Treatment for Multiple Myeloma

Initial Evaluation
Induction Therapy
        Induction therapy agents
        Guidelines for choosing induction therapy
        Corticosteroids
        Thalidomide
        Lenalidomide
        Bortezomib
        Conventional-dose chemotherapy
        Combination therapy
Consolidation Chemotherapy
        High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation
        Single autologous bone marrow or peripheral stem cell transplantation
        Tandem autologous bone marrow or peripheral stem cell transplantation
        High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation
Maintenance Therapy
        Supportive care
Current Clinical Trials

Initial Evaluation

The initial approach to the patient is to evaluate the following parameters:

1. Detection of a monoclonal (or myeloma) protein (M protein) in the serum or urine.
2. Detection of more than 10% of plasma cells on a bone marrow examination.
3. Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays.
4. Presence of soft tissue plasmacytomas.
5. Serum albumin and beta-2-microglobulin levels.
6. Detection of free kappa and lambda serum immunoglobulin light chain.[1]

Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.[2]

Induction Therapy

The choice of induction therapy is unclear at the present time; however, the current basic categories include the use of steroids, thalidomide, and lenalidomide.

Several questions are raised when therapy is being chosen for a patient with symptomatic myeloma at first presentation, including the following:

1. 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.

2. Is autologous stem cell transplantation (ASCT) 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.

3. 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.

Induction therapy agents

Multiple therapeutic agents are available for induction therapy, either alone or in combinations.[3] These include the following:

• Steroids (e.g., dexamethasone and prednisone).
• Thalidomide.
• Lenalidomide.
• Bortezomib.
• Alkylating agents (e.g., melphalan and cyclophosphamide).
• Other cytotoxic drugs (e.g., vincristine, doxorubicin, and liposomal doxorubicin).

Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity. (Refer to the Combination therapy ¹ section of this summary for a list of current clinical trials.)

Guidelines for choosing induction therapy

Until results become available, outside the context of a clinical trial, clinicians may choose induction therapy based on the following guidelines:

1. In patients younger than 70 years, alkylators are avoided up front to avoid stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting if transplantation is considered for consolidation therapy.[4]

2. Bortezomib or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[5,6] (Refer to the Lenalidomide ² and Bortezomib ³ sections of this summary for more information.)

3. The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration.
   • Bortezomib is given in frequent intravenous doses and can cause significant neuropathic toxicities.[6-8] Bortezomib is preferred in the setting of renal impairment.[9]

   • Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT), requiring additional prophylactic medication.[5,10]

4. Patients with standard-risk disease, as defined in the Stage Information About Plasma Cell Neoplasms ⁴ section of this summary, might receive induction therapy alone, followed by careful observation after best response.[11]

5. Patients with high-risk disease might receive induction therapy until best response, followed by consolidation therapy with allogeneic or ASCT.[11]

These guidelines require validation by ongoing clinical trials; participation in clinical trials is the preferred choice, when possible.

Corticosteroids

Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days, which is the same schedule used with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen.[12] Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[12,13][Level of evidence: 3iiiDiv]

Evidence:

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 (MP).

• With a median follow-up of 7.1 years, no difference was observed in overall survival (OS) (median survival times were 32 months–40 months).[14][Level of evidence: 1iiA]

• The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (Refer to the PDQ summary on Gastrointestinal Complications ⁵ for more information on gastrointestinal symptoms.)

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) with a lower dose (≤40 mg weekly). This issue of dexamethasone dose has been evaluated in two of the following prospective, randomized trials:

• In the context of melphalan, as evaluated in a National Cancer Institute of Canada trial (CAN-NCIC-MY7 ⁶).
  • Compared with standard-dose steroids, high-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but there was no difference in efficacy.[15]

• In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial (ECOG-E4A03 ⁷).[5]
  • The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone.[5] (Refer to the Lenalidomide ² section of this summary for more information.)

Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.

Thalidomide

Evidence:

Ten randomized prospective studies involving more than 4,500 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[16-24]

• 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 ten randomized studies reported a survival advantage using thalidomide. In these trials, the patients older than 65 or 75 years at the 2-year follow-ups showed a 44- to 56-month median OS for MP plus thalidomide versus 28- to 30-month median OS for MP (P < .03 in both studies).[22,25][Level of evidence: 1iiA]

• A possible explanation is that these two trials used a lower dose of thalidomide than the other studies (100 mg vs. ≥200 mg), a lower dose of steroids (60 mg of prednisone vs. 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 DVT include the use of high-dose dexamethasone, concomitant erythropoietic growth factors, and concomitant doxorubicin, liposomal doxorubicin, or alkylating agents.[26,27]

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 in a randomized study.[20,22,27-29]

Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.

Lenalidomide

Evidence:

1. A prospective randomized study of 351 relapsed patients compared lenalidomide, an analog of thalidomide, plus high-dose dexamethasone with high-dose dexamethasone plus placebo.[30]
   • 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 [HR] = 0.66, 95% confidence interval [CI], 0.45–0.96, P = .03).[30][Level of evidence: 1iA]

   • The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[30]

2. Similarly, another randomized, prospective trial (NCT00056160 ⁸) 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 months versus 20.2 months (P < .001).[31][Level of evidence: 1iA]

3. A prospective, randomized study (ECOG-E4A03 ⁷) of 445 untreated symptomatic patients compared lenalidomide and high-dose dexamethasone (40 mg on days 1–4, 9–12, and 17–20, every 28 days) with lenalidomide and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22, every 28 days).[5]
   • With a median follow-up of 36 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 (PFS).[5][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% versus 75% in the high-dose arm (P = .006).[5][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.

4. A retrospective analysis of 353 patients who received lenalidomide and high-dose dexamethasone found that the 17% of the patients who experienced a thromboembolic episode had no decrease in OS or time to progression.[32][Level of evidence: 3iiiA]

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[5,30-32] DVT prophylaxis with 81 mg of aspirin has been proposed, but randomized clinical trials have not confirmed any benefit for this recommendation.[29] Empirically, the greater the number of risk factors for DVT, the more intense the recommendation for prophylactic anticoagulation. (Refer to the Thalidomide ⁹ section of this summary for more information about risk factors.) As a result of predominant renal clearance, lenalidomide doses need to be reduced in the setting of impaired renal function (creatinine clearance, 30–50: 10 mg per day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis).[33]

Bortezomib

Evidence:

1. A prospective randomized trial (NCT00111319 ¹⁰) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation because of age (one-third of patients >75 years) compared bortezomib combined with melphalan and prednisone with melphalan and prednisone alone.[6]
   • With a median follow-up of 37 months, the OS favored the bortezomib arm in the 3-year OS rates (69% vs. 54%, P = .03).[6][Level of evidence: 1iiA]

2. 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.
   • With a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR = 0.77, P = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[7][Level of evidence: 1iiA]

   • Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[8,34-37]

3. A prospective, randomized trial (NCT00103506 ¹¹) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[38]
   • With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 months vs. 6.5 months, P < .001) and in OS (82% vs. 75%, P = .05).[38][Level of evidence: 1iiA]

When bortezomib was incorporated with induction therapy, patients with unfavorable molecular cytogenetics did not show any difference in PFS or OS compared with patients with more favorable risk factors. The benefit from bortezomib appears to be maintained across risk groups, but not reproducibly in all studies.[39-43][Level of evidence: 3iiiD]

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[9,44,45] In a retrospective, nonrandomized comparison, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (8% vs. 28%, P < .001) with no loss of efficacy compared with standard biweekly administration.[46]

Conventional-dose chemotherapy

Evidence:

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[47-50][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.[51,52][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.[53] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[53-55]

Combinations, such as those used in EST-2479 ¹², of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[56-59][Level of evidence: 1iiA]

A meta-analysis of studies comparing MP with drug combinations concluded that both forms of treatment were equally effective.[53][Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median OS, 17 months) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone or VAD.[60][Level of evidence: 1iiA]

Combination therapy

Evidence:

Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials should be the preferred approach, when feasible. The combination regimens in these trials represent the most successful from numerous phase II reports during the last several years.

• ECOG-E1A05 ¹³: Bortezomib + dexamethasone versus lenalidomide + bortezomib + dexamethasone.[61]

• SWOG-S0777 ¹⁴: Lenalidomide + dexamethasone versus lenalidomide + bortezomib + dexamethasone.

• EVOLUTION ¹⁵ (NCT00507442) trial: Bortezomib + lenalidomide + dexamethasone versus bortezomib + cyclophosphamide + dexamethasone versus bortezomib + lenalidomide + cyclophosphamide + dexamethasone.

• U.S. Intergroup/Intergroupe Francais du Myélome trial (IFM): Lenalidomide + bortezomib + dexamethasone for three cycles; responders are then randomly assigned to five more cycles of lenalidomide + bortezomib + dexamethasone or high-dose melphalan + stem cell transplantation.

• ECOG-E1A06 ¹⁶: Thalidomide + melphalan + prednisone versus lenalidomide + melphalan + prednisone.

Options for combination regimens:

1. Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[39,61]

2. Lenalidomide + dexamethasone (as demonstrated in SWOG-S0777).[5,30,31]

3. Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-S0777, EVOLUTION trial, and the U.S. Intergroup/IFM trial).[39,61,62]

4. Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[63,64]

5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[65]

6. Lenalidomide + cyclophosphamide + dexamethasone.[66]

7. Bortezomib + melphalan + prednisone.[6]

8. Bortezomib + liposomal doxorubicin +/- dexamethasone.[38,67]

9. Melphalan + prednisone + thalidomide.[18,25]

10. Melphalan + prednisone.[18,25]

Consolidation Chemotherapy

High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation

Evidence:

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.

Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:

• The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[68]

• 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.[4]

• Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.[69-71]

• Upon review of eight updated trials encompassing more than 3,100 patients, at 10 years' follow-up, there was a 10% to 35% event-free survival (EFS) rate and a 20% to 50% OS rate.[72]

Single autologous bone marrow or peripheral stem cell transplantation

Evidence:

While some prospective randomized trials, such as the U.S. Intergroup trial SWOG-9321 ¹⁷, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[73-75][Level of evidence: 1iiA] other trials have not shown any survival advantage.[76-79][Level of evidence: 1iiA]

Two meta-analyses of almost 3,000 patients showed no survival advantage.[80,81][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.[73-75,82] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[83,84]

Tandem autologous bone marrow or peripheral stem cell transplantation

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[85-89]

Evidence:

1. A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplantation with tandem autologous hematopoietic cell transplantation.
   • There was no difference in OS (HR = 0.94; 95% CI, 0.77–1.14) or in EFS (HR = 0.86; 95% CI, 0.70–1.05).[90][Level of evidence: 1A]

2. In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to either conventional oral melphalan and prednisone or VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m²) with stem cell support.[75]
   • With a median follow-up of more 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).[75][Level of evidence: 1iiA]

3. Three different groups have compared two tandem autologous transplants with one autologous transplant followed by a reduced-intensity conditioning allograft from an HLA-identical sibling; treatment assignment was based on the presence or absence of an HLA-identical sibling. The results have been discordant for survival in these nonrandomized trials.
   • One study showed a survival advantage for the two tandem autologous transplants.

   • One study showed a survival advantage for the autologous transplant followed by an allogeneic transplant.

   • One study showed no difference in OS.[91-94][Level of evidence: 3iiiA]

   • 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 graft (P = .01).[91][Level of evidence: 3iiA]

4. A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous stem cell transplant followed by 6 months of maintenance therapy with thalidomide.
   • With a median follow-up of 33 months, the thalidomide maintenance arm showed a benefit in PFS (85% vs. 57% at 3 years, P = .02) and OS (85% vs. 65% at 3 years, P = .04).[95][Level of evidence: 1iiA]

High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation

Evidence:

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.[96][Level of evidence: 3iiiA]

Favorable prognostic features included the following:

• Low tumor burden.
• Responsive disease before transplant.
• 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.[97-100]

Myeloablative allogeneic stem cell transplantation has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[100-102]

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.[103-105] Such strategies aim to maintain efficacy (so called graft-versus-tumor effect) while reducing transplant-related mortality.[106,107] The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[102] Given the lack of evidence so far that the high-risk patients benefit from allogeneic stem cell transplantation in this era of novel new agents, it remains debatable whether allogeneic stem cell transplantation should be offered in the first-line setting outside the context of a clinical trial.[102]

Maintenance Therapy

Clinical trials exploring thalidomide as maintenance therapy have contradictory results.

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.

Evidence:

1. In a single study,[108] it was observed that maintenance therapy with MP prolonged the initial remission duration (31 months) compared with 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 [108] 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.

2. Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration after conventional chemotherapy.[109-112] 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).[113] Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.[114]

3. A randomized study compared maintenance interferon with maintenance thalidomide in 103 previously untreated and treated patients who had at least a minimal response to induction chemotherapy with thalidomide, pegylated liposomal doxorubicin, and dexamethasone. With a median follow-up of 30 months, the thalidomide maintenance arm was better, with 2-year PFS of 63% versus 32% (P = .024) and a 2-year OS of 84% versus 68% (P = .03).[115][Level of evidence: 1iiA]

4. In a trial of 556 previously untreated patients induced with thalidomide, doxorubicin, dexamethasone, and followed by high-dose melphalan with stem cell support, patients were randomly assigned to alpha interferon or to thalidomide maintenance. With a median follow-up of 52 months, there was no significant difference in median survival (P = .77) 60 months for interferon and 73 months for thalidomide.[24][Level of evidence: 1iiA]

5. Maintenance therapy with interferon showed a benefit in PFS (46 months vs. 27 months, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[116][Level of evidence: 1iiA] A larger randomized trial of 805 patients showed no difference in PFS or OS with interferon given after peripheral stem cell transplantation or conventional chemotherapy.[117][Level of evidence: 1iiA]

6. In a randomized trial, 269 patients with newly diagnosed myeloma were given maintenance thalidomide plus prednisolone versus prednisolone alone following both induction therapy and high-dose melphalan with ASCT. The trial showed a benefit in favor of the thalidomide arm after a median follow-up of 3 years: 3-year PFS, 43% versus 23% (P < .001); 3-year OS, 86% versus 75% (P = .004).[118][Level of evidence: 1iiA] As a result of these varying outcomes, further clinical trial results are required to determine whether there is a benefit of maintenance therapy.

7. 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.[119][Level of evidence: 1iiA]

8. In a larger trial by the National Cancer Institute of Canada (CAN-NCIC-MY7 ⁶) 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 arm (2.8 years vs. 2.1 years, P = .002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).[15][Level of evidence: 1iiDiii]

9. 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 by OS at 4 years (77% vs. 74% vs. 87%, P < .04), while no differences were seen for skeletal events.[120][Level of evidence: 1iiA]

10. After autologous transplantation, 129 patients were randomly assigned to indefinite prednisone versus indefinite prednisone with 12 months of thalidomide.
    • With a median follow-up of 3 years, the thalidomide arm was favored by PFS (42% vs. 23%, P < .001) and by OS at 3 years (86% vs. 75%, P = .004).[118][Level of evidence: 1iiA]

Supportive care

Bisphosphonate therapy

Evidence:

1. A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduced pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treatment group vs. 51% in the placebo group after 21 months of therapy, P = .015).[121][Level of evidence: 1iDiii] (Refer to the PDQ summary on Pain ¹⁸ for more information on bisphosphonate therapy.)

2. A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications.[122][Level of evidence: 1iDiii]

   Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[123,124] (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation ¹⁹ for more information on osteonecrosis of the jaw.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[125] The optimal use and duration of bisphosphonates for bony involvement in myeloma have not been studied. Bisphosphonates are usually given intravenously on a monthly basis for 2 years and then extended at the same schedule or at a reduced schedule (i.e., once every 3–4 months), if there is evidence of active myeloma bone disease.[67,126]

3. A double-blind, randomized, controlled trial with 504 patients with newly diagnosed multiple myeloma compared 30 mg of pamidronate to 90 mg of pamidronate and found there was no difference in skeletal-related events, but there was less osteonecrosis (2 events vs. 8 events) seen in the low-dose group.[127][Level of evidence: 1iDiv]

Bone lesions

Lytic lesions of the spine should be radiated if any of the following are true:

• If they are associated with an extramedullary (paraspinal) plasmacytoma.
• If a painful destruction of a vertebral body occurred.
• If computed tomography or MRI scans present evidence of spinal cord compression.[128]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (Refer to the PDQ summary on Pain ¹⁸ for more information on back pain.)

Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[129]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[121]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with multiple myeloma ²⁰. 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 ²¹.

References

1. Dispenzieri A, Kyle R, Merlini G, et al.: International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23 (2): 215-24, 2009.  [PUBMED Abstract]
   
   
2. Raab MS, Podar K, Breitkreutz I, et al.: Multiple myeloma. Lancet 374 (9686): 324-39, 2009.  [PUBMED Abstract]
   
   
3. Palumbo A, Rajkumar SV: Treatment of newly diagnosed myeloma. Leukemia 23 (3): 449-56, 2009.  [PUBMED Abstract]
   
   
4. Goldschmidt H, Hegenbart U, Wallmeier M, et al.: Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma. Br J Haematol 98 (3): 736-44, 1997.  [PUBMED Abstract]
   
   
5. Rajkumar SV, Jacobus S, Callander NS, 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 11 (1): 29-37, 2010.  [PUBMED Abstract]
   
   
6. Mateos MV, Richardson PG, Schlag R, et al.: Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 28 (13): 2259-66, 2010.  [PUBMED Abstract]
   
   
7. Richardson PG, Sonneveld P, Schuster M, et al.: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110 (10): 3557-60, 2007.  [PUBMED Abstract]
   
   
8. Richardson PG, Briemberg H, Jagannath S, et al.: Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24 (19): 3113-20, 2006.  [PUBMED Abstract]
   
   
9. San-Miguel JF, Richardson PG, Sonneveld P, et al.: Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22 (4): 842-9, 2008.  [PUBMED Abstract]
   
   
10. Bladé J, Dimopoulos M, Rosiñol L, et al.: Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 28 (4): 690-7, 2010.  [PUBMED Abstract]
    
    
11. Kumar SK, Mikhael JR, Buadi FK, et al.: Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 84 (12): 1095-110, 2009.  [PUBMED Abstract]
    
    
12. Alexanian R, Dimopoulos MA, Delasalle K, et al.: Primary dexamethasone treatment of multiple myeloma. Blood 80 (4): 887-90, 1992.  [PUBMED Abstract]
    
    
13. Kumar S, Lacy MQ, Dispenzieri A, et al.: Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant 34 (6): 485-90, 2004.  [PUBMED Abstract]
    
    
14. Facon T, Mary JY, Pégourie B, et al.: Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 107 (4): 1292-8, 2006.  [PUBMED Abstract]
    
    
15. Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007.  [PUBMED Abstract]
    
    
16. Rajkumar SV, Rosiñol L, Hussein M, et al.: Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 26 (13): 2171-7, 2008.  [PUBMED Abstract]
    
    
17. Barlogie B, Tricot G, Anaissie E, et al.: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354 (10): 1021-30, 2006.  [PUBMED Abstract]
    
    
18. Palumbo A, Bringhen S, Liberati AM, et al.: Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 112 (8): 3107-14, 2008.  [PUBMED Abstract]
    
    
19. Goldschmidt H, Sonneveld P, Breitkreuz I, et al.: HOVON 50/GMMG-HD3-trial: phase III study on the effect of thalidomide combined with high dose melphalan in myeloma patients up to 65 years. [Abstract] Blood 106 (11): A-424, 2005. 
    
    
20. Waage A, Gimsing P, Juliusson G, et al.: Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomised phase 3 trial. [Abstract] Blood 110 (11): A-78, 2007. 
    
    
21. Ludwig H, Hajek R, Tóthová E, et al.: Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 113 (15): 3435-42, 2009.  [PUBMED Abstract]
    
    
22. Hulin C, Facon T, Rodon P, et al.: Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 27 (22): 3664-70, 2009.  [PUBMED Abstract]
    
    
23. Cavo M, Di Raimondo F, Zamagni E, et al.: Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma. J Clin Oncol 27 (30): 5001-7, 2009.  [PUBMED Abstract]
    
    
24. Lokhorst HM, van der Holt B, Zweegman S, et al.: A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 115 (6): 1113-20, 2010.  [PUBMED Abstract]
    
    
25. Facon T, Mary JY, Hulin C, et al.: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 370 (9594): 1209-18, 2007.  [PUBMED Abstract]
    
    
26. Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111 (8): 3968-77, 2008.  [PUBMED Abstract]
    
    
27. Weber D, Rankin K, Gavino M, et al.: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21 (1): 16-9, 2003.  [PUBMED Abstract]
    
    
28. Baz R, Li L, Kottke-Marchant K, et al.: The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 80 (12): 1568-74, 2005.  [PUBMED Abstract]
    
    
29. Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al.: Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma. Leuk Lymphoma 48 (12): 2330-7, 2007.  [PUBMED Abstract]
    
    
30. Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357 (21): 2123-32, 2007.  [PUBMED Abstract]
    
    
31. Weber DM, Chen C, Niesvizky R, et al.: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357 (21): 2133-42, 2007.  [PUBMED Abstract]
    
    
32. Zangari M, Tricot G, Polavaram L, et al.: Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol 28 (1): 132-5, 2010.  [PUBMED Abstract]
    
    
33. Dimopoulos MA, Christoulas D, Roussou M, et al.: Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 85 (1): 1-5, 2010.  [PUBMED Abstract]
    
    
34. Mitchell BS: The proteasome--an emerging therapeutic target in cancer. N Engl J Med 348 (26): 2597-8, 2003.  [PUBMED Abstract]
    
    
35. Argyriou AA, Iconomou G, Kalofonos HP: Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 112 (5): 1593-9, 2008.  [PUBMED Abstract]
    
    
36. Richardson PG, Xie W, Mitsiades C, et al.: Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 27 (21): 3518-25, 2009.  [PUBMED Abstract]
    
    
37. Richardson PG, Sonneveld P, Schuster MW, et al.: Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 144 (6): 895-903, 2009.  [PUBMED Abstract]
    
    
38. Orlowski RZ, Nagler A, Sonneveld P, et al.: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25 (25): 3892-901, 2007.  [PUBMED Abstract]
    
    
39. Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352 (24): 2487-98, 2005.  [PUBMED Abstract]
    
    
40. Jagannath S, Richardson PG, Sonneveld P, et al.: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21 (1): 151-7, 2007.  [PUBMED Abstract]
    
    
41. Sagaster V, Ludwig H, Kaufmann H, et al.: Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 21 (1): 164-8, 2007.  [PUBMED Abstract]
    
    
42. Chang H, Trieu Y, Qi X, et al.: Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 31 (6): 779-82, 2007.  [PUBMED Abstract]
    
    
43. Avet-Loiseau H, Leleu X, Roussel M, et al.: Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28 (30): 4630-4, 2010.  [PUBMED Abstract]
    
    
44. Dimopoulos MA, Richardson PG, Schlag R, et al.: VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol 27 (36): 6086-93, 2009.  [PUBMED Abstract]
    
    
45. Morabito F, Gentile M, Ciolli S, et al.: Safety and efficacy of bortezomib-based regimens for multiple myeloma patients with renal impairment: a retrospective study of Italian Myeloma Network GIMEMA. Eur J Haematol 84 (3): 223-8, 2010.  [PUBMED Abstract]
    
    
46. Bringhen S, Larocca A, Rossi D, et al.: Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116 (23): 4745-53, 2010.  [PUBMED Abstract]
    
    
47. Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33 (2): 86-9, 1990.  [PUBMED Abstract]
    
    
48. Segeren CM, Sonneveld P, van der Holt B, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105 (1): 127-30, 1999.  [PUBMED Abstract]
    
    
49. Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 (2): 326-30, 1995.  [PUBMED Abstract]
    
    
50. Browman GP, Belch A, Skillings J, et al.: Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group. Br J Haematol 82 (3): 555-9, 1992.  [PUBMED Abstract]
    
    
51. Dimopoulos MA, Pouli A, Zervas K, et al.: Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 14 (7): 1039-44, 2003.  [PUBMED Abstract]
    
    
52. Rifkin RM, Gregory SA, Mohrbacher A, et al.: Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer 106 (4): 848-58, 2006.  [PUBMED Abstract]
    
    
53. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 16 (12): 3832-42, 1998.  [PUBMED Abstract]
    
    
54. Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10 (2): 334-42, 1992.  [PUBMED Abstract]
    
    
55. Bergsagel DE, Stewart AK: Conventional-dose chemotherapy of myeloma. In: Malpas JS, Bergsagel DE, Kyle RA, et al.: Myeloma: Biology and Management. 3rd ed. Philadelphia, Pa: WB Saunders Co, 2004, pp 203-17. 
    
    
56. Pavlovsky S, Corrado C, Santarelli MT, et al.: An update of two randomized trials in previously untreated multiple myeloma comparing melphalan and prednisone versus three- and five-drug combinations: an Argentine Group for the Treatment of Acute Leukemia Study. J Clin Oncol 6 (5): 769-75, 1988.  [PUBMED Abstract]
    
    
57. Bladé J, San Miguel JF, Alcalá A, et al.: Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. J Clin Oncol 11 (6): 1165-71, 1993.  [PUBMED Abstract]
    
    
58. Oken MM, Harrington DP, Abramson N, et al.: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 79 (8): 1561-7, 1997.  [PUBMED Abstract]
    
    
59. Gertz MA, Lacy MQ, Lust JA, et al.: Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis. J Clin Oncol 17 (1): 262-7, 1999.  [PUBMED Abstract]
    
    
60. Mineur P, Ménard JF, Le Loët X, et al.: VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Br J Haematol 103 (2): 512-7, 1998.  [PUBMED Abstract]
    
    
61. Fonseca R, Rajkumar SV: Consolidation therapy with bortezomib/lenalidomide/ dexamethasone versus bortezomib/dexamethasone after a dexamethasone-based induction regimen in patients with multiple myeloma: a randomized phase III trial. Clin Lymphoma Myeloma 8 (5): 315-7, 2008.  [PUBMED Abstract]
    
    
62. Richardson P, Lonial S, Jakubowiak A, et al.: Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a phaseI/II study. [Abstract] Blood 112 (11): A-92, 2008. 
    
    
63. Reece DE, Rodriguez GP, Chen C, et al.: Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 26 (29): 4777-83, 2008.  [PUBMED Abstract]
    
    
64. Knop S, Liebisch H, Wandt H, et al.: Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-8516, 2009. 
    
    
65. Kumar S, Flinn IW, Noga SJ, et al.: Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the phase I/II multi-center EVOLUTION study. [Abstract] Blood 112 (11): A-93, 2008. 
    
    
66. Kumar S, Hayman S, Buadi F, et al.: Phase II trial of lenalidomide (Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. [Abstract] Blood 112 (11): A-91, 2008. 
    
    
67. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.: Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27 (30): 5015-22, 2009.  [PUBMED Abstract]
    
    
68. Bladé J, Vesole DH, Gertz Morie: High-dose therapy in multiple myeloma. Blood 102 (10): 3469-70, 2003.  [PUBMED Abstract]
    
    
69. Siegel DS, Desikan KR, Mehta J, et al.: Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 93 (1): 51-4, 1999.  [PUBMED Abstract]
    
    
70. Badros A, Barlogie B, Siegel E, et al.: Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 114 (3): 600-7, 2001.  [PUBMED Abstract]
    
    
71. Lenhoff S, Hjorth M, Westin J, et al.: Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group. Br J Haematol 133 (4): 389-96, 2006.  [PUBMED Abstract]
    
    
72. Barlogie B, Attal M, Crowley J, et al.: Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol 28 (7): 1209-14, 2010.  [PUBMED Abstract]
    
    
73. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996.  [PUBMED Abstract]
    
    
74. Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348 (19): 1875-83, 2003.  [PUBMED Abstract]
    
    
75. Palumbo A, Bringhen S, Petrucci MT, et al.: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 104 (10): 3052-7, 2004.  [PUBMED Abstract]
    
    
76. Segeren CM, Sonneveld P, van der Holt B, et al.: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 101 (6): 2144-51, 2003.  [PUBMED Abstract]
    
    
77. Fermand JP, Katsahian S, Divine M, et al.: High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23 (36): 9227-33, 2005.  [PUBMED Abstract]
    
    
78. Bladé J, Rosiñol L, Sureda A, et al.: High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106 (12): 3755-9, 2005.  [PUBMED Abstract]
    
    
79. Barlogie B, Kyle RA, Anderson KC, et al.: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 24 (6): 929-36, 2006.  [PUBMED Abstract]
    
    
80. Lévy V, Katsahian S, Fermand JP, et al.: A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 84 (4): 250-60, 2005.  [PUBMED Abstract]
    
    
81. Koreth J, Cutler CS, Djulbegovic B, et al.: High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13 (2): 183-96, 2007.  [PUBMED Abstract]
    
    
82. Pineda-Roman M, Barlogie B, Anaissie E, et al.: High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients. Cancer 112 (8): 1754-64, 2008.  [PUBMED Abstract]
    
    
83. Giralt S, Stadtmauer EA, Harousseau JL, et al.: International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia 23 (10): 1904-12, 2009.  [PUBMED Abstract]
    
    
84. Harousseau JL: Hematopoietic stem cell transplantation in multiple myeloma. J Natl Compr Canc Netw 7 (9): 961-70, 2009.  [PUBMED Abstract]
    
    
85. Barlogie B, Tricot GJ, van Rhee F, et al.: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135 (2): 158-64, 2006.  [PUBMED Abstract]
    
    
86. Barlogie B, Tricot G, Rasmussen E, et al.: Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107 (7): 2633-8, 2006.  [PUBMED Abstract]
    
    
87. Barlogie B, Zangari M, Bolejack V, et al.: Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 6 (6): 469-74, 2006.  [PUBMED Abstract]
    
    
88. Bruno B, Rotta M, Patriarca F, et al.: Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 113 (14): 3375-82, 2009.  [PUBMED Abstract]
    
    
89. Rotta M, Storer BE, Sahebi F, et al.: Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 113 (14): 3383-91, 2009.  [PUBMED Abstract]
    
    
90. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al.: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101 (2): 100-6, 2009.  [PUBMED Abstract]
    
    
91. Bruno B, Rotta M, Patriarca F, et al.: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356 (11): 1110-20, 2007.  [PUBMED Abstract]
    
    
92. Garban F, Attal M, Michallet M, et al.: Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 107 (9): 3474-80, 2006.  [PUBMED Abstract]
    
    
93. Moreau P, Garban F, Attal M, et al.: Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood 112 (9): 3914-5, 2008.  [PUBMED Abstract]
    
    
94. Rosiñol L, Pérez-Simón JA, Sureda A, et al.: A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 112 (9): 3591-3, 2008.  [PUBMED Abstract]
    
    
95. Abdelkefi A, Ladeb S, Torjman L, et al.: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 111 (4): 1805-10, 2008.  [PUBMED Abstract]
    
    
96. Gahrton G, Tura S, Ljungman P, et al.: Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13 (6): 1312-22, 1995.  [PUBMED Abstract]
    
    
97. Tricot G, Vesole DH, Jagannath S, et al.: Graft-versus-myeloma effect: proof of principle. Blood 87 (3): 1196-8, 1996.  [PUBMED Abstract]
    
    
98. Verdonck LF, Lokhorst HM, Dekker AW, et al.: Graft-versus-myeloma effect in two cases. Lancet 347 (9004): 800-1, 1996.  [PUBMED Abstract]
    
    
99. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al.: Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 18 (16): 3031-7, 2000.  [PUBMED Abstract]
    
    
100. Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27 (8): 801-7, 2001.  [PUBMED Abstract]
     
     
101. Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35 (12): 1133-40, 2005.  [PUBMED Abstract]
     
     
102. Lokhorst H, Einsele H, Vesole D, et al.: International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 28 (29): 4521-30, 2010.  [PUBMED Abstract]
     
     
103. Einsele H, Schäfer HJ, Hebart H, et al.: Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 121 (3): 411-8, 2003.  [PUBMED Abstract]
     
     
104. Maloney DG, Molina AJ, Sahebi F, et al.: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102 (9): 3447-54, 2003.  [PUBMED Abstract]
     
     
105. Badros A, Barlogie B, Morris C, et al.: High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 97 (9): 2574-9, 2001.  [PUBMED Abstract]
     
     
106. Crawley C, Lalancette M, Szydlo R, et al.: Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 105 (11): 4532-9, 2005.  [PUBMED Abstract]
     
     
107. Badros A, Barlogie B, Siegel E, et al.: Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20 (5): 1295-303, 2002.  [PUBMED Abstract]
     
     
108. Belch A, Shelley W, Bergsagel D, et al.: A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 57 (1): 94-9, 1988.  [PUBMED Abstract]
     
     
109. Mandelli F, Avvisati G, Amadori S, et al.: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322 (20): 1430-4, 1990.  [PUBMED Abstract]
     
     
110. Westin J, Rödjer S, Turesson I, et al.: Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Cooperative Study Group. Br J Haematol 89 (3): 561-8, 1995.  [PUBMED Abstract]
     
     
111. Osterborg A, Björkholm M, Björeman M, et al.: Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood 81 (6): 1428-34, 1993.  [PUBMED Abstract]
     
     
112. Browman GP, Bergsagel D, Sicheri D, et al.: Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 13 (9): 2354-60, 1995.  [PUBMED Abstract]
     
     
113. The Myeloma Trialists' Collaborative Group.: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113 (4): 1020-34, 2001.  [PUBMED Abstract]
     
     
114. Zee B, Cole B, Li T, et al.: Quality-adjusted time without symptoms or toxicity analysis of interferon maintenance in multiple myeloma. J Clin Oncol 16 (8): 2834-9, 1998.  [PUBMED Abstract]
     
     
115. Offidani M, Corvatta L, Polloni C, et al.: Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study. Br J Haematol 144 (5): 653-9, 2009.  [PUBMED Abstract]
     
     
116. Cunningham D, Powles R, Malpas J, et al.: A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol 102 (2): 495-502, 1998.  [PUBMED Abstract]
     
     
117. Barlogie B, Kyle R, Anderson K, et al.: Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/m2 + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321. [Abstract] Blood 102 (11): A-135, 2003. 
     
     
118. Spencer A, Prince HM, Roberts AW, et al.: Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27 (11): 1788-93, 2009.  [PUBMED Abstract]
     
     
119. Berenson JR, Crowley JJ, Grogan TM, et al.: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99 (9): 3163-8, 2002.  [PUBMED Abstract]
     
     
120. Attal M, Harousseau JL, Leyvraz S, et al.: Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108 (10): 3289-94, 2006.  [PUBMED Abstract]
     
     
121. Berenson JR, Lichtenstein A, Porter L, et al.: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16 (2): 593-602, 1998.  [PUBMED Abstract]
     
     
122. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.  [PUBMED Abstract]
     
     
123. Badros A, Weikel D, Salama A, et al.: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24 (6): 945-52, 2006.  [PUBMED Abstract]
     
     
124. Kademani D, Koka S, Lacy MQ, et al.: Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 81 (8): 1100-3, 2006.  [PUBMED Abstract]
     
     
125. Lacy MQ, Dispenzieri A, Gertz MA, et al.: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 81 (8): 1047-53, 2006.  [PUBMED Abstract]
     
     
126. Terpos E, Sezer O, Croucher PI, et al.: The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 20 (8): 1303-17, 2009.  [PUBMED Abstract]
     
     
127. Gimsing P, Carlson K, Turesson I, et al.: Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 11 (10): 973-82, 2010.  [PUBMED Abstract]
     
     
128. Rades D, Hoskin PJ, Stalpers LJ, et al.: Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys 64 (5): 1452-7, 2006.  [PUBMED Abstract]
     
     
129. Catell D, Kogen Z, Donahue B, et al.: Multiple myeloma of an extremity: must the entire bone be treated? Int J Radiat Oncol Biol Phys 40 (1): 117-9, 1998.  [PUBMED Abstract]