Optimal Therapy for Unfit Elderly Patients

Do new standards of care incorporating immunomodulatory agents and proteasome inhibitors benefit all elderly patients with Multiple Myeloma? The introduction of the immunomodulatory agents (IMiDs; thalidomide, lenalidomide and pomalidomide) and the proteasome inhibitors (PIs; bortezomib and carfilzomib) has not only greatly improved the prognosis of younger patients with MM, also in the elderly patients ≤65 years, the addition of bortezomib, thalidomide or lenalidomide to melphalan and prednisone improved outcome. However, when considering the outcome as described in population based registries (PBR), reflecting real life, the elderly patients appear to benefit less. This lack of impact does not seem to be explained by a biological different, more aggressive disease in the elderly. The limited benefit of novel agents in the elderly as described in PBR might be explained by the fact that the majority of elderly patients are not being included in randomized clinical trials (RCT) because of not fulfilling the eligibility criteria because of co-morbidities. Usually, in these patients treatment is either not given, is given but without the addition of novel agents or with a lower dose of novel agents. That this fact (at least partly) explains the difference in outcome between RCT and PBR indeed, is supported by several observations showing that if novel therapy is given to the elderly outside of RCT, there is an increase in OS, even in the oldest patients. Of course such data analyses are biased by the fact that the reasons for either less or no treatment are unknown, however these data do indicate that also a subgroup of elderly patients do benefit from novel therapies. The challenge therefore is to determine who will benefit from therapy. Are there tools available to define the subpopulation of elderly MM patients that will benefit from treatment? Given the improvement in outcome that can be reached by the implementation of IMiDs and PIs in the treatment of elderly patients with MM, even in patients not being treated in the setting of RCT, there is an urgent need to determine in whom therapy is feasible and in whom treatment will not only fail but might even compromise quality of life. The Comprehensive Geriatric Assessment identifies the general health status including functional, cognitive, social, nutritional, and psychological parameters. It has not only been found to predict OS but also adverse events during chemotherapy. There are however two limitations. Firstly, data on the prospective value of CGA in patients with hematological malignancies are limited, without data on MM patients in specific. A recent systematic review in hematological malignancies revealed 15 studies, showing that geriatric impairments could be detected even in patients with a normal performance status. Comorbidity, physical capacity and nutritional status were independently associated with OS. Only two studies investigated the association between geriatric assessments and chemotherapyrelated toxicity. Moderate to severe comorbidity was a risk factor for non-hematological toxicity in one study, whereas in the other study patients deemed to be unfit showed a 20% chemotherapy-related death, being only 2% in fit patients. Secondly, the CGA is time consuming. Therefore, several studies investigated the possibility of shorter screening versions in order to identify fit patients who are able to receive standard of care with acceptable toxicity and vulnerable patients in whom extensive GA is needed to individualize therapy. A recent publication of the International Myeloma Working Group showed that a concise frailty score, based on age (80 years, score 0,1,2 respectively), CCI (≤1 or ≥2, score 0 or 1) and (instrumental) Activities Daily Life score (ADL >4 or ≤4, score 0 or 1, iADL>5 or ≤5, score 0 or 1), predicted non-hematological toxicity in 869 patients ≥65 years uniformly treated within 3 randomized clinical trials. Frail patients (score ≥2) had a 1.8 times higher discontinuation rate as compared to fit patients (scor 0). No difference was found in hematological toxicity. In a multivariate analysis frailty (HR 1.64, 1.24-2.17), ISS 3 (HR 1.49, 1.17-1.89) and high risk FISH (HR 1.75, 1.38-2.22) equally predicted Progression Free Survival, whereas for OS the HR was highest for the frailty score (HR 3.11, 1.97-4.90) versus (1.77, 1.26-2.63, ISS) and (1.83, 1.26-2.63, high risk FISH)30. Importantly, of the frail patients 17% were 75 years of age. Considerably less toxicity was observed with the use of lenalidomide instead of thalidomide added to melphalan and prednisone, both in the ECOG trial as well as the HOVON/NMSG trial, whereas efficacy was similar. In contrast, superior efficacy as compared to MPT has recently been described in the First trial comparing lenalidomide/dexamethasone until progression (Rd) or for 18 cycles (Rd18) with 12 cycles of MPT. With Rd both PFS and OS was found to be significantly better. The data will be discussed in more detail during the meeting also with regarding to age. Given the first data on the predictive value of geriatric scores (fit - unfit - frail) determined by limited geriatric assessments, this should be implemented in clinical practice. Unfortunately, there are no studies prospectively investigating the clinical outcome in a randomized trial either adapting the dose of anti-MM according to these geriatric assessments or not. Awaiting the results of these clinical trials practical guidelines were recently published that can be used to personalize therapy in the elderly patients being currently treated. In order to realize continuation of treatment by minimizing toxicity, dose modification schemes as proposed in table 1 are of importance.