MULTIPLE MYELOMA

MULTIPLE MYELOMA

Current Diagnosis

• Malignant clonal plasma cell disorder

• Characterized by presence of a monoclonal immunoglobulin in the serum or urine in most patients

• Typical manifestations include anemia, osteolytic bone lesions, and renal failure

• Initial workup should include a bone marrow aspiration and biopsy with fluorescent in situ hybridization studies to determine

molecular cytogenetic type

    •   Standard risk: trisomies (hyperdiploidy), t(11;14), and t(6;14)

    •   Intermediate risk: t(4;14)

    • High risk: 17p-, (t14;16) or t(14;20)

Current Therapy

• Do not begin treatment until symptomatic multiple myeloma develops (CRAB: calcium elevated, renal failure, anemia, bone lesions) or other myeloma defining events are present.

• Decide whether an autologous stem cell transplant is feasible. If it is, one must avoid melphalan (Alkeran) therapy as initial treatment.

• Initial therapy is typically consists of a triplet regimen such as lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone1 (VRd)

• Patients who are candidates for autologous stem cell transplantation should collect stem cells after 3-4 cycles of induction. After collection, patients proceed to either early transplantation, or resume initial therapy and postpone transplant until relapse.

• Patients who are not stem cell transplant candidates receive initial therapy for a duration of approximately 12 months. Frail patients can be treated with the doublet regimen of Rd, in which case, therapy is continued until progression if tolerated.

• Relapsed or refractory myeloma should be treated with one of the active drugs given alone or in combination. Active agents include thalidomide, lenalidomide, bortezomib, carfilzomib (Kyprolis), pomalidomide (Pomalyst), daratumumab (Darzalex), ixazomib (Ninlaro), elotuzumab (Empliciti), panobinostat (Farydak), corticosteroids, anthracyclines, and alkylators.

1 Not FDA approved for this  indication

Multiple myeloma is characterized by the neoplastic proliferation of clonal plasma cells. It is typically associated with a monoclonal (M) protein in the serum and/or urine.

Epidemiology

In the United States, multiple myeloma constitutes 1% of all malignant diseases and slightly more than 10% of hematologic malignancies. The annual incidence is 4 to 5 per 100,000; the incidence in African Americans is twice that in whites. The apparent recent increase in rates is probably caused by increased availability and use of medical facilities and improved diagnostic techniques, particularly in the older population. The median age at diagnosis is approximately 70 years.

Risk Factors

The cause of multiple myeloma is unclear. Exposure to radiation might play a role. Persons in agricultural occupations who are exposed to pesticides, herbicides, or fungicides have an increased risk of multiple myeloma. Benzene and petroleum products, hair dyes, engine exhaust, furniture worker products, obesity, and chronic immune stimulation have also been reported as risk factors. The risk of developing multiple myeloma is higher for patients with a first- degree relative with the disease. Clusters of two or more first-degree relatives or identical twins have been recognized.

Clinical Manifestations

Weakness, fatigue, bone pain, recurrent infections, and symptoms of hypercalcemia or renal insufficiency should alert the physician to the possibility of multiple myeloma. Anemia is present in 70% of patients at the time of diagnosis. An M protein is found in the serum or urine in more than 97% of patients with multiple myeloma by immunofixation studies and the serum-free light chain assay. Lytic lesions, osteoporosis, or fractures are present at diagnosis in 80% of patients and can be detected by conventional radiography or whole body low dose computed tomography. Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) are also helpful in patients who have skeletal pain but no abnormality on radiographs or when there are other clinical concerns about the extent of the disease. Hypercalcemia is present in 15% of patients, and the serum creatinine value is 2 mg/dL or greater in almost 20% of patients at diagnosis.

Diagnosis

If multiple myeloma is suspected, the patient should have, in addition to a complete history and physical examination:

•   Determination of values for hemoglobin, leukocytes with differential count, platelets, serum creatinine, calcium, and uric acid

•   A radiographic survey of bones, including humeri and femurs

•   Serum protein electrophoresis with immunofixation

•   Quantitation of immunoglobulins, serum free light chain (FLC) assay

•   Bone marrow aspirate and biopsy

•   Routine urinalysis

•   Electrophoresis and immunofixation of an adequately concentrated aliquot from a 24-hour urine specimen

•   Fluorescence in situ hybridization (FISH)

•   Measurement of β2-microglobulin, C-reactive protein, and lactate dehydrogenase

Box 1 lists the International Myeloma Working Group updated criteria for diagnosis of myeloma and related disorders. Metastatic carcinoma, lymphoma, leukemia, and connective tissue disorders can resemble multiple myeloma and must be considered in the differential diagnosis. Patients with multiple myeloma must be differentiated from those with monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma (SMM). Patients with MGUS and SMM may remain stable for long periods and not require treatment (see Box 1). The patient’s symptoms, physical findings, and all laboratory and radiographic data must be considered in the decision to begin therapy. If there are doubts about whether to begin treatment, therapy should be withheld and the patient should be reevaluated in 2 to 3 months. No evidence indicates that early treatment of multiple myeloma is advantageous.

Box 1
International Myeloma Working Group Diagnostic Criteria
Monoclonal Gammopathy of Undetermined  Significance

• Serum M protein < 3 g/dL

•   Clonal bone marrow–plasma cells < 10%

• Absence of end-organ damage (CRAB) attributable to a plasma cell proliferative disorder

Smoldering Multiple Myeloma

• Serum M protein ≥ 3 g/dL and/or clonal bone marrow–plasma cells 10–60%

•   Absence of myeloma defining events or amyloidosis

Multiple Myeloma

• Presence of clonal bone marrow plasma cells 10% or greater or biopsy proven plasmacytoma

• Presence of end-organ damage (CRAB) thought to be related to a plasma cell proliferative disorder or other myeloma defining event (clonal bone marrow plasma cells 60% or higher, serum free light chain ratio 100 or more provided involved free light chain level is 100 mg/L or more, more than one focal lesion on magnetic resonance imaging)

Abbreviations: CRAB = calcium elevated, renal failure, anemia, bone lesions; M = monoclonal.

Derived from 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-e548.

Treatment

Patients with symptomatic multiple myeloma may be classified as having high-risk, intermediate-risk, or standard-risk disease. High- risk disease is defined as the presence of del(17p), t(14;16), or t(14;20) with FISH. The presence of t(4;14) is considered intermediate-risk disease. Lactate dehydrogenase, circulating plasma cells, and β2- microglobulin levels are additional important risk factors.

Approximately 15% to 20% of patients with symptomatic multiple myeloma have high-risk disease.

If clinical trials are not available, one may separate patients into those eligible for an autologous stem cell transplant (SCT) versus those not eligible. An autologous SCT adds about 1 year of survival on average when compared with patients treated with conventional-dose chemotherapy alone.

Eligibility for autologous SCT in multiple myeloma varies from country to country. In the United States, decisions are made on a patient-by-patient basis depending on the physiologic age rather than the chronologic age. In most institutions, patients older than 70 years or with serum creatinine greater than 2.5 mg/dL, Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, or New York Heart Association (NYHA) functional status class III or IV are considered ineligible for autologous SCT. Although patients with kidney failure may have an autologous SCT, the morbidity and mortality are higher.

Initial Therapy for Transplant-Eligible Patients

Bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone (Decadon)1  (VRD) is the preferred standard initial therapy for multiple myeloma. In a randomized trial conducted by the Southwest Oncology Group, VRD was superior to lenalidomide plus dexamethasone (Rd) in terms of progression free survival (PFS) and overall survival (OS). Bortezomib and dexamethasone are typically administered once weekly. In the VRD regimen lenalidomide is given at a dose of 25 mg daily on days 1–14 of a 21 day cycle. Bortezomib plus cyclophosphamide (Cytoxan) 300 mg/m2 orally once weekly plus dexamethasone 40 mg once weekly (VCD) is an option for patients presenting with acute renal failure. Bortezomib should be given at weekly intervals because it is equally efficacious and is associated with less peripheral neuropathy. It is also preferable to administer bortezomib subcutaneously to diminish the risk of neuropathy. An alternative to VRD if lenalidomide is not available is bortezomib, thalidomide (Thalomid), and dexamethasone1 (VTD).

Autologous Stem Cell Transplantation

Following 3 to 4 months of induction therapy with one of the initial regimens, one must collect the stem cells in patients eligible for transplantation. The stem cells must be collected before the patient is exposed to prolonged therapy, especially melphalan (Alkeran).

Granulocyte colony-stimulating factor (G-CSF, Neupogen) with or without cyclophosphamide (Cytoxan)1 is used for mobilizing stem cells. G-CSF plus cyclophosphamide is preferred in patients who are treated with lenalidomide plus dexamethasone induction, who are older than 65 years, or who have received such therapy for over 4 months. Plerixafor (Mozobil) may also be used for mobilization of hematopoietic stem cells. It is advisable to collect 6 × 106 CD34+ cells/kg, which is sufficient for two transplants in patients less than 65 years of age.

The timing of autologous SCT takes into account the patient’s wishes, and it may be done early (when the patient recovers from stem cell collection) or delayed until relapse. There is no difference in overall survival among patients who receive an autologous SCT immediately following collection of stem cells and those who receive it at first relapse. In general, we prefer an early transplant because this provides a better quality of life and time without therapy.

Melphalan3 200 mg/m2 is the preferred conditioning regimen for autologous SCT. This regimen has fewer adverse side effects than melphalan3 140 mg/m2 plus total body irradiation. If a patient obtains a VGPR or CR with the first transplant, little benefit results from a second (tandem) transplant.

The mortality rate with autologous SCT is approximately 1%.

Unfortunately, multiple myeloma is not eradicated, and the autologous peripheral stem cells are contaminated by myeloma cells or their precursors.

Bone marrow transplantation from an identical twin donor (syngeneic) is the treatment of choice if such a donor is available. Results are superior to allogeneic transplantation.

Maintenance Therapy Following Autologous Stem Cell Transplantation

In a large prospective study, multiple myeloma patients were given a tandem transplant and then randomized to no maintenance, pamidronate (Aredia)1 maintenance, or pamidronate plus thalidomide maintenance. Although thalidomide improved the response rate and overall survival, it often resulted in peripheral neuropathy. Moreover, the overall survival benefit was lost with longer follow-up.

Three randomized trials have tested the value of lenalidomide as maintenance therapy following stem cell transplantation. An overall survival benefit has been observed in a meta-analysis of the 3 trials. This benefit appears to be mainly restricted to standard-risk patients. An increased risk of second cancers has been noted with lenalidomide maintenance and further follow-up is needed. In another randomized trial improved overall survival with bortezomib maintenance has been reported, but it is not clear whether the benefit is due to the maintenance therapy or differences in induction therapy between the two groups. We recommend lenalidomide maintenance for standard risk patients following autologous SCT. In intermediate and high-risk patients, we recommend bortezomib-based maintenance.

Allogeneic Transplantation

Allogeneic bone marrow transplantation has been tested in myeloma but treatment-related mortality is high and graft-versus-host disease is a troublesome problem. Further, only 5% to 10% of patients with multiple myeloma are eligible. Allogeneic transplantation is currently not recommended for routine use outside of a clinical trial. An exception to this are young patients with high-risk disease in first relapsed after autologous transplantation who are willing to assume the high treatment-related mortality associated with allogeneic SCT.

Nonmyeloablative allogeneic (mini-allo) transplant following autologous SCT has been tested but has not been consistently shown to be superior to autologous SCT. The mortality is 10% to 15%, and there is a substantial risk of graft-versus-host disease. Efforts are being made to reduce the toxicity of this approach. Currently, we believe that nonmyeloablative approaches should be limited to clinical trials.

Initial Therapy for Patients Who Are Ineligible for Autologous Stem Cell Transplantation

From the 1960s to the early 1990s, alkylating agent–based chemotherapy with oral administration of melphalan and prednisone1 (MP) was used as initial therapy in patients who were not candidates for SCT. Subsequently, the addition of thalidomide to MP (MPT regimen)1 was found to produce overall survival improvement compared with MP.

Another option for patients who are not candidates for transplantation was bortezomib (Velcade) plus MP (the VMP regimen).

However, melphalan-based regimens have several adverse effects, and have fallen out of favor. Further in a recent randomized trial, Rd was found to be superior to MPT. Thus, the initial therapy for patients not eligible for transplantation now resembles that of transplant eligible patients. Currently, we prefer VRD as initial therapy. Other options include VCD and VTD. For frail patients, the doublet regimen of Rd can be used.

We continue the initial chemotherapy regimen for approximately 12 months followed usually by Rd maintenance. If Rd is used, treatment is continued till progression if treatment is well-tolerated. There is risk of myelodysplasia from continued treatment with alkylating agents. The role of thalidomide, bortezomib, and lenalidomide for maintenance therapy in transplant-ineligible patients has not been proved.

In general, lenalidomide or thalidomide therapy requires prophylaxis with aspirin1  (81 mg or 325 mg daily) against deep venous thrombosis. If lenalidomide or thalidomide is given with high- dose dexamethasone,1 doxorubicin (Adriamycin),1 liposomal doxorubicin (Doxil), or erythropoietin (Epogen, Procrit), then full-dose warfarin (Coumadin)1 or a low-molecular-weight heparin1should be given. Anticoagulation is also recommended for patients who have a history of previous thromboembolic events, are on bedrest, are obese, or have any other risk factors for thrombosis. Bortezomib does not produce a higher risk of thromboembolic events.

Relapsed or Refractory Multiple Myeloma

Almost all patients with multiple myeloma who survive eventually relapse. If relapse occurs more than 6 months after treatment is discontinued, the initial chemotherapy regimen should be reinstituted. Most patients respond again, but the duration and quality of response are usually inferior to the initial response.

Recently, several new drugs have been approved for the treatment of multiple myeloma including pomalidomide (Pomalyst), carfilzomib (Kyprolis), daratumumab (Darzalex), elotuzumab (Empliciti), panobinostat (Farydak), and ixazomib (Ninlaro).

Thalidomide

Thalidomide (Thalomid) is usually instituted in a dose of 50 to 100 mg daily and, if necessary, escalated to 200 mg daily if tolerated. It is most often used in combinations such as VTD. Side effects include sedation, fatigue, constipation, rash, deep venous thrombosis, edema, bradycardia, and hypothyroidism. Virtually all patients develop a sensorimotor peripheral neuropathy. The use of thalidomide in pregnancy is contraindicated, and the STEPS program (System for Thalidomide Education and Prescribing Safety) must be followed to prevent teratogenic effects.

Bortezomib

Bortezomib (Velcade) is a proteasome inhibitor that produces a response rate of approximately 35% in patients with relapsed or refractory myeloma. It is most often used in combinations such as VRD, VCD, or VTD to maximize response rates. The most troublesome side effect is peripheral neuropathy, which can occur in 35% to 40% of patients. The neuropathy is often painful, but does improve in most patients after discontinuing bortezomib. The risk of neuropathy can be greatly reduced by using bortezomib in a once weekly subcutanoeus schedule.

Lenalidomide

Lenalidomide (Revlimid) as a single-agent produces an objective response in approximately 30% of patients with relapsed or refractory multiple myeloma. The major side effects are cytopenias, and the dose needs to be modified accordingly. The combination of lenalidomide plus low dose dexamethasone (Rd) is the backbone of several myeloma treatment regimens.

Carfilzomib

Carfilzomib (Kyprolis) is a new proteasome inhibitor approved for the therapy of patients with multiple myeloma who have received at least 2 prior therapies, including both an immunomodulatory agent and bortezomib, and have disease progression on or within 60 days of the completion of the last therapy. Carfilzomib needs to be administered intravenously twice weekly. In a recent randomized trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) was found to have superior response rate, progression free survival, and overall survival compared with Rd.

Pomalidomide

Pomalidomide (Pomalyst) is an analog of lenalidomide and thalidomide. It has shown significant clinical activity in patients who are refractory to both bortezomib and lenalidomide (dual refractory). It is approved for patients with multiple myeloma who received at least 2 prior therapies, including both lenalidomide and bortezomib, and have disease progression on or within 60 days of the completion of the last therapy. It is administered orally at a dose of 2–4 mg daily for 21 days every 28 days. The major side effects are cytopenias and fatigue.

Panobinostat

Panobinostat (Farydak) is a pan-deacetylase inhibitor that is approved for the treatment of multiple myeloma in patients who have received at least 2 prior therapies, including both an immunomodulatory agent and bortezomib. It is administered orally at a starting dose of 20 mg three times a week for 2 weeks every 3 weeks. It is given in combination with bortezomib and dexamethasone. It is associated with severe diarrhea in approximately 25% of patients, so use must be restricted to younger patients in good performance status who have failed other treatments but are not yet refractory to bortezomib. If the drug is used, the dose must preferably be lower than the approved label dose, and the dose of bortezomib and dexamethasone must also be reduced to a once weekly schedule. The drug approval carries a black-box warning concerning cardiac arrhythmias and severe diarrhea.

Elotuzumab

Elotuzumab (Empliciti) is a monoclonal antibody that is approved for the treatment of relapsed myeloma. It targets the signaling lymphocytic activation molecule F7 (SLAMF7). In a randomized trial of 646 patients, elotuzumab plus Rd was superior to Rd, median PFS 19.4 months versus 14.9 months, respectively, P<0.001.

Daratumumab

Daratumumab (Darzalex) is a monoclonal antibody that is approved for the treatment of relapsed myeloma. It targets CD38, a molecule universally expressed on myeloma cells. Daratumumab has a response rate of approximately 30% in heavily pre-treated patients. Two randomized trials have found improvement in PFS with the addition of daratumumab to Rd and bortezomib-dexamethasone, respectively.

Ixazomib

Ixazomib (Ninlaro) is an oral proteasome inhibitor approved for the treatment of relapsed myeloma. It is a boronic acid derivative similar to bortezomib. It is administered once-weekly orally. Compared with bortezomib it has a lower risk of peripheral neuropathy.

Other New Drugs

New drugs that are in clinical trials include new proteasome inhibitors (marizomib5, oprozomib5, and dinaciclib5.

Supportive Therapy

Radiotherapy

Palliative radiation in a dose of 20 to 30 Gy should be limited to patients who have disabling pain and a well-defined focal process that has not responded to chemotherapy. Analgesics in combination with chemotherapy usually can control the pain. This approach is preferred to local radiation because pain often occurs at another site, and local radiation does not benefit the patient with systemic disease. In addition, the myelosuppressive effects of radiotherapy and chemotherapy are cumulative and can restrict future therapy.

Radiation is required for spinal cord compression from plasmacytoma. Postsurgical radiation after stabilization of fractures or impending fractures is rarely needed.

Hypercalcemia

Hypercalcemia must be suspected if the patient has anorexia, nausea, vomiting, polyuria, increased constipation, weakness, confusion, stupor, or coma. If it is untreated, renal insufficiency usually develops. Hydration, preferably with isotonic saline and prednisone (25 mg orally four times daily), is effective in many patients with mild to moderate hypercalcemia (calcium < 13 mg/dL). If more-severe hypercalcemia occurs, zoledronic acid (Zometa) at a dose of 4 mg intravenously over 15 minutes or pamidronate (Aredia) 90 mg given intravenously over at least 2 hours is indicated. Calcitonin (Miacalcin) may be used if rapid reduction of calcium levels is needed.

Hemodialysis may be necessary for extremely severe hypercalcemia. The dosage of prednisone must be reduced and discontinued as soon as possible.

Renal Insufficiency

Approximately 20% of patients with multiple myeloma have a serum creatinine level of 2.0 mg/dL or more at diagnosis. Myeloma kidney (cast nephropathy) and hypercalcemia are the two major causes.

Myeloma kidney is characterized by the presence of large, waxy, laminated casts in the distal and collecting tubules. Some light chains are very nephrotoxic, but no specific amino acid sequence of the nephrotoxic light chain has been identified.

Dehydration, infection, nonsteroidal antiinflammatory agents, and radiographic contrast media can contribute to acute kidney failure.

Hyperuricemia or amyloid deposition can produce renal insufficiency. Nephrotic syndrome rarely occurs in multiple myeloma unless amyloidosis is present.

Maintenance of a high fluid intake producing 3 L of urine per 24 hours is important for preventing kidney failure in patients with Bence Jones proteinuria. If hyperuricemia occurs, allopurinol (Zyloprim) in doses of 300 mg daily provides effective therapy.

Acute kidney failure should be treated promptly with appropriate fluid and electrolyte replacement. Patients with kidney failure should be treated with either VCD or VTD to reduce the tumor mass as quickly as possible. A trial of plasmapheresis is reasonable in an attempt to prevent chronic dialysis. Hemodialysis and peritoneal dialysis are equally effective and are necessary for patients with symptomatic azotemia.

Anemia

Almost every patient with multiple myeloma eventually becomes anemic. Increased plasma volume from the osmotic effect of the M protein can produce hypervolemia and can spuriously lower the hemoglobin and hematocrit values. Patients with significant symptoms should be considered for red blood cell transfusion. If a transfusion is indicated, irradiated leukocyte-reduced red cells are preferred.

In patients with newly diagnosed myeloma, induction chemotherapy is often associated with a prompt improvement in hemoglobin levels, so it is better to avoid the use of erythropoietin. Erythropoietin (Epogen) should be seriously considered in relapsed patients receiving chemotherapy who have a persistent, symptomatic hemoglobin level of 10 g/dL or less.

Erythropoietin reduces the transfusion requirement and increases hemoglobin concentration in more than half of patients. Those with low serum erythropoietin values are more likely to respond. Most physicians proceed with a trial of erythropoietin 150 U/kg three times weekly, or 40,000 U once a week. Darbepoetin, a long-lasting erythropoietin (Aranesp), may be given weekly or biweekly.

Erythropoietin should be discontinued when the hemoglobin reaches 11 g/dL.

Skeletal Lesions

Bone lesions manifested by pain and fractures are a major problem. A skeletal radiographic survey should be repeated at 6-month intervals, or sooner if pain develops. Patients should be encouraged to be as active as possible because confinement to bed increases demineralization of the skeleton. Trauma must be avoided because even mild stress can result in a fracture. Fixation of long bone fractures or impending fractures with an intramedullary rod and methyl methacrylate gives excellent results.

All patients with multiple myeloma who have lytic lesions, pathologic fractures, or severe osteopenia should receive an IV bisphosphonate. Pamidronate (Aredia) 90 mg intravenously over 2 hours every 4 weeks or zoledronic acid (Zometa) 4 mg intravenously over 15 minutes every 4 weeks are equally efficacious. The dosage of bisphosphonates should be reduced with renal insufficiency. Because renal insufficiency or nephrotic-range proteinuria can occur, serum creatinine and 24-hour urine protein monitoring is necessary. One should seriously consider stopping the IV bisphosphonate in patients who have responsive or stable disease after 2 years of therapy. In other patients we recommend reducing the dose to once every 3 months. A recent randomized trial has found that denosumab (Xgeva)1, a monoclonal antibody targeting RANKL may be as effective in reducing skeletal events as zoledronic acid, and may be an option in the future for selected patients.

Bisphosphonates should be resumed upon relapse with new-onset skeletal-related events. Osteonecrosis of the jaw can occur in patients receiving bisphosphonates. Although the relationship is unclear, it is essential to obtain a complete dental evaluation and perform preventive dental treatment before beginning bisphosphonates. The patient should practice good oral hygiene during therapy. Invasive procedures (especially dental extractions) should be avoided during bisphosphonate therapy. Osteonecrosis of the jaw should be managed conservatively.

Vertebroplasty or kyphoplasty may be helpful for patients with an acute compression fracture of the spine. Both have been associated with pain relief. Results appear to be better when the procedure is performed shortly after the compression fracture. Leakage of the methyl methacrylate is a potential adverse event. A choice between vertebroplasty and kyphoplasty depends upon the expertise of the physician performing the procedure.

Infections

Bacterial infections are more common in patients with myeloma than in the general population. All patients should receive pneumococcal and influenza immunizations despite their suboptimal antibody response. Substantial fever is an indication for appropriate cultures, chest radiography, and consideration of antibiotic therapy. The greatest risk for infection is during the first 2 months after chemotherapy is initiated. The use of prophylactic antibiotics is controversial. Antiviral prophylaxis (acyclovir [Zovirax] 400 mg twice daily or valacyclovir [Valtrex] 500 mg once daily) should be given to all patients receiving bortezomib because of the increased risk of herpes zoster. Intravenous immunoglobulin (IVIg, Gammagard)1 may be helpful in selected patients who have recurrent serious infections despite the use of prophylactic antibiotics. It is inconvenient, associated with side effects, and very expensive. Consequently, few of our patients receive IVIg.

Hyperviscosity Syndrome

Symptoms of hyperviscosity can include oronasal bleeding, gastrointestinal bleeding, blurred vision, neurologic symptoms, or congestive heart failure. Most patients have symptoms when the serum viscosity measurement is more than 4 cP, but the relationship between serum viscosity and clinical manifestations is not precise. The decision to perform plasmapheresis, which promptly relieves the symptoms of hyperviscosity, should be made on clinical grounds rather than serum viscosity levels. Hyperviscosity is more common in immunoglobulin (IgA) myeloma than in IgG myeloma.

Extradural Myeloma (Cord Compression)

The possibility of cord compression must be considered if weakness of the legs or difficulty in voiding or defecating occurs. The sudden onset of severe radicular pain or severe back pain with neurologic symptoms suggests compression of the spinal cord. MRI or CT of the entire spine must be performed immediately. Radiation therapy in a dose of approximately 30 Gy is beneficial in about one half of patients. Dexamethasone (Decadron)1 should be administered in addition to radiation therapy. Surgical decompression is necessary only if the neurologic deficit does not improve.

Venous Thromboembolism

Patients with multiple myeloma have an increased risk of venous thromboembolism. This is due to the malignancy itself as well as therapy with lenalidomide or thalidomide with corticosteroids.

Aspirin1 given prophylactically is beneficial. If there is a history of previous thromboembolic events or if other risk factors are present, anticoagulation with full-dose warfarin or low-molecular-weight heparin is indicated.

Emotional Support

All patients with multiple myeloma need substantial and continuing emotional support. The physician’s approach must be positive in emphasizing the potential benefits of therapy. It is reassuring for patients to know that some survive for 10 years or more. It is vital that the physician caring for patients with multiple myeloma has the interest and capacity for dealing with incurable disease over the span of years with assurance, sympathy, and resourcefulness.

References

1.     Attal M., Lauwers-Cances V., Marit G., et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–1791.

2.    Dimopoulos M.A., Oriol A., Nahi H., et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319–1331.

3.     Durie BGM, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial, Lancet. 389(10068):519–527, 2017.

3.    Krishnan A., Pasquini M.C., Logan B., et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195–1203.

4.     Kyle R.A., Rajkumar S.V. Epidemiology of the plasma-cell disorders. Best Pract Res Clin Haematol. 2007;20:637–664.

5.      Kyle R.A., Yee G.C., Somerfield M.R., et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464–2472.

6.    Lonial S., Dimopoulos M., Palumbo A., et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621–631.

7.    Lacy M.Q., Hayman S.R., Gertz M.A., et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008–5014.

8.       McCarthy P.L., Owzar K., Hofmeister C.C., et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–1781.

9.       Mikhael J.R., Dingli D., Roy V., et al. Management of newly diagnosed symptomatic multiple myeloma: updated mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88:360–376.

10.    Moreau P., Masszi T., Grzasko N., et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621–1634.

11.   Palumbo A., Chanan-Khan A., Weisel K., et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754–766.

12.    Rajkumar S.V., Jacobus S., Callander N.S., et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low- dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29–37.

13.    Rajkumar S.V., et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.

14.    Sonneveld P., Schmidt-Wolf I.G.H., van der Holt B., et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30:2946–2955.

15.    Stewart A.K., et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.

3  Exceeds dosage recommended by the  manufacturer.

5  Investigational drug in the United  States.

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