Australian experts have been ‘startled’ to discover that many patients with multiple myeloma do not receive recommended imaging and staging, sparking concerns about missed diagnoses and overtreatment of benign forms of the disease.

The findings come from an analysis of real-world data of more than 2400 newly diagnosed patients enrolled in the Myeloma and Related Diseases Registry (MRDR) from 44 sites across Australia and New Zealand.

The analysis published in Clinical Lymphoma, Myeloma & Leukemia, covering eight years of registry data, has highlighted a ‘huge shortfall’ in diagnostic workup, says Professor Andrew Spencer, Head of the Malignant Haematology and Stem Cell Transplantation Service at The Alfred Hospital and MRDR committee member.

“The registry was set up for a number of reasons, part of which was to get more accurate data about survival outcomes in MM across Australia because the available data looked to be woefully inaccurate,” Professor Spencer told the limbic.

This was due at least in part to people with more benign conditions, such as smouldering myeloma, being labelled as having myeloma, he said.

“There are relatively benign disorders that can look the same when you do a bone biopsy so there’s difficulty around getting the right diagnosis so that was one of the drivers of setting up the registry as well as to enable us to benchmark outcomes and look at how care is being delivered.”

Overall, survival outcomes for MM patients with data in the MRDR (PFS 30.8 months and OS 65.8 months) compared favourably to other recently published real-world populations across Europe, Asia and the US.

According to MRDR,  patients not receiving an ASCT had a PFS and OS of 30 months and 68.9 months, respectively. These survival outcomes were superior to those reported in the pivotal FIRST trial.

Those data were particularly significant, said Professor Spencer, because continuous lenalidomide had only been available in Australia as first line treatment for transplant-ineligible NDMM since February 2017 and was still not accessible in New Zealand. This meant a significant proportion of these MRDR patients were treated with a fixed duration of bortezomib-based first line.

Lack of diagnostic imaging

According to the registry data, recommended imaging for plasma cell disorder workup was not always undertaken in this real-world cohort, highlighting an area where practice change may lead to improved patient care and outcomes, said Professor Spencer. He said he and other members of the MRDR steering committee were ‘alarmed’ that there appeared to be patients who were being categorised with more benign MM-related disorders who in fact hadn’t had any radiological imaging done.

“That’s one of the cornerstones of diagnosing myeloma – that there’s evidence of boney disease – and if you’ve not done the imaging how do you know what they’ve got? That was one of the more startling observations – we looked long and hard at the data and we don’t think its because it’s just not entered; we do think there needs to be further eduction about diagnosing and staging these patients.”

The review showed that some 16.8% of MRDR MM patients and 18.4% of SMM patients did not complete any diagnostic imaging assessment, implying the diagnosis of particularly MM had been based on alternative criteria and raising the question of a missed diagnosis of MM in the case of patients with disease labeled as SMM.

Of the 368 (38%) of MM patients with data in the MRDR without lytic lesions seen on skeletal survey, only 105 (28.5%) had further imaging completed, with 48 (45.7%) subsequently having myeloma bone disease confirmed.

And of the 973 patients with data in the MRDR with a diagnosis of MGUS/SMM, 352 (36%) did not have any imaging undertaken.

International Myeloma Working Group (IMWG) consensus guidelines mandate whole body CT as a minimum assessment for all monoclonal PCD except low-risk MGUS, the registry steering committee noted. And they said the importance of recognition of myeloma bone disease ‘cannot be overstated’, given it may be asymptomatic, is associated with non-healing fractures despite effective anti-MM therapy, and increases the risk of further skeletal-related events, which are are themselves associated with significant morbidity and mortality, shorter survival and inferior quality of life.

Considering the potential serious consequences of skeletal-related events for patients, the finding represented an opportunity for practice change to provide immediate improvement in patient outcomes, according to Professor Spencer.

Meanwhile, with just over half (50.7%) of MRDR patients having the information needed to calculate a revised ISS score (R-ISS) – and the proportion of patients with this information available in a clinically useful timeframe much smaller – Professor Spencer questioned the usefulness of the tool to stratify risk at diagnosis and guide treatment decision in a real-world setting.

“The revised ISS, which is a more refined system that incorporates chromosome testing, is considered the gold standard. But when we looked at the registry only about 50% of patients in Australia have chromosome testing results available – and of those, the overwhelming majority don’t get those results for weeks. So you’ve already started therapy without knowing what the results are.”

He said there were more timely ways of getting such results, which he had been trialling at the Alfred Hospital.

“There are more elegant ways of doing this with gene expression profiling where you get a result in 72 hours which we’ve been using at my centre in trials with newly diagnosed patients. And we’re starting to explore whether this could be funded in Australia as a diagnostic approach.”

Overtreatment

The analysis also picked up a minority of real-world patients who had MM therapy initiated without fulfilling the currently accepted SLiM or CRAB (increased calcium level, renal dysfunction, anaemia, destructive bone lesions) IMWG diagnostic criteria, suggesting that physicians, patients, or both may be unwilling to wait for a MM-defining event to occur, noted Professor Spencer.

“I think what it boils down to is that the physician and the patients look at the numbers and they treat based on fear of progression, perhaps not understanding that even if the numbers look bad a lot of these people won’t progress to myeloma or they won’t do so for a long time.”

These patients could be well for years before requiring treatment – by then the therapeutic landscape could be quite different, he adds.

“It may be a lot better and these patients won’t have been subjected to the toxicity and inconvenience of treatment when they didn’t need to be treated and that’ the complexity of diagnosis and an area where there needs to be reinforcement around the natural history of the disease.”