Triple drug therapy for myeloma: when is more, better?

MYELOMA is predominantly a disease of the elderly, with the median age of patients being 65–70 years. In Australia, it is estimated that 2000 Australians were diagnosed with multiple myeloma in 2019, and approximately 18 000 people in Australia are living with myeloma at any one time.

The typical journey of a patient with myeloma is one of response, remission and relapse. As such, management must focus on obtaining durable disease remissions while maintaining quality of life in this elderly population. Younger patients routinely receive induction therapy followed by high dose chemotherapy with autologous stem cell transplant (AuSCT).

For elderly (non-transplant eligible) patients, treatment selection has been until recently a choice between the thalidomide-derivative lenalidomide or the proteasome inhibitor, bortezomib, both typically combined with dexamethasone. Recently, the Pharmaceutical Benefits Advisory Committee recommended a three-drug combination for myeloma, namely lenalidomide with bortezomib and dexamethasone, otherwise known as RVd. The question that faces treating clinicians now is: which patients do we select for the triple therapy? The decision of course must be based on a balance between efficacy and toxicity.

Clearly the RVd combination is a highly efficacious regimen for transplant-ineligible patients with newly diagnosed myeloma. Indeed, the median progression-free survival for patients receiving the three-drug combination was 43 months. This is impressive given the median survival for myeloma is 7 years. Moreover, we know that the first two lines of therapy for patients with myeloma is the most critical. While all patients relapse after first-line therapy, only 61% of patients go on to second-line therapy, and just 38% and 15% reach third- and fourth-line therapy respectively. This has been confirmed in the Australian context using the Monash University Myeloma and Related Diseases Registry.

Therefore, maximising first-line therapy remains the best opportunity to optimise long term patient outcomes. Consequently, clinicians should be aiming to get the most durable remissions from these first two lines of therapy. It would seem obvious then to use a three-drug combination, where feasible, to achieve the best response rate and consequently a long first remission. This is a “no-brainer” in younger transplant-eligible patients who achieve high response rates with RVd and so move into the AuSCT phase in deeper remissions and consequently longer survival.

However, for older patients, the price paid for combining three drugs is the potential for more side effects. Indeed, the Australasian Leukaemia Lymphoma Group, supported by the Medical Research Future Fund, is about to undertake a large study of more than 300 patients, addressing the very question of the tolerance of RVd compared to Rd (lenalidomide and dexamethasone) or Vd (bortezomib and dexamethasone) in older patient populations.

It is obvious that the likelihood of drug toxicity will be dependent on the patient’s pre-treatment frailty. But how do we assess frailty? Can we rely on clinicians just “eyeballing” the patient to make a decision between a two-drug or three-drug regimen? Ask any physician who treats myeloma and they will say that the best tolerated regimen is lenalidomide-dexamethasone, followed by bortezomib-dexamethasone, then lenalidomide with bortezomib and dexamethasone (RVd). Our challenge is to balance tolerance with efficacy. So, is it possible to make a less subjective assessment (than we do today) of the patient’s capacity to tolerate these regimens?

Selecting patients for the “right treatment” must go beyond just examining the characteristics of those entered on clinical trials. It is well recognised that although trial data are crucial for determining the efficacy of various therapies, the patients that enter such clinical trials do not always represent real-world patients and real-world outcomes. Indeed, in myeloma trials, the median age and performance status of patients on trials is typically less than in the real world.

In an attempt to deal with this issue, geriatricians have been developing practical tools to evaluate a patient’s frailty as part of a geriatric assessment. Comprehensive geriatric assessment aims to identify and manage age-related problems, allowing clinicians to select therapy appropriately, avoiding over- and undertreatment and reducing the risks of toxicity. However, full geriatric assessment is challenging to perform in daily clinical practice. Thus, more feasible indexes have been developed for myeloma, including the International Myeloma Working Group Frailty Index, the Revised Myeloma Comorbidity Index and the Mayo Frailty Index (here and here). These include a combination of patient characteristics (eg, age, performance status), biological parameters (eg, renal and lung function, NT-Pro-BNP [N-terminal pro-brain natriuretic peptide] and disease parameters (cytogenetics). However, some await to be formally validated and none are currently routinely used. Until we develop and routinely use objective frailty assessments, we are at risk of inducing unwanted side effects as we chase better responses and longer remissions.

The next drug in line to add to upfront triple therapy is daratumumab, an anti-CD38 monoclonal antibody. This immunotherapy is the first of a new era of such drugs in myeloma. Trials of antibody drug conjugates, bispecific T cell engagers (BiTE) therapy, and chimeric antigen receptor T cell (CAR-T) therapy are advanced and very promising. The place of such immunotherapy for patients with myeloma will be the focus of intense research over the next 10 years. Again though, we need to balance toxicities with benefit in this elderly patient population, especially as these treatments are used later in the patient’s disease.

It is clear in myeloma that the best outcome is to get deep and durable responses early in the patients’ disease journey; relatively few patients get beyond second- or third-line therapy. It is evident that the combination of lenalidomide and a proteasome inhibitor with dexamethasone is the standard-of-care front-line therapy for all patients with myeloma who can tolerate it. It behoves all clinicians to focus on developing and using reliable tools that predict frailty so we can choose the best combinations that give the best remissions with acceptable toxicity.

Professor H Miles Prince AM is the Director of Cancer Immunology and Molecular Oncology at Epworth Healthcare, and a haematologist at the Peter MacCallum Cancer Centre, Melbourne. He is also a Professor of Medicine at Melbourne and Monash Universities, and Chair of the Medical Scientific Advisory Committee for Myeloma Australia.

 The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.