Efficacy of Daratumumab outside the clinical trial setting

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.

Study Design:

• Patients (pts) included: 126 patients (pts) selected from records at the Mayo Clinic, who had received more than one cycle of DCT between 1^st December 2015 and 31^st December 2016; data cut-off date = 28^th February, 2017
• Median pt age = 67 (range = 43-93)
• Pts refractory to the last line of therapy = 116 (92%)
• Pts refractory to double agent daratumumab = 17 pts (13%)
• High-risk cytogenetics = 38 pts (33%)
• Median number of prior therapies = 4 (range = 1-14)
• Time to first DCT from diagnosis = 4.3 years (range 0.4-13)
• Pts receiving different DCT’s: DPd = 52 (42.3%), DRd = 34 (27.0%) and DVd = 23 (18.2%); ‘other DCTs’ = 17 (13.5%) including 3 pts (2.4%) who received DKd, 2 patients (1.6%) each who received DPVd, D-CAdT and D-CHOP and 1 (0.8%) who received D-CAd, DId, DIR, DKP, DM, DVRd and DTd (see Table 2. for definitions)

Results:

• At data cut-off, 12 pts (13%) had died due to progressive disease and one due to pneumonia
• Response was evaluable in 122 (97%) pts
• Median follow-up = 5.5 months (95% CI, 4.2-6.1)
• Median follow-up by treatment group: DPd = 5.5 (95% CI, 4.1-6.4), DRd = 5.8 (95% CI, 4.1-6.7), DVd = 3.9 (95% CI, 1.8-5.5), other DCT groups = 6.1 (95% CI, 3.0-10.2) months (P = 0.24)
• Median OS = not reached (NR) with any regimen
• ORR = 47 %; VGPR or better = 20%; CBR = 66%
• ORR by treatment group: DPd = 46%, DRd = 50%, DVd = 57% and other DCT groups = 35%
• VGPR as best response: DPd = 16%, DRd = 29%, DVd = 14% and other DCT groups = 18%
• Clinical Benefit Rate (CBR) – pts attaining MR or better as the best response: DPd = 64%, DRd = 68%, DVd = 67% and other DCT groups = 65%
• Median time-to-best response = 3.3 months (95% CI, 2.4-4.6) overall; DPd = 3.2 months (95%CI, 2.3-4.8), DRd = 4.1 months (95%CI, 2.3-NR), DVd = 1.8 months (95%CI, 1.2-NR) and other DCT groups = NR (95%CI, 1.6-NR), p = 0.33
• Median Duration of Response (DoR) = NR (95% CI, 5.1-NR), p=0.13
• Median PFS = 5.5 months (95% CI, 4.2-7.8)
• Median PFS by treatment group: DPd = 5.2 (95% CI, 2.7-NR), DRd = 7.8 (95% CI, 5.0-NR), DVd = 3.8 (95% CI, 2.0-NR) and other DCT subgroups = 3.9 (95% CI, 2.8-8.2) months; p = 0.34
• PFS (12 month) = 29.7%
• Median Time To Next (myeloma) Treatment (TTNT) = 5.7 months (95% CI, 4.6-6.8)
• Median TTNT by treatment group: DPd = 5.7 (95% CI, 4.2-NR), DRd = 6.0 (95% CI; 5.3-NR), DVd = 4.0 (95% CI, 2.0-NR) and other DCT subgroups = 4.1 (95% CI, 2.8-6.8) months, p=0.13
• Median PFS and TTNT were worse for pts with high risk cytogenetics and those with penta- and quadruple- refractory disease, and those refractory to one or more agent used in the DCT

Safety:

• Hematological adverse events (AEs): 81.7% of all patients
• Grade ≥3 anemia = 13.5%, neutropenia = 32.5%, thrombocytopenia = 19.0%
• Common side-effects: infections = 37.3%, fatigue = 31.6%, infusion reactions = 17.3%, peripheral neuropathy = 10.3% and diarrhea = 10.3%
• Grade 3 or higher hematological toxicities = 41%
• Pts that sustained a reaction to daratumumab = 22.7%

Conclusion:

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.

Table 1. Definition of refractory status.

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

Table 2. Definition of drug combinations. Patients in this study received daratumumab plus any combination of the following.

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

Abstract

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.