Induction Therapy
        Corticosteroids
        Thalidomide
        Lenalidomide
        Bortezomib
        Conventional-dose chemotherapy
Consolidation Chemotherapy
        High-dose chemotherapy: autologous bone marrow or peripheral stem cell transplantation
        High-dose chemotherapy: allogeneic bone marrow or peripheral stem cell transplantation
Maintenance Therapy
Supportive Care
        Bisphosphonate therapy
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[1,2] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.

Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated as follows:

1. Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin assays; however, specific immunoglobulin quantification always overestimates the M protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M protein should be done by the same method.[3]



2. Measure and follow the amount of M protein light chains excreted in the urine per 24 hours. Measure the total amount of protein excreted per 24 hours and multiply this value by the percentage of urine protein that is M protein as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.



3. Identify the heavy- and light-chain of the M protein by immunofixation electrophoresis.



4. Measure the hemoglobin, leukocyte, platelet, and differential counts.



5. Determine the percentage of marrow plasma cells. Be aware that marrow plasma cell distribution may vary in different sites.



6. Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.



7. Evaluate renal function with serum creatinine and a creatinine clearance. Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin. In most myeloma patients, the glomeruli function normally allowing only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.



8. Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins, and serum viscosity.



9. Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones. Whole-body, low-dose, nonenhanced multidetector computed tomography (CT) and magnetic resonance imaging (MRI) are being evaluated as measures for therapy response monitoring.[4,5] MRI of the spine or long bones is more sensitive in detecting lytic lesions, but any prognostic or therapeutic value for this information remains to be determined.[5]



10. Perform MRI if a paraspinal mass is detected or if symptoms suggest spinal cord or nerve root compression.



11. If amyloidosis is suspected, do a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.[6]



12. Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[7,8]



13. A high plasma cell labeling index (≥3%) and the presence of circulating myeloma cells are considered poor prognostic factors.[9]

These initial studies should be compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse. The major challenge is to separate the stable asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who should be treated immediately.[10,11]

Patients with MGUS have an M protein in the serum and/or urine and less than 10% plasma cells in the marrow but no other signs or symptoms of disease. The patients with smoldering myeloma have similar characteristics but may have greater than 10% of marrow plasma cells. Since 1% to 2% of MGUS patients per year will progress to develop myeloma (most commonly), amyloidosis, a lymphoma, or chronic lymphocytic leukemia, these types of patients must be followed carefully.[12] Treatment is delayed until the disease progresses to the stage that symptoms or signs appear. Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions, or have improved survival if chemotherapy is started early while they are still asymptomatic as opposed to waiting for progression before treatment is initiated.[10,11,13,14]

Current therapy for patients with symptomatic myeloma can be divided into categories of induction therapies, consolidation therapies (which are less applicable for the very elderly), maintenance therapies, and supportive care (such as bisphosphonates). (For more information on supportive care therapies such as bisphosphonates, refer to the Pain summary.) Several questions are raised when choosing therapy for a patient with symptomatic myeloma at first presentation:

• Is the patient eligible for a clinical trial? The sequence and combinations of new and older therapies can only be determined by prospective clinical trials.
• Is autologous stem cell transplantation a possible consolidation option for this patient? If so, alkylating agents should be avoided during induction therapy to avoid compromise of stem cell collection and to lessen leukemogenic risk.
• Does the patient have comorbidities? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications would influence the choice of induction therapies as well as the choice of whether to consider consolidation therapies.

Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days in the same schedule as administered with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen.[15] Response rates of 60% to 70% in previously untreated patients appeared as high as those in patients treated with VAD.[15,16][Level of evidence: 3iiiDiv] A prospective trial randomly assigned 488 patients older than 65 years to receive dexamethasone alone, melphalan plus dexamethasone, dexamethasone plus interferon-alpha, and melphalan plus prednisone; with a median follow-up of 7.1 years, no difference was observed in overall survival (OS) (median survival times were 32 to 40 months).[17][Level of evidence: 1iiA] The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (For more information on gastrointestinal symptoms, refer to the Gastrointestinal Complications summary.)

There has never been a randomized trial comparing single-agent oral dexamethasone at a traditional high dose (40 mg a day for 4 days, repeated after 4 days off) versus a lower dose (40 mg or less weekly). This issue of dexamethasone dose has been evaluated in two prospective randomized trials, one in the context of melphalan from the National Cancer Institute of Canada (CAN-NCIC-MY7), and the other in the context of lenalidomide from the Eastern Cooperative Oncology Group (E-4A03) and published only in abstract form.[18,19] High-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but with no difference in efficacy compared to standard dose steroids.[18] The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone (refer to the Lenalidomide section of this summary for more information).[19] Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.

Eight randomized prospective studies (including E-E1A00 and the Commissie Voor Klinisch Toegepast Onderzoek trial [HOVON 50]) involving more than 3,000 patients have been published in final or preliminary abstract form examining the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[20-27] All of the trials reported improved response rates with the introduction of thalidomide and no hematopoietic damage, allowing adequate stem cell collection when applicable or allowing combinations with other myelosuppressive agents. Only two of the eight randomized studies reported a survival advantage using thalidomide. In both trials, the patients older than 65 years at the 2-year follow-ups showed 45-month to 56-month median overall survival (OS) for melphalan plus prednisone plus thalidomide (MPT) versus 28-month to 30-month median OS for melphalan plus prednisone (MP) (P = .0008 in both studies).[25,28][Level of evidence: 1iiA] A possible explanation is that these two trials used a lower dose of thalidomide than the other studies (100 mg instead of 200 mg or higher), a lower dose of steroids (60 mg of prednisone instead of high-dose dexamethasone), and involved the use of alkylating agents. As previously described in the section on corticosteroids, high-dose dexamethasone can complicate interpretation of clinical trials by worsening cardiopulmonary toxicity and deaths, especially in the context of thalidomide or lenalidomide, both of which are thrombogenic agents.

Factors that have been implicated to worsen the risk of deep venous thrombosis (DVT) include high-dose dexamethasone, concomitant erythropoietic growth factors, or concomitant use of doxorubicin, liposomal doxorubicin, or alkylating agents. Personal cardiovascular risk factors can also influence the rate of DVT. Various clinical trials have included different DVT prophylaxis measures, including aspirin (81 mg–100 mg a day), warfarin, or low-molecular-weight heparin, but the validity of these measures has not been studied prospectively.[22,25,26,29-31] Prospective electrophysiologic monitoring provides no clear benefit versus clinical evaluation for the development of clinically significant neuropathy while on thalidomide.

A prospective randomized study of 351 relapsed patients compared lenalidomide, an analogue of thalidomide, plus high-dose dexamethasone to high-dose dexamethasone plus placebo.[32] The lenalidomide combination showed a significantly higher time-to-tumor-progression (11.3 months vs. 4.7 months, P < .001) with a 16-month median follow-up, and median OS had not been reached, versus 20.6 months in the placebo group (hazard ratio = 0.66, 95% confidence interval, 0.45–0.96, P = .03).[Level of evidence: 1iiDiii][32][Level of evidence: 1iA] The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[32] Similarly, another randomized prospective trial CC-5013 of 353 previously treated patients favored the lenalidomide plus high-dose dexamethasone arm versus dexamethasone plus placebo; with a median follow-up of 26 months, the median time-to-progression was 11.1 months versus 4.7 months (P < .001) and the median OS was 29.6 versus 20.2 months (P < .001).[33][Level of evidence: 1iA] A prospective randomized study (E-4A03) of 445 untreated symptomatic patients, published in abstract form only, compared lenalidomide and high-dose dexamethasone (40 mg D1–4, 9–12, 17–20 every 28 days) to lenalidomide and low-dose dexamethasone (40 mg D1, 8, 15, 22 every 28 days).[19] With a median follow-up of 25 months, this trial showed improved OS for patients in the low-dose dexamethasone arm (87% vs. 75% at 2 years, P = .006), despite no difference in progression-free survival.[19][Level of evidence: 1iiA] The extra deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity and faster progression with subsequent therapies. DVTs were also more frequent in the high-dose arm (25% vs. 9%). OS favored the low-dose arm with a 2-year survival of 87% (low-dose) versus 75% (high-dose) (P = .006.)[19][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone. Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide, but both have the same tendency for DVT.[19,32,33]

A prospective randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone; OS at 1 year favored bortezomib (80% vs. 66%) (P = .003).[34][Level of evidence: 1iiA] Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[35,36]

A prospective randomized trial (DOXIL-MMY-3001) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[37] With a median follow-up of 7 months, the combination was better in both median time-to-progression (9.3 mo vs. 6.5 mo, P < .001) and in OS (82% vs. 75%, P = .05).[37][Level of evidence: 1iiA]

Patients with unfavorable molecular cytogenetics did not show any difference in progression-free or OS compared with patients with more favorable risk factors when bortezomib was incorporated with induction therapy. The benefit from bortezomib appears to be maintained across risk groups.[34,38-40][Level of evidence: 3iiiD]

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[41-44][Level of evidence: 3iiiDiv] No randomized studies support the widespread use of this regimen in untreated patients. This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia. Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low complete response rate. An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[45,46]Level of evidence: 3iiiDiv]

Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results.[47] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[47-49]

Combinations such as those used in E-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[50-53][Level of evidence: 1iiA] A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.[47][Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median 17 months) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone (VBMCP) or VAD.[54]

The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy. From the experience with thousands of patients treated in this way, it is possible to draw a few conclusions. The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[55] Chemotherapy patients can now be treated as outpatients. Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.[56] Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.[57-59]

While some prospective randomized trials such as the U.S. Intergroup trial SWOG-9321, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[12,60,61][Level of evidence: 1iiA] other trials have not shown any survival advantage.[62-65][Level of evidence: 1iiA] A meta-analysis of 575 patients with individual data showed no survival advantage.[66][Level of evidence: 1iiA] Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[12,60,61]

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[67-69] In a trial of 399 previously untreated patients younger than 60 years, the patients were randomly assigned to a single or double (tandem) autologous stem-cell transplantation.[70] With a median follow-up of more than 6 years, the double-transplant group had a superior EFS (20% vs. 10% at 7 years, P = .03) and OS (42% vs. 21% at 7 years, P = .01).[70][Level of evidence: 1iiA] Patients with a reduction of paraprotein of greater than 90% after the first transplant (the best responders) had the least incremental benefit from the second transplant (retrospective subgroup analysis).[70] In a trial of 321 previously untreated patients under 60 years, patients were randomly assigned to a single or tandem transplant; with a median follow-up of 55 months, the double transplant group had superior EFS (35 months vs. 23-month median, P = .001), but there was no difference in 7-year survival (43% vs. 46%, P = .90).[71][Level of evidence: 1iiA] In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to conventional oral melphalan and prednisone versus VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m²) with stem cell support.[61] With a median follow-up of greater than 3 years, the double transplant group had superior EFS (37% vs. 16% at 3 years, P < .001) and OS (77% vs. 62%, P < .001).[61][Level of evidence: 1iiA] A trial of 162 consecutive newly diagnosed patients compared two tandem autologous transplants versus one autologous transplant followed by an allograft from an HLA-identical sibling (assignment was based on the presence or absence of an HLA-identical sibling); with a median follow-up of 45 months, the median OS was 54 months for the tandem autologous grafts versus 80 months for the allogeneic arm (P = .01).[72][Level of evidence: 3iiA]

Maintenance therapy with interferon showed a benefit in progression-free survival (PFS) (46 vs. 27 months, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[73][Level of evidence: 1iiA] A larger randomized trial of 805 patients showed no difference in PFS or OS with interferon applied after peripheral stem cell transplantation or conventional chemotherapy.[74][Level of evidence: 1iiA]

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.[75][Level of evidence: 3iiiA] Favorable prognostic features included low tumor burden, responsive disease before transplant, and application of transplantation after first-line therapy. Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses following the infusion of donor lymphocytes.[76-79] Allogeneic marrow transplants have significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma reaction makes this procedure attractive.[79,80] Further research is required to make allogeneic transplants less dangerous and to find methods for initiating an autoimmune response to the myeloma cells. Nonmyeloablative allogeneic stem cell transplant is under development.[81-83] Such strategies aim to maintain efficacy (so called graft-versus-tumor-effective) while reducing transplant-related mortality.[84] Early reports indicate that significant graft-versus-host disease and transplant-related mortality remain challenges with this approach.[82,85] In one phase II prospective study, high-risk patients (beta-2-microglobulin >3 mg/dl or chromosome 13 deletion) with an HLA-identical sibling donor underwent nonmyeloablative allogeneic stem cell transplantation after autologous stem cell transplantation.[86] This approach requires further evaluation.

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. In a single study,[87] it was observed that maintenance therapy with MP prolonged the initial remission duration (31 months) compared to no maintenance treatment (23 months). No effect on OS was found because the majority of patients who relapsed in the no maintenance arm responded again to MP, while those on maintenance MP did not respond to further treatment. The Canadian group [87] suggests that induction chemotherapy be continued as long as the M protein continues to fall; therapy can be discontinued after the M protein reaches a plateau that remains stable for 4 months.

Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration.[88-91] While the impact of interferon maintenance on disease-free survival and OS has significantly varied among trials, a meta-analysis of 1,543 patients treated on 12 trials randomizing between interferon maintenance and observation indicated that interferon maintenance was associated with improved relapse-free survival (27% vs. 19% at 3 years, P < .001) and OS (12% odds reduction, P = .04).[92] Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.[93]

A study of 125 responding patients with first-line VAD induction who were randomly assigned to maintenance corticosteroids at 10 mg or 50 mg on alternate days showed improved PFS (14 months vs. 5 months, P = .003) and OS (36 months vs. 26 months, P = .05) for the patients receiving the higher-dose corticosteroids.[94][Level of evidence: 1iiA] In a larger trial by the National Cancer Institute of Canada (NCIC-CTG-MY.7) of 585 patients treated with first-line MP, 292 patients were randomly assigned to pulse dexamethasone (40 mg a day for 4 days monthly) versus no maintenance; PFS favored the dexamethasone maintenance (2.8 vs. 2.1 years, P = .0002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).[18][Level of evidence: 1iiDiii]

Two months after autologous transplantation, 597 patients younger than 65 years were randomly assigned to no maintenance, pamidronate, or pamidronate plus thalidomide; the thalidomide arm was favored by EFS (36% vs. 37% vs. 52%, P < .009) and OS at 4 years (77% vs. 74% vs. 87%, P < .04), while no differences were seen for skeletal events.[95][Level of evidence: 1iiA]

A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduces pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treated group vs. 51% in the placebo group after 21 months of therapy, P = .015).[96][Level of evidence: 1iDiii]

A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications.[97][Level of evidence: 1iDiii] However, bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients) including osteonecrosis of the jaw and avascular necrosis of the hip.[98,99] (For more information on osteonecrosis of the jaw, refer to the Oral Complications of Chemotherapy and Head/Neck Radiation summary.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[100]

Lytic lesions of the spine should be radiated if they are associated with an extramedullary (paraspinal) plasmacytoma, if a painful destruction of a vertebral body occurred, or if CT or MRI scans present evidence of spinal cord compression.[101]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (For more information on back pain, refer to the PDQ summary on Pain.) Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[102] Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[96]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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