Pathophisiology and therapy of Multiple Myeloma

By Dr. Maria Benito

Multiple myeloma (MM) –a malignant disease characterized by the infiltration and proliferation of clonal plasma (B-cell lineage) in the bone marrow, typically accompanied by the secretion of monoclonal immunoglobulins in serum or urine, and frequent development of osteolytic bone lesions as a result of the increased activity of osteoclasts adjacent to MM cells and suppressed osteoblast differentiation and activity– is one of the most intractable malignancies. Other manifestations of MM include impaired hematopoiesis and pancytopenia, extensive skeletal destruction and hypercalcemia.

Despite novel therapies, MM has one of the worse prognoses amongst most hematological malignancies being the second hematological malignancy accounting for more than 10% of all blood cancers and 2% of annual cancer-related deaths due to lack of curable drugs.

Patients may present with bone pain or with symptoms that are often non-specific, such as nausea, vomiting, malaise, weakness, recurrent infections, and weight loss. Many patients present with only laboratory abnormalities, such as anemia, renal disease, and elevated protein levels.

The diagnostic in a patient with suspected MM should include a complete blood count, serum chemistries, creatinine, lactate dehydrogenase, and beta2-microglobulin tests; immunoglobulin studies, skeletal survey, and bone marrow evaluation should also be included. In order to confirm the diagnosis of MM, increased numbers of immature, abnormal, or atypical plasma cells in the bone marrow, a monoclonal protein in the serum or urine, or characteristic bone lesions are required to be present.

All MM cases elapse through the phase of asymptomatic expansion of clonal plasma cells, and evolve to terminal phases such as extramedullary tumors and plasma cell leukemia due to the accumulation of novel mutations –including drug sensitivity– resulting in relapse and/or leukemic conversion.

The number of plasma cells in the bone marrow increases considerably with the stage of the disease. Thrombocytopenia is usually observed in MM stage-III, while platelet count (PLT) and thrombopoietin (TPO) is stage-dependent. Elevated TPO concentration in MM patients might be an unfavourable marker of the disease stage. The pathophysiology of MM-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment.

Angiogenesis through the activation of endothelial cells –both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment– plays an essential role in MM biology, and is a constant hallmark of MM progression and has prognostic potential. Pro- and anti-angiogenic cytokines modulate cell interaction, while extracellular matrix degrading proteases participate in the pathophysiology of MM. Hypoxia –through hypoxia-inducible factor-1 (HF-1a)– and constitutive activation of nuclear factor-κb (NF-kb) participates in the tumour-induced neo-vascularization.

The phosphatidylinositol 3-kinase/protein kinase B (PI3K)/AKT signalling pathway plays a critical regulatory role in MM pathophysiology –including survival, proliferation, migration, angiogenesis, and drug resistance–, and has emerged as a key therapeutic target.

Initiation of chemotherapy and assessment of eligibility for autologous stem cell transplantation (ASCT) requires careful valuation. Most patients with MM receive bisphosphonate therapy, thromboprophylaxis, and prophylaxis against infection. Intravenous zoledronic acid (Reclast) or pamidronate is recommended for all patients with MM who are receiving treatment, regardless of the presence of bone lesions.

Together with ASCT and advances in supportive care, the use of novel drugs –including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), histone deacetylase inhibitor (HDIs) and monoclonal antibodies (mAbs), or acombination of them– has substantially increased response rates and survival in the past several years. The ultimate goal of treatment is to eradicate all clones, including subclonal populations with distinct biological characteristics to avoid relapse.

The combination of autologous stem cell transplant (ASCT) with novel agents such as IMiDs, PIs, and mAbs have resulted in improved progression-free survival, overall survival and quality of life.

Transformation of a normal plasma cell into a neoplastic cell is a multistep process due to genetic and molecular events as well as to important and irreversible alterations in the bone marrow micro-environment. The myeloma cell is immersed in the bone marrow micro-environment where it mutually interacts with stromal cells (BMSC), osteoblasts, osteoclasts, lymphocytes and endothelial cells; it also depends on the presence of growth factors produced by BMSC to regulate activity of lympho-hemopoietic cells.

MM treatments include chemotherapeutic and immunotherapy agents that have the potential to cause cardiac toxicities. Venous thromboembolism (VTE) –most frequently as a deep vein thrombosis (DVT)– and potentially life-threatening cardiovascular (CV) disease –including hyperlipidemia and hypertension, and non-CV conditions such as diabetes– commonly occur in patients with cancer, specifically MM. When present, VTE and CV disease can limit patient tolerance for anti-myeloma treatment and, therefore, decrease therapeutic options.

The progression from plasma cell to malignant myeloma cells (MMCs) is characterized by multiple oncogenic events like hyperdiploidy and deregulation of cyclin D1, although malignant plasma cell remains mostly dependent on bone marrow microenvironment for survival. B-Cell Activating Factor (BAFF) –a component of this tumour microenvironment– has been implicated as a key player in this interaction.

Multiple studies have shown that BAFF functions as a survival factor for MMCs, which express several BAFF-binding receptors. Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC’s capability to bind BAFF, and with the level of dependency of MMCs on the bone marrow. Binding BAFF receptors on MMCs activate the Nuclear Factor-κb (NF-κb) pathway –a crucial pathway in many B-cell malignancies–, and MAP-kinase pathways such as c-Jun NH₂terminal kinase (JNK) and the phosphatidylinositol 3-kinase (PI3K) pathway; both these pathways results in prolonged survival and increased proliferation. Serum BAFF levels are significantly elevated in MM patients rendering BAFF signalling a possible biomarker for tumour burden, disease progression and prognosis, and as a potential target for the treatment of MM.

Amongst the mechanisms of immune evasion by MM cells reduced expression of tumour antigens and human leukocyte antigen (HLA) molecules by the malignant plasma cells, enhanced expression of inhibitory ligands, such as programmed cell death ligand 1 (PD-L1) by the plasma cells, and recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) should be highlighted.

Different strategies used in MM treatment include chimeric antigen receptor (CAR) T cells, checkpoint inhibition –targeting programmed cell death-1 (PD-1), PD-L1 or PD-L2 restore T cell activity against tumour cells, although present safety concerns in clinical trials–, and vaccination –PVX-410– to modulate patient antitumour immune response, and chimeric antigen receptor (CAR) T cells.

Treatments

The availability of several novel drugs with different and innovative mechanisms of action has increased the therapeutic options but has also increased complexity in the management of patients with MM. However, although treatments markedly improve myeloma, most patients still suffer from relapse.

Rapid control of the disease, appropriate treatment selection –considering the patient characteristics, frailt, and the clinical guidelines–, and effective supportive care strategies remain integral to prevention and management of the disease. Autologous hematopoietic cell transplantation (ASCT) for young patients and the availability of novel agents for young and elderly patients with MM –for whom treatment options were once limited to alkylators– have dramatically changed the perspective of treatment and significantly improved outcomes.

Recent studies suggest that autologous transplantation continues to improve response rates and progression-free survival. Emerging treatments include immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations, all of which seem to synergize with a transplant platform. Allogeneic transplantation is limited in scope by the concern of prohibitive toxicity and is applicable mainly to younger patients with high-risk disease. However, the allogeneic approach offers even more options of immunotherapy at relapse, including donor lymphocyte infusions, immunomodulatory drug maintenance, and withdrawal of immune suppression.

The classic antimutoral agents used in MM include cyclophosphamide, anthracyclines, radiation therapy and ASCT. Multiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed MM, including immunomodulatory agents (IMiDs) –thalidomide, lenalidomide, and pomalidomide–, proteasome inhibitors (PIs) –bortezomib, carfilzomib and ixazomib–, histone deacetylase inhibitors (HDIs) –panobinostat– and monoclonal antibodies (mAbs) –atacicept, anti-BCMA, and tabalumab–, or combination of them are currently used for MM.

Novel therapies

A variety of novel agents have been studied with the aim of finding a suitable treatment including the mAbs daratumumab and elotuzumab. New targeted agents –signal transduction modulators, kinesin spindle protein inhibitors, and inhibitors of NF-kb, MAPK, AKT and mTOR inhibitors– are currently under investigation.

Various new anti-myeloma drugs interfere in the MEK/ERK, JAK2/STAT3, and PI3 K/Akt signaling pathways interactions and are currently being investigated in clinical trials, which include RAF-inhibitors (sorafenib), BRAFF inhibitors (vemurafenib), kinesin spindle protein inhibitors (filanesib), Akt inhibitors (perifosine), and BH3 mimetics (venetoclax).

The intrinsic apoptosis pathway in MM cells is regulated by a balance between anti-apoptotic (BCL-2, BCL-XL, MCL-1) and pro-apoptotic (BAX, BAK, NOXA) proteins. Perifosine –an Akt inhibitor– inhibites the nuclear translocation of NF-κb, while venetoclax –a new selective BCL-2 inhibitor– promotes apoptosis in MM cell lines in myeloma cells.

However, personalized therapy with targeted agents is not yet standard clinical practice. Ongoing combinatorial strategies are expected to include monoclonal antibodies, immune checkpoint inhibitors, vaccines, and CAR-T cells are emerging as a new treatment in RRMM with the final goal of finding a balance among efficacy, toxicity, and cost, and to achieve long-lasting control of the disease and eventually even cure.