Updates Represent a “Paradigm Shift” for Multiple Myeloma Treatment
Unlike other malignancies, the disease definition of multiple myeloma is clinicopathological: not only must myeloma be confirmed on biopsy by a pathologist, but the definition also requires overt clinical manifestations of harm before treatment can be initiated. This creates a “hurry-up-and-wait” conundrum – patients with probable myeloma cannot get therapy early to prevent organ damage.
This is particularly frustrating for patients with smoldering multiple myeloma, who have an “ultra-high” risk of progression to full-blown disease.
Recently, on October 27, 2014, the International Myeloma Working Group (IMWG; the research division of the International Myeloma Foundation) released an updated version of diagnostic criteria for multiple myeloma. The guidelines, published in The Lancet Oncology, represent a paradigm shift for multiple myeloma treatment – and, since earlier treatment will lead to better outcomes, new hope for improved survival in patients diagnosed with this disease.
It has been 11 years since the IMWG issued its last diagnostic criteria in 2003. However, the authors of the recent manuscript write, “This definition can no longer be justified.”
“[The previous definition] was fine when we had very limited options for therapy, but it’s not fine when we have such great treatments that have more than doubled the survival of multiple myeloma patients,” said S. Vincent Rajkumar, MD, lead author of the Lancet Oncology manuscript. Dr. Rajkumar is also a professor of medicine and chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. “Early therapy is critical if we are ever going to cure this disease.”
New Definitions Incorporate Technical Advances
Multiple myeloma is a blood cancer affecting the plasma cells, and is almost always preceded by two asymptomatic premalignant conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. Previously, diagnosis of multiple myeloma has relied on the presence of one or more “CRAB” features: increased calcium level, renal failure, anemia, and destructive bone lesions.
The new diagnostic criteria – an overview of which is listed in the SIDEBAR – allows physicians to identify “pre-CRAB” patients using validated biomarkers before end-organ damage has occurred. The three markers, called “myeloma defining events” include:
- Sixty percent or greater clonal plasma cells on bone marrow examination
- An involved/uninvolved free light chain ratio of ≥100 or greater, provided the absolute level of the involved free light chain is ≥100 mg/L (a patient’s “involved” free light chain – either kappa or lambda – is the one that is above the normal reference range; the “uninvolved” light chain is the one that typically is in, or below, the normal range)
- More than one focal lesion on magnetic resonance imaging (MRI) that is ≥5 mm in size
The presence of at least one of these three markers will be considered sufficient for a diagnosis of multiple myeloma, regardless of the presence or absence of CRAB features or symptoms.
The update also allows for the use of modern imaging methods – MRI, photon emission tomography (PET), or PET–computed tomography (PET-CT) – to detect osteolytic bone lesions which will enable more accurate diagnosis and intervention, before fractures or other serious problems arise. If imaging studies show changes that are not clear-cut, a repeat examination in three to six months is recommended. “Prior to these methods, we primarily relied on skull x-ray, which may be quite late in showing bone damage,” Dr. Rajkumar said.
Paving the Way for a Cure
This manuscript is a collective effort – more than 180 IMWG researchers decided it was time to update the guidelines, Dr. Rajkumar said, and 34 authors worked on the final product. The process was a major undertaking; in addition to an extensive literature review, several key papers needed to be published to support the major changes.
“There are 34 authors on this manuscript from various institutions and various institutions – some of whom are the world’s leading experts in myeloma,” Dr. Rajkumar said. “I am very confident that this will be incorporated into clinical practice, as well as clinical trials.”
One of the most daunting hurdles, however, has been crossed, he added. “We are now willing to treat multiple myeloma before symptoms happen. The fact that, philosophically, we are willing to do that will enable new criteria to come up and new biomarkers to help us identify more at-risk patients.”
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-48.
Revised IMWG Diagnostic Criteria for Multiple Myeloma and Smouldering Multiple Myeloma
Definition of multiple myeloma
Clonal bone marrow plasma cells ≥10 percent or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:
- Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
- Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance 177 μmol/L (>2 mg/dL)
- Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value o Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
- Any one or more of the following biomarkers of malignancy:
- Clonal bone marrow plasma cell percentage ≥60%
- Involved/uninvolved serum free light chain ratio ≥100
- >1 focal lesions on MRI studies
Definition of smoldering multiple myeloma
Both criteria must be met:
- Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10 to 60 percent
- Absence of myeloma defining events or amyloidosis