The continuous addition of novel agents has led to the emergence of questions regarding the relevance of AHSCT in the treatment of MM. But in contrast to popular perception, the morbidity, mortality, and societal costs from non-transplant therapies are not negligible. The Mayo Stratification of Myeloma and Risk Adapted Therapy (mSMART) consensus statement has described the concept of TwiSTT (time without symptoms, treatment, and treatment toxicity). In addition to improving TwiSTT, AHSCT also spares the patient from the financial toxicity of newer novel agents which are currently more expensive than AHSCT [12,13,14].
Despite the valuable role of AHSCT in MM, it is rather a worldwide phenomenon that many transplant-eligible patients do not get the same. A study from Europe pooling 1802 patients revealed that 68.9% of eligible MM patients received an AHSCT. Another study specific to Eastern and Central Europe pooling 522 patients reported that 55.1% of eligible MM patients received an AHSCT [15, 16]. In the Indian scenario, it was reported by Nair et al. that only 26% of transplant-eligible myeloma patients underwent the procedure. The study observed that the most common reasons for eligible patients not undergoing transplants were fear (47%) and financial reasons (46%). The median age of patients who underwent transplants was lower than those who were not transplanted (52 years vs. 60 years) . In comparison, 39.1% of the eligible MM patients in our series underwent an AHSCT, with the median age of transplanted patients in our series being lower compared to those who were not transplanted (53 years vs. 63 years). Another study from a major tertiary center in Southern India pooled 389 patients, of which only 23 (5.9%) underwent an AHSCT . Though the percentage of patients who underwent transplants in our patient population is higher compared to prior data from India, the use of AHSCT is still limited when compared to the west. Interestingly though nearly 80% of patients aged more than 65 years were eligible for AHSCT only 14% of patients underwent the procedure. The common reasons implicated for poor transplant rates in the developing world include fear, poor affordability, and lack of access. However, one needs to consider physician bias about the tolerability of transplants in older patients. This bias was visible in our patient population. In the elderly patients though the majority were fit to undergo AHSCT only 29% of patients were offered the procedure. This bias may also stem from the limited inclusion of patients beyond 65 years old in clinical trials that studied AHSCT .
Frailty can be defined as a collective deterioration of multiple physical and physiological functions leading to a lower tolerance of stressors such as cancer and its treatments [20, 21]. Determination of fitness or frailty is an important challenge, especially to decide upon the intent and intensity of treatment among elderly patients with malignancy. However, there is currently no universally accepted method of frailty assessment. As an example, a systematic review by Buta et al. identified 70 different methods to define frailty .
Our study highlights the use of standardized fitness assessment tools in elderly myeloma patients. Of the numerous available fitness assessment tools, the CCI, the R-MCI, and the HSCT-CI are often utilized in trials involving MM patients. The International Myeloma Working Group (IMWG) frailty score was not used in our study since the same has not been validated for retrospective use . The CCI has indeed been the most studied comorbidity scale and has been widely used in various contexts (including situations not involving malignant disorders). Studies using the CCI have assigned fitness as fit, intermediate fit, and unfit for those with 0, 1–2, or >2 points. The CCI classified 75.3% of the overall patient population in our dataset as being unfit for AHSCT. This index classified all patients >65years years as being unfit. Also, published literature reveals a low predictive value of the CCI for patients aged more than 40 years. Thus, despite having collected data, no further analysis was performed concerning CCI [10, 11, 24, 25]. The R-MCI is a myeloma-specific index that considers pulmonary function, renal function, the Karnofsky Performance Status, frailty, age, and unfavorable cytogenetics as input parameters. The maximum overall score is 9 points. Low, intermediate, and high risk are classified as per scores 0–3, 4–6, and 7–9, respectively. The maximum score for parameters such as renal function, lung function, frailty, and cytogenetics is 1 point each. However, the maximum score for Age and Karnofsky Performance status are 2 and 3 points, respectively. Thus, we hereby note that the R-MCI index is weighted in such a way that a patient with poor performance status and/or age >70 years could receive relatively higher R-MCI scores . The HSCT-CI comprehensively comprises 17 different categories of organ dysfunction, but notably does not include age as an input parameter . Nevertheless, in our series, both the HSCT-CI and the R-MCI demonstrated that at least 4 out of 5 patients aged beyond 65 years were AHSCT eligible. In our data set, the HSCT-CI classified a similar proportion of patients aged ≤ 65 years and > 65 years as transplant eligible, the R-MCI assigned a significantly lower number of patients aged ≤ 65 years as transplant-ineligible when compared to patients aged > 65 years. This could be attributed to the fact that the R-MCI considers age in years as an input parameter, assigning higher scores for those with advanced age.
The median age at diagnosis of MM is 54 years in India, which is a decade earlier compared to the West . Most of the clinical trials utilizing AHSCT in myeloma have enrolled patients younger than 65 years of age. However, myeloma is mainly a disease of advanced age, and using a cut-off at 65 years would exclude a significant proportion of patients from the potential benefits of AHSCT. The same bias against older patients continues beyond clinical trials, and we identify it as another significant reason for the low rates of AHSCT among eligible MM patients. Patient eligibility for AHSCT is ideally done based upon overall health status which can be judged by using standardized fitness assessment tools as shown in our study. In contrast to results described by us and similar studies in India, data from advanced countries in the west show a different trend. Analysis of both the EBMT (European blood and marrow transplantation) and the CIBMR (center for international blood and marrow research) registries have shown a constant increase in the use of AHSCT among patients 65 and older from 1991 to 2010 [29, 30].
It has been reported that there was no difference in terms of treatment-related mortality (1%) for patients aged 60–65 years versus those aged beyond 65 years . It has been argued that patients up to 80 years could be considered for AHSCT provided eligibility. Another study with a median age of 72 years concluded that satisfactory results could be expected with melphalan at a dose of 140mg/m2 . In our study, patients who underwent transplants had better survival compared to patients who were not transplanted irrespective of age. More importantly, none of the transplanted patients aged more than age 65 years had significant morbidity or mortality due to transplant.
There has been a continued improvement in survival in MM with regard to early mortality and outcomes in older patients. Between 2001 and 2010, 1038 patients were grouped as two cohorts: those diagnosed between 2001 and 2005 and those diagnosed between 2006 and 2010. It was observed that the median OS for the 2001–2005 group was 4.6 years and for the 2006–2010 group was 6.1 years. The investigators importantly remarked that the improvement was primarily seen among patients over 65 years. The 6-year OS for those above 65 years of age was 31% and 56% for those in 2001–2005 versus the 2006–2010 group . In a multicenter retrospective collaborative study of the Japanese society of myeloma and the European Myeloma network, it was noted that AHSCT helped enhance outcomes in the elderly. It has been remarked that “transplant eligibility” in itself is a prognostic factor  as seen in our study. Thus, it is safe to conclude that AHSCT is a safe and effective approach among fit, older patients with MM as seen in our study population, and transplant eligibility itself was also prognostic in our study.
Ours is a retrospective study involving a heterogeneous population, and it was not possible to elucidate the possible impact upon OS by factors such as treatment-related mortality (TRM), relapse, comorbidities, differences in induction and maintenance treatments, socioeconomic background, and others.
We acknowledge that “financial unaffordability” is an important factor leading to the low rates of AHSCT among eligible MM patients . Low rates of AHSCT in eligible populations may also be due to false physician perception about patient fitness to undergo AHSCT as shown in our study.