The concept of a cure in MM: a comparison of survival outcomes

Multiple myeloma (MM) is commonly described as incurable, yet patients with MM now have a very different outlook to patients 10 years ago. The advent of novel agents has seen the treatment journey transformed, with many more options now available for patients at different stages, experiencing multiple relapses. However, the concept of a cure in MM has been debated, as this depends on the chosen definition and whether that be a ‘complete cure’ or a longer period of being in a ‘disease free’ state.

Despite survival advantages with novel therapies, MM is still in general considered incurable, as patients are resigned to ongoing treatment that results in disease control, rather than a cure in its purest definition. Other malignancies, such as Hodgkin Lymphoma (HL) and Diffuse Large B Cell Lymphoma (DLBCL), are considered curable as patients can hope for a normal life-span after a short course of therapy. However, with longer survival times for MM patients, many physicians have challenged whether MM should continue to be described as incurable. In order to test the definition of a cure in MM, Praful Ravi and colleagues at the Mayo Clinic, Rochester, MN, USA, conducted a retrospective analysis of to compare the survival of young patients (< 50 years of age) with MM to the survival of young patients with follicular lymphoma (FL), HL and DLBCL. Their findings were published in Blood Cancer Journal in February 2018.

Key Highlights:

• MM cohort = 212 patients (pts) < 50 years of age, diagnosed with MM at the Mayo Clinic between January 2005 and December 2015
• Lymphoma cohort = pts < 50 years of age with FL = 168 pts,  DLBCL = 195 pts, and HL = 233 pts; all were enrolled in the SPORE Molecular Epidemiology Resource (MER) at the Mayo Clinic between January 2005 and June 2015

All data points are given in the order: MM, FL, DLBCL, and HL

• Median age at diagnosis (years): 45, 42, 41, and 32
• Median follow-up (years): 5.8 (95% CI 5.0–6.7), 5.0 (4.3–5.8), 4.9, and 4.1 (3.6–4.7)
• Survival outcomes and comparisons with the background population:
  • 5-year OS: 70.2% (63.7–77.4), 93.1% (88.7–87.6), 80.0% (73.9–86.6), and 94.5% (91.4–97.8)
  • 5-year PFS: 28.3% (22.0–36.3), 59.1% (51.0–68.5), 69.0% (62.4–76.3), and 85.0% (80.3–90.0)
• There was no difference in OS and PFS curves for MM patients stratified by the International Staging System (ISS)
• Standardized excess mortality ratio (SMR) was used to compare observed vs expected survival
• A significant SMR was seen at the time of diagnosis in all four diseases: 19.5 (15.2–24.5), 4.2 (2.3–7.2), 13.0 (9.2–18.4), and 5.2 (2.6–9.3) (comparing survival to the age- and sex-matched background population)
• As patients are more likely to be cured within the first 3 years after diagnosis, a 36-month landmark analysis was carried out to compare outcomes:
  • Number of pts: MM = 143; FL = 114; DLBCL = 110; HL, n = 140
  • 3-year OS rates: 75.6% (68.1–83.9), 95.8% (91.9–100.0), 95.8% (91.9–100.0), 99.2% (97.8–100.0)
  • SMR: 20.7 (14.7–28.3), 3.8 (1.5–7.8), 3.1 (0.8–8.0), and 0.9 (0.0–5.1)
  • SMR was significantly high for MM, and FL, but not DLBCL and HL, with a 20-fold excess mortality risk for MM at both diagnosis and 3-years post-diagnosis

It was concluded that MM remains an incurable disease, with a cure defined as ‘treatment with subsequent complete resolution of the disease’ and the expectation that patients can hope for a normal life expectancy. However, this was a retrospective analysis, using young patients (≤ 50 years of age) treated heterogeneously. Whilst these patients, in general, are expected to have better survival outcomes, it is unknown whether young age might add a stronger genetic component and therefore more aggressive disease. Nevertheless, it was clear from this study that patients with MM in this age range had substantially worse outcomes than patients of a similar age with HL and DLBCL.

Traditionally, survival beyond 5-years was considered a cure in cancer and in this respect MM has reached that goal, but the definition has now changed, with longer treatment-free periods and indefinite survival times now the ultimate goal of a cancer cure. With current regimens, this is not yet the case for MM, but with promising cellular technologies such as CAR T-cells on the horizon, this will certainly be challenged in the near future. The more difficult goal for physicians will then be obtaining these therapies for all their patients at an affordable cost.