OUR HISTORY

Multiple myeloma (MM) is the second most frequent hematologic neoplastic disorder and involves an abnormal proliferation of clonal plasma cells. Its causes are still unknown, its incidence is about 4.6 per 100,000 person-year and is generally stable, while mortality is slightly decreasing. This pathology especially affects elderly patients: the median age at diagnosis is 68 years (Kumar et al. Nat Rev Dis Primers. 2017;3:17046.).

Bone marrow plasma cells produce and secrete antibodies. Normal plasma cells are polyclonal: namely, they are different from each other and produce different antibodies. Basically, multiple myeloma represents the proliferation of a clone (a group of abnormal plasma cells identical to each other).

Plasma cells originate mainly in the bone marrow, and most patients are affected by a secretion of immunoglobulins. However, around 15-20% of patients are affected by alterations in free light chain levels (non-secreting myeloma).
Defined as CRABs (increased Calcium, Renal failure, Anaemia, and Bone lesions), symptoms derive from the presence of monoclonal cells, which induce end-organ damage such as hypercalcemia, renal insufficiency, anemia and bone pain. The latter can gradually progress to bone lesions due to an increased degree of bone weakening. 

MM is included in a broader group of pathologies defined as monoclonal gammopathies, the most frequent of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS), which entails the infiltration of plasma cells in the bone marrow and the secretion of monoclonal proteins. MGUS is asymptomatic and may progress in MM. This also happens in the case of Smoldering Multiple Myeloma (SMM), which represents an intermediate stage between MGUS and MM.

Usually, MGUS and SMM are accidentally diagnosed during routine health check-ups and there are not specific genetic or epigenetic events marking the transition from MGUS to SMM to MM. However, it is demonstrated that around 20% of patients affected by MGUS or SMM progress to MM.

Plasmacytoma is a mass of monoclonal neoplastic plasma cells and is the expression of a localized, medullary or extramedullary disease. The first type arises in bones; the second one in soft tissues, more frequently in the upper-respiratory tract.
Periodical check-ups are mandatory after removal surgery and radiotherapy, since a local relapse or a systemic evolution to MM are possible.

Diagnostic criteria for symptomatic MM include any one or more biomarkers of malignancy validated by the concurrent presence of at least one CRAB feature.




Diagnostic criteria (biomarkers of malignancy):

- clonal bone marrow plasma cell percentage ≥60%, estimated by bone marrow aspirate or biopsy
- presence of κ/λ serum free light chains (FLC). Involved:uninvolved serum free light chain ratio (FLCr) ≥100
- >1 focal lesions on Magnetic Resonance Imaging (MRI) studies (≥5 mm in size)










CRAB features:

- hypercalcemia: 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 <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)
- anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L
- bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement (See SV Rajkumar et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548)

In order to determine the start of treatment, physicians consider other ancillary symptoms often related to the effects of monoclonal cells. The most frequent of these secondary symptoms is peripheral neuropathy, which affects the peripheral nervous system. MM is also related to a greater risk of infection due to the hypogammaglobulinemia, which occurs after the reduction of immune functions.  Finally, between 2 to 6% of patients are affected by hyperviscosity syndrome, which principally consists of mucosal bleeding, visual changes, and neurologic symptoms.

In patients affected by symptomatic MM, treatment is always recommended. In the last decade, the median survival rate is estimated to be 8-10 years, thanks to the introduction of new agents, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.

Treatment goals are better responses, improved progression-free survival (PFS) and overall survival (OS); or merely improvements in quality of life (QoL) and disease control in the case of frail patients. Treatment is consequently tailored according to patient age, comorbidities and performance status.

Patients aged ≤65-70 years with normal cardiac, pulmonary and hepatic functions and without significant risks of infection are eligible for a more intensive treatment with autologous stem-cell transplantation (ASCT) that is organized in 4 steps: pre-transplant induction, transplantation, post-transplant consolidation, and maintenance treatment.
Induction usually consists of 3-6 cycles in order to rapidly control the disease and its symptoms. Standard therapy is a combination of 3 agents, usually a corticosteroid (i.e. dexamethasone) associated with a proteasome inhibitor (i.e. bortezomib) and with an immunomodulatory drug (i.e. thalidomide, lenalidomide) and/or an alkylating agent (cyclophosphamide).

In some cases, second-generation proteasome inhibitors (i.e. ixazomib) are better tolerated due to lower neuro-peripherical toxicity.
After induction, the subsequent step is the hematopoietic autologous stem-cell transplantation (ASCT), during which patients receive high-dose chemotherapy followed by a re-infusion of their own stem cells (high-dose melphalan at 200mg/m² is the standard regimen).

Post-transplant consolidation is essential in order to improve response. Different countries adopt different standards for consolidation treatment. In Italy, consolidation may include a second ASCT. In other cases, the same regimen as induction is usually adopted in order to obtain a favorable prognosis.

Finally, maintenance therapy is intended to extend the duration of remission without compromising patient quality of life. Currently, the most frequently adopted maintenance treatments are based on the use of lenalidomide. Thalidomide and bortezomib were used in the past and are currently used in some settings. Lenalidomide is better in terms of efficacy and tolerability, since it is associated with a lower incidence and severity of neurotoxicity than bortezomib or thalidomide.
In elderly patients, transplantation can be adopted following a careful and patient-tailored evaluation of every organ status and of the biological age rather than the chronological one.
In some cases, allogenic transplantation can also be a valid option, usually with young high-risk patients and after relapse. “Allogenic” means that the transplant process involves a healthy “donor” and a receiving patient (“recipient”). 

During the last decades, PFS and OS have been deeply improved in patients aged ≥65-70 ineligible for intensive therapy, especially after the introduction of second-generation agents such as thalidomide, bortezomib and lenalidomide. Since elderly patients are a very heterogeneous population in terms of physical and social conditions, it is essential to ponder all the potential toxicities while selecting the appropriate therapy. For instance, some studies showed a significant benefit with melphalan-prednisone-thalidomide (MPT) in terms of OS, although many hematologic toxicities and peripheral neuropathy events were reported.

Another standard therapy is bortezomib-melphalan-prednisone (VMP), which showed positive responses, even though peripheral neuropathy is a significant toxicity of long-term bortezomib therapy. This contra-indication is usually corrected through dose reductions (i.e. from twice- to once-weekly administration). Age and physical condition are relevant criteria in the dose-selection process and different guidelines have been adopted in order to assess patient frailty. 

Many retrospective analyses demonstrated that chemo-sensibility and duration of remission are the first prognostic factors to consider for a long-term disease management. Relapse is definitely common in multiple myeloma, even after many years. A second transplantation may be an option if the time of relapse is ≥18 months after the first transplantation or after many different previous treatment lines with no response.

Some studies showed that median survival improved in patients who underwent salvage ASCT rather than in those who underwent salvage therapy with immunomodulatory agents and/or proteasome inhibitors. In transplant-ineligible elderly patients, risks and benefits need to be carefully analyzed and drugs are selected according to the severity of relapse.

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