Treatment approach for young, fit, newly diagnosed multiple myeloma patients (2018)

Mrs. K is a 62-year-old woman who notes a 6-month history of worsening midthoracic back pain with marginal relief from increasing doses of ibuprofen. She is a school librarian working in a rural community and married, with 3 children out of the house. An X-ray of the thoracic spine reveals small lytic lesions, which are confirmed on subsequent magnetic resonance imaging (MRI) scans of the thoracic spine and lumbar spine. Blood studies revealed elevated globulin levels prompting the following workup on referral to the medical oncologist: normal serum calcium level, normal serum creatinine levels (0.8 mg/dL), hemoglobin 10.8 g/dL, serum albumin 3.2 g/dL, immunoglobulin G (IgG) κ isotype by serum immunofixation, serum electrophoresis shows an M-protein spike of 3.8 g/dL, total serum IgG 4.7 g/dL, low IgM/IgA, serum free κ light-chain levels 2550 mg/L, serum free λ light-chain levels 21 mg/L, free λ/κ ratio >100, and serum β-2–microglobulin 4.2 mg/dL. A 24-hour urine protein electrophoresis showed 55 mg proteinuria, with 30% urine M protein. Skeletal survey revealed >20 small lytic lesions and no impending fractures in weight-bearing areas. Bone marrow biopsy revealed 50% cellularity and 70% atypical plasma cells with κ restriction consistent with myeloma, and fluorescence in situ hybridization (FISH) testing revealed hyperdiploidy in 55% of cells. Mrs. K is informed of the diagnosis of IgG κ multiple myeloma (MM) revised international staging system (ISS) stage II disease and the need for therapy.1 She requests consultations with 2 of the leading world experts; however, she wants to return to her rural community for initial therapy and is refusing clinical trial participation. Would you advise any other testing here?

It is important to highlight some of the recent changes in the imaging recommendations from the International Myeloma Working Group (IMWG).2-4 There has been an increased use of novel imaging to assess both bone disease burden and the disease response in clinical trials,5-7 and these data do eventually impact clinical practice. We now recognize, based on recent studies looking at prospective comparison of skeletal surveys with positron emission-computed tomography (PET-CT) and whole-body MRIs,8,9 that skeletal surveys do not reveal lytic bone disease until 70% of the bone has decalcified and that damage is detected much earlier with both PET-CT and MRI techniques. A patient may appear to have no bone lesions on skeletal survey but will have bone damage detected by novel imaging qualifying them for a symptomatic disease and active therapy, thus preventing morbidity and debility from bone fractures.

PET-CT have shown prognostic value as well, and it has been shown in several prospective trials10 that having 3 or more 18F-fluorodeoxyglucose avid lesions at the time of diagnosis confers shorter progression-free survival (PFS) as well as poor overall survival (OS) for newly diagnosed, transplant-eligible myeloma patients. Additionally, posttransplant suppression (complete suppression of those lesions) confers superior OS, even in patients who have complete response. Based on these observations, clinical trials are utilizing PET-CTs for newly diagnosed patients at baseline as well as postinduction and posttransplantation. PET-CT negativity has been incorporated in the updated IMWG response criteria.11 PET-CTs also help us recognize extramedullary disease, which is an aggressive phenotype of high-risk myeloma, and if we are not doing PET-CTs, we will not recognize these patients at baseline.6 The IFM2009 clinical trial12 data have also shown us that minimal residual disease (MRD) assessments by flow cytometry and PET-CT serve as surrogate markers for improved survival outcome, but not all patients are negative with both techniques. This trial has also shown that patients may be MRD negative by flow cytometry and still positive on PET-CTs, showing us the heterogeneous nature of the disease when it comes to skeletal involvement. It is important to recognize that the MRD flow only represents sampling from the pelvic bone, and the disease may be active in other areas of involvement (vertebral bones, skull, long bones, etc.); we will not necessarily find that just by doing MRD flow cytometry on the pelvic bone. Therefore, PET-CTs are becoming more important.

The second issue to highlight is the genomic heterogeneity of MM biology, which is more complex than just conventional cytogenetics and FISH differences. The field is moving quickly toward getting more comprehensive biologic information on MM patients by way of gene expression profiling (GEP) as well gene mutational panel studies (RNA sequencing and whole-exome sequencing), and the MMRF CoMMpass study13,14 is a big example of that. We can recognize different molecular subgroups of myeloma with different clinical outcomes, no longer leaving one to wonder why 2 ISS I patients with “normal” cytogenetics behave so differently in regard to survival outcomes. GEP studies have already identified at least 7 different molecular subgroups of myeloma patients with different prognoses, and they help us to identify the high-risk patients in a broader category. There are 2 GEP signatures that were identified by the Arkansas group15 as well as the HOVON group16 that can identify 20% patient at very high risk of early relapse/death. There are clinical trials evaluating alternative strategies for high-risk patients; GEP-based high-risk patients can be offered such options.