EHA 2016: Managing multiple myeloma in elderly/frail patients. Professor Antonio Palumbo (University of Torino, Italy) discusses the impact of age on outcomes (abstract E1295) and Professor Roman Hajek (University of Ostrava, Czech Republic) talks about preferred therapeutic strategies for elderly MM patients.

Managing multiple myeloma in elderly/frail patients

 

Although multiple myeloma is a disease of old age, elderly patients vary a great deal in terms of fitness and ability to tolerate treatment. In addition to chronological age and performance status, treatment decisions and prognoses in elderly MM patients should be based on assessments of frailty. In 2015 the International Myeloma Working Group (IMWG) proposed a frailty score which was based on validated geriatric assessment tools and was shown to predict survival and toxicities in elderly patients with newly-diagnosed MM.¹

Professor Thierry Facon and co-workers (poster presentation P656) applied the IMWG frailty score on 1,517 patients included in the FIRST trial. This pivotal phase 3 trial showed that continuous lenalidomide and dexamethasone (Rd) treatment was associated with significantly prolonged PFS and OS compared with fixed-duration Rd for 18 cycles of melphalan, prednisone and thalidomide (MPT) in transplant-ineligible patients with newly-diagnosed MM.² The analysis by Professor Facon and co-workers showed that the majority of patients were frail (54%, vs 17% fit and 30% intermediate). Frail patients were older and had poorer performance status and worse renal function. PFS and OS were prolonged in fit and intermediate patients compared with frail patients (hazard ratio [HR] for PFS: 0.67 [p<0.001] and 0.81 [p=0.004], respectively; HR for OS: 0.42 and 0.62, respectively [p<0.0001 on both]). Response rates were similar across frailty groups with overall response rates of 74-79%. Whilst discontinuation rates and grade ≥3 haematological adverse event rates were similar across frailty groups, fit patients were less likely to experience a grade ≥3 non-haematological adverse event compared with frail patients (HR 0.77; p=0.0021. The investigators concluded that the analysis supports the use of the frailty score for predicting the risk of death in patients with newly-diagnosed MM.

 

A group of researchers at the University of Athens School of Medicine in Greece (Katrsitis et al, poster P657) reported on a prospective evaluation of a range of different geriatric assessment tools in unselected real-world patients aged over 65 years with symptomatic MM. The analysis comprised 144 patients with a median age of 76 years; the tools used were the G8 geriatric assessment screening tool (G8-GAS), VES-13, GDS, Katz Activity of Daily Living (ADL), Lawton Instrumental Activity of Daily Living (IADL), MMSE, KPS (%), ECOG PS, the number of falls in the past 1 and 6 months, lower-extremity function and disability, nutritional assessment tools (DETERMINE and Mini Nutritional Assessment), social support score, cognition evaluation tools (MMSE), Geriatric Depression Scale, and comorbidity indices (Charlson Comorbidity Index [CCI], CIRS-G, ACE-27). The results showed that several of the tools had prognostic significance including the number of falls in the past 6 months (p=0.002), lower extremity function (p=0.014), Mini Nutritional Assessment (p=0.014), G8-GAS (p<0.001), KPS <50% (p<0.001), ECOG PS >2 (p=0.04) and MMSE (p=0.024). Unlike the IMWG frailty score, KPS ≤50% (p=0.003) and ECOG PS >2 (p=0.05), Geriatric Depression Scale (p=0.018) and G8-GAS score (p=0.015) were all associated with early death. In multivariate analysis the number of falls in the past 6 months (HR: 4.7, p=0.007) and the score of the G8-GAS tool (HR: 4.7, p=0.004), but not the IMWG frailty score, were independent predictors of survival.

 

Another study from Athens (Nikolaou et al, poster E1303) assessed frailty in a population of younger MM patients (median age 69 years) based on renal scores, Katz and Akpom’s basic activities of daily living (BADL) scale, Lawton and Brody’s IADL, and the CCI. Somewhat paradoxically, the investigators found that the frailty score was a better predictor of OS amongst MM patients aged under 65 years.

 

Another theme at EHA 2016 with respect to management of elderly MM patients was the use of carfilzomib once weekly instead of twice weekly for improved tolerability in frail patients. Professor Xavier Leleu from Poitiers (presentation S100) reported on the results of Carmysap, a phase 1/2 multicentre open-label single-arm study to determine the maximum tolerated dose (MTD) of carfilzomib administered once weekly in combination with melphalan and prednisone (KMP) followed by weekly carfilzomib maintenance in elderly patients with newly-diagnosed MM. A total of 30 patients were treated with carfilzomib doses of up to 70mg/m². There was one report of dose-limiting toxicity (DLT) in the 36mg/m² cohort (grade 4 lymphopenia), one in the 45mg/m² cohort (lysis syndrome complicated with grade 4 renal insufficiency, two in the 56mg/m² cohort (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 in the 70mg/m² cohort (vomiting grade 3 and liver cholestase enzyme grade 3). The ORR in the study is 87.5%, with 33% achieving at least CR. At a median follow-up at 12 months, one patient had progressed and one patients had died of cardiac dysfunction considered related to carfilzomib in the 56 mg/m² cohort. Overall, there were 22 SAEs reported for a total of more than 200 cycles of KMP administered. The investigators concluded that the MTD has not been reached and 70mg/m² should be the recommended phase 2 dose.

 

A similar study reported by Dr Sara Bringhen form Turin (presentation S102) evaluated weekly carfilzomib in combination with cyclophosphamide and dexamethasone (KCyd) in transplant-ineligible patients with newly-diagnosed MM. ORR during induction was 88% with 12% achieving CR. At one year PFS was 79.4%; 18% of patients discontinued treatment due to an adverse event. The investigators concluded that weekly KCyd as induction followed by weekly carfilzomib maintenance appeared safe and effective, with response rates comparable to those seen with twice weekly carfilzomib.

 

In the refractory-relapsed setting, Mr James Berenson from Los Angeles presented the CHAMPION phase 1/2 study (poster S661) which showed that once-weekly carfilzomib at a dose of 70mg/m² in combination with dexamethasone was associated with an ORR of 77% (13% achieving at least CR) and a median PFS of 14.3 months in MM patients with up to 3 prior lines of therapy. Patients with bortezomib-refractory and lenalidomide-refractory MM showed ORRs of 63% and 69%, respectively. Once-weekly carfilzomib is currently being evaluated in a phase 3 superiority study, the ARROW study (NCT02412878).

 

 

References

1. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 2015;125:2068-74.
2. Hulin C. Effect of age on efficacy and safety outcomes in patients with newly diagnosed multiple myeloma receiving lenalidomide and low-dose dexamethasone (rd): the FIRST trial. Haematologica 2015;100:1-804.