Despite frequent attainment of Complete Response (CR) or at least Very Good Partial Response (VGPR) with modern induction regimens, virtually all patients with Plasma Cell Myeloma will relapse. There is no standard of care for therapy of relapsed myeloma, and will depend upon a range of factors, including patient age and comorbidities, therapies used in first-line, duration of first remission, the biological behavior of the myeloma at progression, and availability of therapies in the local health landscape.
DT-PACE is an intensive, multi-chemotherapy regimen and has been prospectively studied in the “pre-novel agent” era by Lee et al,r and more recently retrospectively assessed in series of patients including a significant proportion who had received prior IMID or proteasome inhibitor based therapy.r
Lee et al prospectively enrolled 236 patients in a study to evaluate the comparative efficacy of DT-PACE when compared to tandem autologous transplantation in previously treated patients with myeloma. Patients were aged between 31 and 84 years. Of the 236 enrolled patients, 7 never started treatment, 6 patients were dialysis-dependent and had cisplatin withheld and another 67 patients had < 50% dose treatment either because of age or comorbidity. Before being treated with DT-PACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities.r
Gerrie et al retrospectively analysed the outcomes of 75 patients with relapsed or refractory myeloma treated between 1999 to 2010 at either PMH Toronto or the Mayo clinic Scottsdale. Patients had a median age of 56 and had received a median of 3 prior treatment regimens. 49% had received prior thalidomide, 23% had lenalidomide, 32% had bortezomib. 33% had received a prior autologous transplant (the non-transplanted patients wither had had rapidly progressive disease, poor performance status or other organ impairment precluding transplant or were too old). 20% of patients had secondary plasma cell leukaemia, and 4% leptomeningeal disease.r
Both the prospective study by Lee et alr and the retrospective analysis of salvage DT-PACE by Gerrie et alr confirm that it is an efficacious choice as a salvage regimen in relapsed/refractory myeloma (even with prior exposure to novel agents or prior ASCT), particularly as a bridge to transplantation. It is important to note however there are several differences between these studies in terms of the protocol delivered, as well as toxicity outcomes. In particular, in the Gerrie retrospective, thalidomide was omitted entirely in many of the cycles administered (62%) i.e. DPACE was given rather than DT-PACE.
Also, the median dose of thalidomide achieved (200 mg) was much lower than in the Lee study (target 400 mg) suggesting that to obtain a response with this regimen, full dose thalidomide is less important than delivering the ‘traditional’ cytotoxics. The lower rates of thromboembolism, constipation and neuropathy seen in this retrospective study probably reflect the lower dose or omission of thalidomide. Electrolyte disturbances were seen more frequently in the retrospective analysis and close monitoring is recommended and routine electrolyte supplementation may be of benefit.r
Response to 2 cycles of DT-PACE for induction was evaluated in 229 patients. The partial remission rate (PR) after 2 cycles of DT-PACE was 32%, with 16% attaining a CR or near-CR (n-CR) (defined as only immunofixation electrophoresis-positive). Patients who received 100% dose of DT-PACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% vs 17% (p < 0.0001); CR + nCR, 27% vs 6% (p < 0.0001).
Patients with high LDH (n = 98) showed a better response than those with a normal LDH (n = 138): PR or better 43% vs 27% (p = 0.01), CR + nCR, 25% vs 11% (p = 0.01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% vs 33% (p = 0.84); CR + nCR, 17% vs 15% (p = 0.73).
90% of patients completed only 1 or 2 cycles. 50% completed one cycle, 40% two cycles. 33% achieved a PR and 16% a VGPR (ORR 49%). CR rates were not reported. 36% had stable disease and 9% progressed on treatment.
The median PFS was 5.5 months (95% CI 4.3-9.8) and median OS 14 months (95% CI 8.7-19.3). However, 34 of 64 patients who responded or had stable disease proceeded to ASCT- their median PFS was 13.4 (CI 7.7-20.1), and median OS 20.5 months (14.8-63.8)
ECOG 3 to 4 patients had significantly poorer OS (5.5. vs 15.9 for 0-2) and PFS (2.6 vs 5.5 months). Those who had already received a prior ASCT had poorer outcomes (OS 7.5 vs no prior ASCT 15.9).r
Note that the DT-PACE backbone may be suitable for partnering with other novel agents. The Total Therapy 3 study added bortezomib (1.0 mg/m2 days 1, 4, 8, 11) given as 2 cycles prior to, and 2 further cycles after, tandem high-dose melphalan autologous transplants.r In this study, thalidomide dosage was capped at 200mg daily.
Although tolerated well overall, only approximately 50% patients were able tolerate full doses of DT-PACE. Toxicity was monitored for 3 months after the first 2 cycles. 65% patients experienced > Grade 2 neutropenia whereas only 11% experienced > Grade 2 thrombocytopenia associated with 22 haemorrhagic events - 8 GIT, 8 haematuria, 2 serious epistaxis and 5 bleeds at CVAD entry sites. Other toxicities are summarised below.r
||All grades (%)
||Grade 3-4 (%)
|ANC < 0.5 X 109/L
|Platelets < 75 x 109/L
|Nausea and vomiting
|Congestive heart failure
Treatment related death was documented in 5% of patients (neutropenic sepsis x2, PE, GI bleed). Haematologic toxicity was significant with Grade 3-4 anaemia (Hb<80) in 48% and grade 3-4 thrombocytopenia (Plt <50) in 69%: bleeding occurred in 17 of 75 patients however grade 3 bleeding only occurred in 2 patients. Prophylactic platelets were administered if Plt <10) Grade 3-4 neutropenia occurred in 88% despite 76% of cases receiving G-CSF support. The median day of ANC nadir was D11.
Febrile neutropenia occurred in 23 of 123 cycles (19%). In order to achieve the modest rates of infection/febrile neutropenia, most patients were given prophylactic antibiotics (64%) (described as “Antifungal, antiviral, antibiotics” at clinician discretion). Electrolyte disturbances were frequent with hypocalcaemia and hypomagnesaemia recorded in 69 & 60% of cycles respectively (grade 3-4 in 10 & 12%).
The regimen was only moderately emetogenic with nausea and vomiting of any grade occurring in 21% (2% grade 3-4) however anti-emetic prophylaxis was not documented. Other notable toxicities were mucositis in 17% (but of grade 3-4 in only 4%), new or worsening renal insufficiency in 14% of cycles and neuropathy 10% (grade 3-4 only 3%).r