More patients than ever could be eligible for transplant

Traditionally, an arbitrary measure – age – has been the marker of a patient’s eligibility for autologous stem cell transplantation (ASCT).¹ Which side of the golden age of 65 a patient was determined their treatment choice – to transplant – or not to transplant. These days, with a growing number of objective health assessment scales, chronological age is becoming less relevant, and the fitness of the patient is growing in prominence.¹

the limbic spoke with Professor Mohamad Mohty, Professor of Haematology and Head of the Haematology and Cellular Therapy Department at the Saint-Antoine Hospital and University Pierre and Marie Curie, France during his 2017 tour of Australia to discuss the changing face of multiple myeloma patients and what this means for the clinicians who treat them.

Prof. Mohty explains how haematologists are becoming used to clinical judgement of patient fitness for treatment.

“Gone are the days of using age as the primary marker for eligibility for transplant. These days rather than just using chronological age, we also look at the physiological age of the patient” he explains.

Rather, the physiology and fitness of the patient is more important than their date of birth.

“If they are relatively healthy, have few or no comorbidities, then the fact they are over the age of 65 years has no real bearing. You might have a relatively young patient, say 55-years old with heart failure or diabetes – this patient may not be eligible to transplant and use high-dose chemotherapy. On the other hand, you may have a 70-year old patient with no prior history or comorbidity, very fit – this patient should be handled like a ‘young’ patient.”¹ Professor Mohty says

This approach has been adopted in Australia, where guidelines state the traditional notion that patients aged above 65 years are ineligible for ASCT is no longer appropriate.¹ It is clear that older patients who are biologically fit do benefit from intensive treatment.^1,2

In assessing eligibility for ASCT (generally in patients aged up to 70 years), individual assessment that takes into consideration the patient’s age, comorbidities, frailty (variously defined as poor endurance, weakness and low physical activity) and disability (dependency in activities of daily living due to physical or mental impairment) is required (please refer to the section on patients ineligible for ASCT).^1,3 They recommend clinical tools such as the haematopoietic stem cell transplant co-morbidity index may be useful to assess suitability for ASCT.^{1,4 “}These tools are quite useful,” notes Prof. Mohty, “but over time their utility in clinical practice may become less as clinicians become at ease with identifying patient fitness. However, we need to ensure we are diligent in screening patients to ensure patients receive the most intensive therapy they can tolerate.”

As the eligibility and fitness assessment of patients evolves, more patients become engaged in their health and wellness, clinicians might expect to see a rise in the number of patients eligible for transplant over time.⁵ Prof. Mohty reiterates, “While the majority of the patients we see are still ineligible for ASCT, we are seeing more patients over the age of 65 years being treated with transplant because they are fit enough to handle the treatment. We should not be afraid to consider transplants in these patients as the evidence is there to demonstrate a real benefit for them in terms of survival – which, after all, is what we are trying to achieve.”

The increased use of transplant in the ‘elderly’ is a trend that is also evident in Europe. In a 2015 publication in Bone Marrow Transplantation, Auner et al. described the highest increase in patients undergoing ASCT was in patients over the age of 65 years – which accounted for 3% of all transplants between 1991 to 1995, but up to 18.8% of transplants between 2006 to 2010.⁵ They reported survival improved considerably more in older than younger patients in recent years, with survival over 2- and 5-years around 80.2% and 49.7% respectively for those over the age of 70 years.³

“With the goal of improved survival in mind, so long as the patient can handle the transplant process it is preferred,”¹ says Prof. Mohty. “As we all know, sequencing of therapy is probably one of the most topical issues in multiple myeloma now – so too the importance of transplantation where tolerated.”

Keep the pressure on with intensive therapy

When it comes to overall survival, durability of response is the driving factor behind it.¹ There is evidence demonstrating the importance of intensity of therapy on the durability of response, in terms of complete response (CR) in patients younger than 65 years of age.

In one study, high-dose chemotherapy with ASCT produced higher rates of CR (44%) than patients who received standard-dose chemotherapy with ASCT (8%), p<0.001).⁶

Again, this approach is supported by Australian guidelines where high dose therapy and ASCT remains the standard frontline treatment for patients aged ≤65 years, and patients between 65 to 70 years with good performance status and organ reserve (Grade A recommendation, level 1B evidence for patients age ≤65; grade B recommendation, level 2A evidence for patients aged >65 years).¹

The same principle of intensive therapy applies to all patients explains Prof. Mohty. “It is important to treat as intensively as possible to achieve remission – even minimal residual disease (MRD) negativity. For those who are deemed transplant ineligible because they are not fit enough for ASCT, you want to balance intensity of therapy with the least side effects possible.

For these patients, periods of treatment, followed by short drug-free ‘holidays’ can offer a balance between the two. However, it is important if this approach is taken to keep treating patients for as long as possible to sustain remission and prolong time to relapse.”¹

“If you take the example of bortezomib-based frontline regimens, as you have the option to treat patients with intensive therapy in 6-week cycles. If you stop treatment early, so before 30-or-so doses, you cannot expect to see the full benefits we observe in the trials,”⁷ explains Prof. Mohty.

As reported in the VISTA clinical trial, where patients received nine 6-week cycles of bortezomib-melphalan-prednisone versus melphalan-prednisone, overall survival benefits were still observed at the 60.1-month (median) follow-up.⁸

In these frontline transplant ineligible patients, this treatment regimen did not raise any significant safety signals beyond traditional melphalan-prednisone.^7,8 For Prof. Mohty, it comes down to a commitment to whatever frontline regimen you choose, “we need to make sure that our patients complete the course for the best possible outcomes.”^7,8

 In this case, Prof. Mohty continues “particularly in these less fit, transplant ineligible patients, we adopt a more consistent approach – balancing tolerability with intensity of treatment – but remembering we need to treat for longer to reap the rewards.”^7,8

This article was sponsored by Janssen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Janssen.

References:

1. Medical Scientific Advisory Group (MSAG) to the Myeloma Foundation of Australia (MFA). Clinical Practice Guideline Multiple Myeloma, V4 March 2017.
2. Muchtar E et al. Autologous stem cell transplant for multiple myeloma patients 70 years or older. Bone Marrow Transplant, 2016.
3. Charlson M et al. J Clin Epidemiol47(11):1245–51.
4. Saad A et al. Biol Blood Marrow Transplant 2014;20(3):402–408 e1.
5. Auner HW et al. Bone Marrow Transplant 2015;50:209–215.
6. Child JA et al. N Engl J Med 2003;348:1875–1883.
7. San Miguel JF et al. N Engl J Med 2008;359:906–917.
8. San Miguel JF et al. J Clin Oncol 2013;31(4):448–455.