General MM,  

Frailty replaces old age in geriatric assessments for MM 

Multiple Myeloma (MM) is predominantly a disease of old age, affecting 35-40% of patients over the age of 75. Patients are treated according to their suitability for bone marrow transplant. Historically, this decision was based on age, with patients older than 75 years considered non-eligible for transplant, and those younger than 75 and in general good health eligible for a transplant. However, with an increasing awareness that patients should be assessed for treatment on an individual basis, rather than just age, improved means of identifying patients that are frail and unsuitable for transplant have been devised. In addition, since many of the clinical trials have excluded patients over 75, treatment decisions are difficult for this age group as efficacy data is limited.

In a review written for the journal Current Opinion in Oncology, Sonja Zweegman from the Department of Hematology, VU University Cancer Center Amsterdam, The Netherlands, along with colleagues Monika Engelhardt and Alessandra Larocca, outlined the need for improved measures in order to identify frail patients, and explained the changes now in place for assessment, and the treatment decisions that might follow.

 Key Points:
  • MM Patients ≥ 75 years of age can be highly heterogeneous and should be assessed as either fit, intermediate-fit or frail
  • Many treatments have only been assessed in fit and intermediate-fit patients, so identifying ‘geriatric impairment’ is necessary to enable correct treatment choice
  • First line treatments for patients non-eligible for transplant include:
    • bortezomib, melphalan and prednisone (VMP)
    • thalidomide, melphalan and prednisone (MPT)
    • lenalidomide and dexamethasone (Rd)
  • Treatments, both in clinical trials and real-life practice, are generally less effective in patients ≥ 75 years
  • This may be due to higher comorbidity rates, increased toxicity of both PIs and IMiDs and higher discontinuation rates, as well as lower doses of drugs offered by physicians in clinical practice
  • Better results in OS have been reported outside of clinical trials, indicating that a sub-group of elderly patients benefit from novel therapies
  • Identifying which patients fall into this subset is important, as higher risks have been noted for patients ≥75 years of age with real impairment
  • Comprehensive geriatric assessment (CGA) to assess elderly patients that will benefit from novel treatments include:
    • International Myeloma Working Group (IMWG) frailty index – validated and found to have significant prognostic value
    • Revised Myeloma Comorbidity Index (R-MCI) - validated in a German cohort; advantages include accurate assessment of physical conditions and simple clinical applicability R-MCI was
  • Assessments can be performed quickly using:
  • Clinical trials that include patients ≥ 75 years, with the aim of steering ‘frailty-directed treatment selection’ are underway, with results expected in 1-3 years
  • Preliminary data from these studies can already help direct treatment decisions
  • Regimens with lower doses of all drugs are recommended as frailty scores increase, and were outlined
  • In particular decreasing the dose of dexamethasone from 40 mg to 20 mg/week was well tolerated in frail patients without additional toxicity
  • Shorter induction therapy followed by maintenance is also recommended
Conclusion

With an increasingly aging population, studies for new therapies need to be extended into the elderly population with results stratified using the new indicators for a measure of fit, intermediate-fit and frail. Identifying patients in these categories will help steer appropriate treatment options, to limit toxicity and discontinuation, and improve quality of life. Further practical details regarding the frailty index can be found in the updated ESMO Clinical Practice Guidelines.

 Abstract

PURPOSE OF REVIEW: 

To describe how to better identify frail multiple myeloma patients and to treat them appropriately.

RECENT FINDINGS:

Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly.

SUMMARY:

Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.

References
  1. Zweegman S.et al. Elderly patients with multiple myeloma: towards a frailty approach? Curr Opin Oncol. 2017 Sep;29(5):315-321. doi: 10.1097/CCO.0000000000000395.
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