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The two pivotal trials to assess daratumumab in Relapsed and Refractory Multiple Myeloma (RRMM) patients, in combination with other commonly used regimens, are the CASTOR and POLLUX studies. PFS and OS data from these trials were highly impressive and led to FDA approval for use in triplet regimens. However, both studies included patients that had a small number of prior therapies, and excluded patients that were refractory to either lenalidomide (POLLUX) or bortezomib (CASTOR). In addition, patients had no prior exposure to daratumumab and a lower number of average prior therapies, with only 30% refractory to the last line of therapy.
Therefore, studies to assess the effect of daratumumab in heavily pre-treated patients with prior exposure to different reagents are necessary. In a study carried out at the Department of Hematology and Department of Internal Medicine at the Mayo Clinic, Rochester, USA, and published in the American Journal of Hematology, 126 heavily pre-treated patients who had received daratumumab combination treatment (DCT) were reviewed.
This study examined the efficacy of daratumumab combination regimens in a more realistic treatment cohort: a heavily pre-treated population with greater exposure to prior treatments, and more patients that were refractory to the last line of therapy. In addition, patients received daratumumab on average more than 4 years after diagnosis, compared to 3.9 and 3.5 years in the CASTOR and POLLUX trials, respectively. Whilst a clear benefit from daratumumab was observed with a 12 month PFS of 30%, it is notably lower than the 61% and 83% observed in the CASTOR and POLLUX trials, respectively. Therefore, the outcomes are lower in heavily pre-treated patients, compared to those selected for clinical trials. This ties in with previous data indicating that daratumumab is more effective when used earlier in the treatment journey, and the authors of this study recommend that DCTs should be used at first relapse. The limitations of this study include the fact that it is retrospective and had a short follow-up period.
Refractory Status |
Drugs |
---|---|
double |
bortezomib and lenalidomide |
triple |
bortezomib and lenalidomide plus either carfilzomib, or pomalidomide |
quadruple |
bortezomib, lenalidomide, carfilzomib and pomalidomide |
penta |
bortezomib, lenalidomide, carfilzomib and pomalidomide, and daratumumab or isatuximab |
Abbreviation |
Drug regimen |
---|---|
pD |
pomalidomide and dexamethasone |
DRd |
lenalidomide and dexamethasone |
DVd |
bortezomib and dexamethasone |
‘other’ chemotherapeutic agents |
‘other’ DCTs includes all combinations below: |
DKd |
carfilzomib and dexamethasone |
DKP |
carfilzomib and pomalidomide |
DPVd |
pomalidomide, bortezomib and dexamethasone |
DVRd |
bortezomib, lenalidomide and dexamethasone |
DId |
ixazomib and dexamethasone |
DIR |
Ixazomib and lenalidomide |
D-CAd |
cyclophosphamide, adriamycin and dexamethasone |
DTd |
thalidomide and dexamethasone |
D-CAd |
cyclophosphamide, adriamycin and dexamethasone |
D-CAdT |
cyclophosphamide, adriamycin and dexamethasone |
D-CHOP |
cyclophosphamide, adriamycin, vincristine and prednisolone |
DM |
melphalan |
Outside of clinical trials, experience with daratumumab-based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43-93) years. High-risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1-14) and time to first DCT from diagnosis was 4.3 years (range, 0.4-13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty-two (41%), 34 (27%), 23 (18%) and 17 (14%) received DPd, DRd, DVd and 'other' DCTs, respectively. Overall response rate was 47%. Median follow-up was 5.5 months (95%CI, 4.2-6.1). Median progression free survival (PFS) was 5.5 months (95%CI, 4.2-7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta-refractory MM (n=8) vs quadruple refractory MM (n=18) and others (n=100) (2.2 [95%CI, 1-2.4] vs 3.1 [95%CI, 2.1-NR] vs 5.9 [95%CI, 5.0-NR]; p<0.001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95%CI, 3.1-6.0] vs 8.2 [95%CI, 4.6-NR]; p=0.02); and those who received >2 prior therapies vs others (5.0 months [95%CI, 3.7-5.9] vs NR [95%CI, NR-NR]; p=0.002). Non-hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pre-treated patients are lower than those reported in clinical trials.
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