Low incidence of SPMs after ASCT with novel agents

Over the last decade, the use of novel agents, such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), has led to a significant increase in the median overall survival rate in MM patients. However, long-term complications such as second primary malignancies (SPM) are more likely to occur as patients live longer.

Firoozeh Sahebi from City of Hope, Duarte, US, and colleagues, investigated the incidence of SPM in Multiple Myeloma (MM) patients who were registered in the European Society for Blood and Marrow Transplantation (EBMT) database. Data was collected by Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma (CALM). CALM is a non-interventional prospective study which ‘reviewed the relapse rates in patients with myeloma or lymphoma whose stem cells were mobilized using plerixafor (NCT01362972)’. This study was limited to Newly Diagnosed Multiple Myeloma (NDMM) patients (pts) who had an upfront autologous stem cell transplantation between 2008-2012. This study was published in Biology of Blood and Marrow Transplantation in January 2018.

Patient characteristics:

• A total of 3204 MM patients (pts) were enrolled; median age = 59 years (19–77 years)
• Pts that underwent their first transplant within 12 months from the diagnosis = 2567 (80.1%) and pts that had their transplant after 12 months = 637 (19.9%)
• Induction regimens differed in the 2714 pts
• Transplant after one line of therapy = 65.2%; after 2 lines of therapy = 23.9%; after > 2 lines of therapy = 10.9%; radiation therapy prior to auto-HSCT = 19.8%

Key findings:

• Median follow-up = 58.6 months (0.53–105 months)
• Total SPM identified = 135, with a cumulative incidence of 4.3% at 60 months (95% CI, 3.5%–5.1%) and 5.3% at 72 months (95% CI, 4.4%–6.3%)
• Median time to SPM = 33 months (2.1–86.5 months)
• 94 pts developed solid SPM with a cumulative incidence of 1.4% at 72 months
• 30 pts developed hematologic SPM with a cumulative incidence of 3.6% at 72 months
• OS:
  • Entire cohort = 65.3% at 60 months (95% CI, 63.4%-67.2%)
  • Post development of SPM = 37.5% at 60 months (95% CI, 23.6%-51.5%)
  • Pts that developed hematologic malignancies = 15.2% at 36 months (95% Cl, 0%–32.5%)
  • Pts that developed solid SMP = 58% at 36 months (95% Cl, 46.8%–70.0%)
• Higher incidence of SPM in pts >65 years of age (Gray test P = 0.012)
• Lower OS associated with prior radiation (P = 0.022), poor Karnofsky score (P = 0.01), disease status < partial response at transplant, >65 years (P = 0.005), based on a univariate analysis
• No significant influence on the incidence of SPM with the use of prior radiotherapy, CD34+ cell dose collected or infused, Karnofsky score, disease status at transplantation, mobilization status, and use of plerixafor
• Higher incidence of SPM in pts treated with alkylating agents alone or IMiDs alone as induction therapy vs PI therapy, although not statistically significant
• Probability of developing SPM = 7.0%; death from causes other than SPM = 61.0%

An important observation in this study was the low incidence rate for SPM in patients receiving high dose chemotherapy and ASCT, as well as a lower cumulative probability of SPM in comparison to the probability of death from any other cause. A statistically significant association between lower survival rate and patients over the age of 65 was identified. It is recommended that detecting and intervening early for SPM ‘should become part of long-term care’ for surviving MM patients. The authors acknowledged that limitations included the inability to assess the effect of maintenance therapy and that only patients that had undergone high dose chemotherapy and ASCT were assessed.