH Clinical News December 2017