Multiple myeloma (MM) is a B-cell neoplasm characterized by aberrant expansion of plasma cells within the bone marrow and extramedullary sites, including cortical bone.

It accounts for 10-15% of hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. The classic clinical manifestations are: lytic bone lesions, hypercalcemia, anemia and other cytopenias, and renal dysfunction. Recurrent upper respiratory infections, peripheral neuropathy, and cryoglobulinemia can also be seen in association with MM.

It is important to note that the size of the M-protein does not correlate with extent of disease, as a significant percentage of patients have either non-secretory myeloma or more commonly oligo-secretory disease. The most important predictors of prognosis are the International Staging System (ISS) stage and cytogenetic findings. Other findings associated with high-risk disease include: extensive extramedullary disease, significant renal impairment or failure, plasmablastic features, and plasma cell leukemia. It is likely that gene expression profiling will augment prognostic capabilities in the future.

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The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib are the mainstays of therapy, and with currently available multi-drug induction regimens, greater than 90% of patients will respond to initial therapy, with at least a partial response (PR), or greater than 50% decline in monoclonal protein concentration.

High-dose melphalan and autologous stem cell transplantation (ASCT) remains a cornerstone of therapy in appropriately selected patients. Maintenance therapy with lenalidomide following induction therapy and/or ASCT has been shown in randomized trials to lengthen progression-free survival (PFS).

Key symptoms include:

  • Fatigue and generalized weakness

  • Musculoskeletal symptoms, especially bone pain

  • Unintentional weight loss

  • Night sweats

  • Recurrent infections, especially upper respiratory infections

  • Paresthesias

Key signs may include:

  • Conjunctival pallor

  • Edema of the lower extremities

  • Bony protuberances

  • Pain to palpation of the spine or a long bone

Differential diagnosis includes:

  • Monoclonal gammopathy of undetermined significance

  • Smoldering multiple myeloma

  • Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia

  • Plasmablastic lymphoma

  • Prostate cancer

Individuals most at risk:

  • There is a higher incidence of MM among African Americans

  • There is a slightly higher incidence of MM among males than females

  • A small percentage of patients with MM have a family history of the disease

  • Toxic exposures known to be associated with MM include: agent orange, benzene, radiation, and pesticides

The initial laboratory evaluation of a patient with suspected MM should include a comprehensive metabolic panel, complete blood count with differential, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine for both total protein and urine protein electrophoresis (UPEP) with IFE, quantitative immunoglobulins, serum-free light chain analysis, and Beta-2-microglobulin (B2M). The recently FDA-approved HevylightTM assay, which nepholometrically quantifies intact immunoglobulin, will enhance diagnostic capabilities, and should prove to be particularly useful in IgA myeloma, wherein the monoclonal protein frequently co-migrates with physiologic proteins and is thus difficult to accurately measure.

Bone marrow evaluation is an essential part of the diagnostic evaluation. The marrow may show diffuse or focal plasma cell involvement. The plasma cells are often dysplastic, with prominent nucleoli and an increase in the nuclear to cytoplasmic ratio. Plasma cell clonality is documented on the basis of either kappa or lambda light chain restriction, which is established based on flow cytometry, using anti-kappa and anti-lambda antibodies against cytoplasmic light chain, or through immunohistochemical staining of the core biopsy specimen for cytoplasmic light chain. A congo red stain should be performed in cases where amyloid light-chain (AL) amyloidosis is suspected.

Cytogenetic analysis is performed using conventional metaphase karyotype and fluorescence in situ hybridization (FISH) targeting common MM-related mutations such as: trisomies, deletion (del) 13, del 17, translocation t(4;14), t(11;14), chromosome 1 amplification, and t(14;16).

A skeletal survey is performed as part of the diagnostic evaluation to assess for MM-related bone abnormalities. Computed tomography (CT) and magnetic resonance imaging (MRI) are more sensitive, and should be utilized in the initial diagnostic evaluation of patients with significant musculoskeletal symptoms. Fluorodeoxyglucose (FDG) PET imaging can be highly informative as well, particularly in patients with suspected extramedullary involvement.

Generally, MM therapy does not need to be initiated emergently. There are a number of important exceptions, however, which include the following:

  • Hypercalcemia with associated mental status changes

  • Hyperviscosity with associated neurological or cardiopulmonary manifestations

  • Renal failure

  • Spinal compression fracture or plasmacytoma, with existing or impending spinal cord compression

Hypercalcemia is managed with aggressive hydration with intravenous fluids, an intravenous bisphosphonate (either pamidronate or zoledronic acid), and prompt initiation of chemotherapy targeting the MM-clone. Calcitonin can be considered in cases of severe or refractory hypercalcemia.

Hyperviscosity is managed through plasmapheresis and prompt initiation of chemotherapy targeting the MM-clone. It is important to emphasize that plasmapheresis alone does not suffice in such circumstances, particularly when dealing with a non-immunoglobulin M (IgM) monoclonal immunoglobulin, as there is rapid equilibration of immunoglobulin G (IgG), in particular between the vascular space and interstitium. Diuretic therapy should be avoided in patients with hyperviscosity.

Renal failure associated with MM is treated with prompt initiation of chemotherapy targeting the MM-clone in an attempt to restore organ function. Such therapy should be initiated rapidly, as in some cases renal function is restored following institution of chemotherapy, and dialysis independence is achieved. The proteasome inhibitor bortezomib is often used in patients with myeloma-related renal impairment as it can be administered safely, without dose reduction, in this context and is effective in terms of rapidly inducing response and limiting further kidney injury.

Hyperuricemia can occur as either a cause or consequence of renal failure in MM; the use of the urate oxidase rasburicase should be considered in these circumstances. If intra-vascular volume depletion is thought to be contributing to renal impairment, intravenous fluids should be administered judiciously. Drugs that are potentially nephrotoxic, such as non-steroidal anti-inflammatory drugs should be discontinued. Intravenous contrast as a part of radiographic procedures should be avoided. Diuretic agents should be used with caution.

Pathologic compression fractures or plasmacytomas of the spine are managed with oral or intravenous corticosteroid in combination with local therapy targeting the lesions – either a decompressive neuro-orthopedic procedure or radiation therapy. Corticosteroid therapy should be initiated promptly. A timely neurosurgical and/or radiation oncology consultation should be obtained.

Newly diagnosed, transplant-eligible

Transplant-eligible patients with standard risk disease are treated with either two drug-regimens such as lenalidomide-dexamethasone or bortezomib-dexamethasone, or with three-drug regimens such as lenalidomide-bortezomib-dexamethasone, bortezomib-thalidomide-dexamethasone, or cyclophosphamide-bortezomib-dexamethasone.

Patients with high-risk disease should be treated with three-drug regimens that incorporate bortezomib. We favor lenalidomide-bortezomib-dexamethasone as an induction regimen based on the high-level of response and favorable toxicity profile associated with this combination. Cyclophosphamide-bortezomib-dexamethasone is also a highly active regimen however, and may be preferred in some situations, including the management of patients with significant renal impairment.

Four-drug combinations such as cyclophosphamide-lenalidomide-bortezomib-dexamethasone have been evaluated as well, but are not routinely used as response rates are not significantly higher than those observed with three-drug regimens, while toxicity is increased.

We typically administer four to six cycles of induction therapy before proceeding with stem cell mobilization. Following stem cell collection, appropriately selected patients undergo high-dose therapy with melphalan 200mg/m2 followed by autologous stem cell transplantation (ASCT). Post-ASCT chemotherapy with lenalidomide is typically initiated approximately three months after transplant. Bortezomib maintenance can be considered for certain patients as well, including those who were previously found to be resistant to or intolerant of lenalidomide as well as those with high-risk disease based on ISS or cytogenetic criteria.

Newly diagnosed, transplant-ineligible

In transplant-ineligible patients, melphalan-prednisone – long a standard of care in this population – has been replaced by regimens such as lenalidomide-dexamethasone, bortezomib-dexamethasone, bortezomib plus melphalan-prednisone, cyclophosphamide-bortezomib-dexamethasone, and lenalidomide-bortezomib-dexamethasone based on compelling data from various clinical trials.

Patients with standard-risk disease are typically treated with two-drug regimens such as lenalidomide-dexamethasone or bortezomib-dexamethasone. Bortezomib-dexamethasone may be preferred in patients with renal impairment, although lenalidomide-dexamethasone can be used in the setting of renal impairment with appropriate dose modification. Lenalidomide plus high-dose dexamethasone is associated with higher response rates than lenalidomide plus low-dose dexamethasone, but also with a higher incidence of high-grade toxicities such as infection, and as such, low dose dexamethasone administered on a weekly schedule is preferred.

Transplant-ineligible patients with high-risk disease should receive three-drug therapy with regimens such as bortezomib-thalidomide-dexamethasone, lenalidomide-bortezomib-dexamethasone, or cyclophosphamide-bortezomib-dexamethasone. There is clinical trial data supporting the use of once weekly bortezomib for transplant-ineligible patients who receive bortezomib as part of a combination regimen, and as such, this approach should be considered as a means to minimize toxicity, particularly treatment-related peripheral neuropathy. Use of subcutaneous bortezomib can also be considered as a means to decrease the risk of peripheral neuropathy.

We generally continue therapy for six to eight cycles in transplant-ineligible patients to achieve maximal response. At that point, various options for further management can be considered, including discontinuation of systemic chemotherapy and reinitiation at time of disease progression, versus continuation of de-intensified therapy as maintenance. There are various approaches to maintenance therapy in this setting, including single-agent lenalidomide versus bortezomib-dexamethasone administered on a weekly schedule.

Relapsed MM

Patients with relapsed disease are risk-stratified according to the current cytogenetic and clinical features of the disease, as well as previous response to therapies. Patients with adverse cytogenetics, aggressive clinical features, short duration (months) of response to prior therapy, or progression on current treatment, are classified as having high-risk disease. Those with absence of adverse cytogenetics, indolent clinical features, and prolonged (more than 12 months) response to previous therapy, are classified as having standard risk relapsed MM.

A patient who is naïve to an agent with known activity in MM is typically treated with a regimen incorporating this agent. In this context, it is important to assess eligibility for ASCT; a patient with relapsed MM who has not previously undergone ASCT can be considered for high-dose therapy, as can the patient who experienced a prolonged response to first ASCT. A patient who previously responded to a particular agent can be retreated at relapse with the same drug alone, or in combination with other agents. Moreover, a patient who previously demonstrated resistance to a specific drug may be treated with that drug in combination with other agents with which synergy exists.

Several treatment regimens have received FDA approval recently on the basis of clinical trial data showing promising results in patients with relapsed disease. These include the oral histone deacetylase inhibitor (HDACi) panobinostat in combination with bortezomib and dex; the oral proteasome inhibitor ixazomib in combination with lenalidomide and dex; the anti-CD38 monoclonal antibody daratumumab as monotherapy or in combination with bortezomib and dexamethasone; and the anti-CS1 monoclonal antibody elotuzumab in combination with lenalidomide and dex.

Patients with high-risk relapsed disease are generally treated with highly active two or three drug combinations that include an immunomodulatory agent and proteasome inhibitor (i.e., lenalidomide-bortezomib-dex; pomalidomide-bortezomib-dex; lenalidomide-carfilzomib-dex; pomalidomide-carfilzomib-dex), monoclonal antibody plus either immunomodulatory agent or proteasome inhibitor (i.e., daratumumab-lenalidomide, daratumumab-bortezomib; or elotuzumab-lenalidomide-dexamethasone), an alkylating agent plus proteasome inhibitor (cyclophosphamide-bortezomib-dex; cyclophosphamide-carfilzomib-dex; bendamustine-bortezomib-dex), an alkylating agent plus immunomodulatory agent (cyclophosphamide-lenalidomide-dex; cyclophosphamide-pomalidomide-dex; or bendamustine-lenalidomide-dex, or histone deacetylase inhibitor plus bortezomib-dex (i.e., panobinostat plus bortezomib-dexamethasone).

Appropriately selected patients who respond to initial therapy in the relapsed setting and for whom stem cell collection is feasible can then be considered for ASCT. Allogeneic transplant represents an option for a subset of treatment-responsive patients with an available human leukocyte antigen (HLA) matched donor, chemotherapy-sensitive disease, and excellent performance status, but in practice the application of this approach has been limited, due to high treatment-related mortality.

Patients with standard-risk relapsed MM are generally treated with a one-or two-drug regimen that includes an agent to which the patient is either naïve or has known sensitivity. Options include a proteasome-inhibitor as monotherapy or as part of a two-drug regimen with dex and an immunomodulatory agent as monotherapy or with dex. Daratumumab as monotherapy or in combination with either lenalidomide or bortezomib is an option in this context as well. As an all-oral regimen, ixazomib-lenalidomide-dexamethasone can be considered in this setting. As in the case of high-risk disease, consolidative high-dose therapy with ASCT can be considered for patients without prior exposure to high-dose therapy, and those who sustained a prolonged response to prior transplant.

Clinical trial participation is an important option for relapsed MM. A large number of promising agents and strategies are in clinical development and have the potential to impact the management of myeloma in the future, notably immunotherapies including CAR-T cell constructs with myeloma-specific targets such as BCMA and regimens that combine checkpoint inhibitors such as pembrolizumab or nivolumab with an established agent such as lenalidomide or pomalidomide. The nuclear export inhibitor selinexor and BCL2 inhibitor venetoclax have been associated with promising results in early phase clinical trials involving patients with relapsed myeloma as well.

Duration of therapy in relapsed MM is determined by the clinical context. The patient with aggressive, high-risk relapsed disease is likely to progress without ongoing therapy and usually requires continuous therapy, although short treatment-free intervals may be necessary during a transition from one regimen to another or for necessary surgical/radiation interventions. In the patient with standard-risk relapsed MM who responds to treatment, options include consolidation with ASCT, maintenance therapy with an agent to which the disease is sensitive, or observation without therapy.

The use of intravenous bisphosphonates such as zoledronic acid and pamidronate has been a critical advance in the field. The primary mechanism of action of the agents is inhibition of the osteoclast, which results in decreased bone resorption. Use of the intravenous bisphosphonates decreases skeletal events such as fracture. Moreover, a randomized, phase III clinical trial involving patients with newly diagnosed MM, demonstrated that those who received intravenous bisphosphonate (zoledronic acid) as compared to oral bisphosphonate (clodronate) not only had fewer bone events, but also had longer progression-free and overall survival.

We utilize prophylactic antibiotics in the management of MM patients as well. An antiviral agent such as acyclovir or valacyclovir is given to patients receiving bortezomib, as there is an increased incidence of herpes zoster reactivation among patients who receive bortezomib. Patients receiving high-dose or prolonged treatment with corticosteroids are considered for Pneumocystis carinii prophylaxis, most often with Bactrim; and patients who receive either thalidomide, lenalidomide or pomalidomide should receive aspirin to reduce the likelihood of a therapy-associated thrombotic event. In patients at high risk for a thrombotic event, including those with prior history of thrombosis, as well as those who are non-ambulatory or post-surgical, anticoagulation should be considered.

With currently available induction regimens, the overall response rate in patients with newly diagnosed disease is greater than 90%. In patients who undergo ASCT following induction therapy, the mean duration of response is approximately 24 months. With the incorporation of post-ASCT maintenance therapy, mean duration of response is 40-45 months.

Epidemiologic data indicates that survival times have nearly doubled over the past decade, and with ongoing efforts in drug development, there is likely to be further improvement in the coming years.

It is important to note, however, that in some patients, particularly those with high-risk as defined by ISS stage, cytogenetic abnormalities such as del17p, t(4;14), t(14;16), and others, response to therapy can be brief. New approaches to the management of such patients are clearly needed and is an important area of ongoing translational and clinical research.

A full evaluation that includes radiographic imaging should be undertaken at time of diagnosis. It is important to identify sites of bone disease, particularly plasmacytomas or impending fracture, that can lead to substantial morbidity and may require localized surgery or radiation therapy.

A 24 hour urine should be obtained at diagnosis for both total protein quantification and urinary protein electrophoresis. The presence of significant non-M-protein proteinuria suggests glomerular injury, and should raise suspicion for entities that can occur in conjunction with MM such as AL amyloidosis and immunoglobulin deposition disease.

Patients presenting with high-risk disease should be treated with three-drug regimens, which are associated with higher rates of response and lower incidence of treatment failure. However, they are at high risk of relapse and in need of continued therapies to prolong progression free survival.

In patients who develop treatment related peripheral neuropathy, appropriate dose reduction, schedule change, or even temporary treatment discontinuation of the offending agent should be undertaken to prevent progression of nerve injury and resulting symptoms.

Normal B-cell differentiation occurs in early (antigen-independent) and late (antigen-dependent) stages, culminating in the production of plasma cells and memory B cells. During antigen-independent differentiation, precursor B cells undergo Variable-Diversity-Joining (VDJ) region rearrangement, and mature into naïve, resting B-cells that circulate in the blood and lymphoid tissue. Upon encountering antigen with specificity for the immunoglobulin receptor, B-cells aggregate in germinal centers and undergo somatic hypermutation and immunoglobulin class switch, producing high affinity IgG or IgA antibodies. A high degree of immunoglobulin heavy chain gene hypermutation is present in MM cells, suggesting that tumor cells derive from a post-germinal center B-cell. Mutations occurring during immunoglobulin receptor somatic hyper-mutation and class switch are likely involved in the pathogenesis of MM.

Chromosomal abnormalities are detected in up to 90% of MM patients. Gain or loss of specific chromosomal regions is frequently observed, including monosomy or partial deletion of chromosome 13, loss of the short arm of chromosome 17, and gains or amplification of chromosomal region 1q.

Primary translocations in MM typically involve the immunoglobulin heavy chain gene at the chromosome 14q32 locus along with partner genes such as cyclin D1 (chromosome 11q13), cyclin D3 (chromosome 6p21), FGFR3/MMSET (chromosome 4p16), and C-MAF (chromosome 16q23). It is believed such translocations lead to dysregulated growth of the affected clone. C-MAF, for example, appears to augment MM cell proliferation and binding to surrounding bone marrow stromal cells (BMSCs). Inhibition of FGFR3, meanwhile, has been shown to promote plasma cell differentiation and induce apoptosis.

The pathogenesis of MM is driven by interactions between MM cells and the bone marrow microenvironment. Adhesion of MM cells to extracellular matrix proteins and accessory cells leads to increased expression of factors such as interleukin-6 (IL-6), insulin-like growth factor (IGF-1), and vascular endothelial growth factor (VEGF), which further stimulates growth and survival of the malignant clone. Various intracellular pathways are involved in this response, including the Ras-Raf-MAPK kinase (MEK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-Akt, and the Janus kinase 2-signal transducer and activator of transcription 3 (STAT3) pathways.

A careful review of musculoskeletal symptoms is important, and sites of potential involvement of plasmacytoma or pathologic fracture should be imaged accordingly.

Cardiopulmonary symptoms such as shortness of breath, exertional dyspnea, orthopnea, and dependent edema should raise concern for secondary AL amyloidosis or light chain deposition disease with cardiac involvement.

Dizziness, visual symptoms, headache, and other neurologic abnormalities should raise concern for hyperviscosity.

Additional tests

  • Serum viscosity

  • Serum cryoglobulins

  • Fat pad biopsy and Congo red stain

  • Brain natriuretic peptide, troponin

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Attal, M, Harousseau, JL, Stoppa, AM. “A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome”. . vol. 335. 1996. pp. 91-97. (Randomized trial showing improved response rate, event-free survival, and overall survival in MM patients receiving high-dose melphalan therapy with autologous stem cell transplantation compared to conventional dose combination chemotherapy.)

Richardson, PG, Schlossman, RL, Alsina, M. “PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma”. Blood. vol. 122. 2013. pp. 2331-7.

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