A utologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m 2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741)

Individualized therapy based on EGFR mutation status has the potential to provide a cost-effective alternative to non-individualized care for patients with advanced adenocarcinoma. Further clinical research is needed to confirm these results.

High-dose chemotherapy with autologous peripheral blood stem cell transplantation is the standard treatment of patients with multiple myeloma today. In this study we used a combination mobilizing chemotherapy containing ifosfamide with G-CSF before stem cell collection. The chemotherapy regimen consisted of ifosfamide (2,500 mg/m² days 1–3), epirubicin (100 mg/m² day 1) and etoposide (150 mg/m² days 1–3) followed by G-CSF (5 µg/kg from day 5). In 30 younger patients (median age 51 years; range 41–60 years) who received the IEV regimen in 100% dosage, a median of 11.15 × 10⁶ CD34⁺ cells/kg (range 0–44.60 × 10⁶ CD34⁺ cells/kg) was collected. In 22 elder patients (median age 64 years; range 59–72 years) similar collection results were obtained with a median of 10.82 × 10⁶ CD34⁺ cells/kg (range 0.99–42.22 × 10⁶ CD34⁺ cells/kg) after the IEV regimen in 75% dosage. The pretreatment chemotherapy cycles before mobilization were fewer in elder patients with a median of 0 cycles (range 0–7 cycles) compared with younger patients with a median of 4 cycles (range 0–7 cycles). These collection results were favorable and allowed to support a tandem transplantation procedure in younger and elder patients in 97 and 95%, respectively. In the majority of patients, the hematological toxicity of IEV was of WHO grade 3/4. The extramedullary toxicity was mild to moderate and there were only few cases (5–10%) of relevant nephrotoxicity or neurotoxicity associated with the application of ifosfamide.

The concept of the DSMM 2 study was to give age-adjusted high-dose treatment to elderly myeloma patients in order to balance efficacy and toxicity. The value of conventional induction chemotherapy before high-dose melphalan and autologous stem cell transplantation and the durability of unmaintaned remissions afterwards was addressed. Between September 2001 and September 2006, 434 multiple myeloma patients 60–70 years of age with 0–1 cycle of pretreatment were recruited from 45 centers. The median age was 65 years. The patients were randomized to receive 4 cycles of conventional induction chemotherapy [A1] (n=216; VAD or idarubicin/Dex in 88%) or no induction chemotherapy [A2] (n=218). Instead of induction chemotherapy, patients in [A2] received only one short course of dexamethasone 40 mg orally (days 1–4 and 8–11). Subsequently, stem cells were mobilized after combination chemotherapy with ifosfamide, epirubicin and etoposide (IEV) followed by G-CSF; stem cells could be collected in 97% of the patients. Then the patients proceeded to tandem MEL140 (melphalan 140 mg/m2) and autologous peripheral blood stem cell transplantation with a time interval between high-dose cycles of 2 months. No consolidation or maintenance treatment was scheduled. Analyses were performed in an intent-to-treat approach. 87% of patients completed the first transplant, 74% the second. Overall, the treatment was well tolerated and grade 3/4 infections and stomatitis after high-dose melphalan occurred in 37% and 9% of patients, respectively. The overall mortality (tumor and/or toxicity) during treatment was 7.1%: 4.5% during the induction phase (6.1% in [A1] versus 2.9% in [A2]), 1.5% after mobilization and 1.1% after high-dose therapy. Notably, the best response (EBMT criteria) at the end of treatment in patients randomized to [A1] (16% CR, 64% PR) or [A2] (18% CR, 69% PR) was not different. An early loss of tumor control with disease progression occurred in 6% in [A1] versus 1% in [A2]. With a median follow-up time of 20 months, there was no significant difference in the median event-free survival (EFS) (22 months in [A1] versus 20 months in [A2]) and not in the overall survival (OS) at 4 years (63% in [A1] versus 65% in [A2]). In ≥ 50% of patients, the time between last treatment and progression was > 16 months. The EFS of patients 60–64 years of age and 65–70 years of age was the same. In conclusion, there was no benefit of conventional induction chemotherapy with VAD- or VAD-like regimens in patients receiving tandem MEL140 with autologous transplantation. This induction treatment therefore may be avoided. Tandem-MEL140 is feasible and well tolerated in the majority of elderly patients with symptomatic myeloma. Its profound and durable anti-tumor effect was demonstrated by prolonged unmaintained remissions. The addition of new agents given as consolidation or maintenance probably will further improve treatment results.