Questions About Cancer? 1-800-4-CANCER

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)

Health Professional Version

Treatment for Multiple Myeloma

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 free 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, lenalidomide, bortezomib, and alkylating agents, often in combination.[3]

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.[4] These include the following:

  • Steroids (e.g., dexamethasone and prednisone).
  • IMiDs (immunomodulatory drugs).
    • Thalidomide.
    • Lenalidomide.
    • Pomalidomide.
  • Proteasome inhibitors.
    • Bortezomib.
    • Carfilzomib.
  • 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 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.[5]
  2. Bortezomib or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[6,7] (Refer to the Lenalidomide and Bortezomib 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.[7-9] Bortezomib is preferred in the setting of renal impairment.[10]
    • Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT), requiring additional prophylactic medication.[6,11]
  4. Patients with standard-risk disease, as defined in the Stage Information About Plasma Cell Neoplasms section of this summary, might receive induction therapy alone, followed by careful observation after best response.[12]
  5. Patients with high-risk disease might receive induction therapy until best response, followed by consolidation therapy with allogeneic or ASCT.[12]

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.[13] Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[13,14][Level of evidence: 3iiiDiv]

Evidence (corticosteroids):

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).[15][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 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).
    • 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.[16]
  • In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial (ECOG-E4A03).[6]
    • The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone.[6] (Refer to the Lenalidomide 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.

IMiDs (immunomodulatory drugs)

Thalidomide

Evidence (thalidomide):

Eleven randomized prospective studies involving more than 4,600 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[17-26]

  • 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 eleven 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).[23,27][Level of evidence: 1iiA]
  • A possible explanation is that the 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.[28,29]

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.[21,29,30] In a randomized, prospective trial, 667 previously untreated patients who received thalidomide-containing regimens were randomly assigned to aspirin (100 mg/day), warfarin (1.25 mg/day) or enoxaparin (40 mg/day). The rate of serious thromboembolic events, acute cardiovascular events, or sudden death was 6.5% and similar for all three interventions.[31]

Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.[32]

Lenalidomide

Evidence (lenalidomide):

  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.[33]
    • 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).[33][Level of evidence: 1iA]
    • The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[33]
  2. Similarly, another randomized, prospective trial (NCT00056160) 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).[34][Level of evidence: 1iA]
  3. A prospective, randomized study (ECOG-E4A03) 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).[6]
    • 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).[6][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).[6][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.[35][Level of evidence: 3iiiA]

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[6,33-35] A randomized, prospective trial of 342 previously untreated patients receiving lenalidomide-containing regimens compared aspirin (100 mg/day) with enoxaparin (40 mg/day); the 2% incidence of venous thromboembolic events was similar for both interventions.[36] Empirically, the greater the number of risk factors for DVT, the more intense the recommendation for prophylactic anticoagulation. (Refer to the Thalidomide section of this summary for more information about risk factors.)

A retrospective review of almost 4,000 relapsed or refractory patients who received lenalidomide in 11 clinical trials suggested an increased incidence of nonmelanoma skin cancers.[37] 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).[38] Uncontrolled trials, including NCT00151203, have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach.[39]

Pomalidomide

Evidence (pomalidomide):

  1. Several phase I and II trials in heavily pretreated patients after bortezomib and lenalidomide showed a response rate ranging from 26% to 63%.[40-42][Level of evidence: 3iiiDiv] Although pomalidomide is taken orally like thalidomide and lenalidomide, pomalidomide causes less neuropathy and asthenia than thalidomide and less myelosuppression and skin rashes than lenalidomide.

Proteasome inhibitors

Bortezomib

Evidence (bortezomib):

  1. A prospective, randomized trial (the VISTA trial [NCT00111319]) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation (SCT) because of age (one-third of patients >75 years) compared bortezomib combined with melphalan and prednisone with melphalan and prednisone alone.[7]
    • With a median follow-up of 60 months, the median OS favored the bortezomib arm (56.4 vs. 43.1 months, P < .001).[43][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.[8][Level of evidence: 1iiA]
    • Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[9,44,45]
  3. A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[46]
    • 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).[46][Level of evidence: 1iiA]
  4. Two studies compared bortezomib plus thalidomide plus dexamethasone versus thalidomide plus dexamethasone after SCT and showed improved PFS (3-year PFS of 68% vs. 48% [P = .042] in previously untreated patients and median PFS of 20 months versus 14 months in relapsed patients [P = .001]) but no difference in OS.[47,48][Level of evidence: 1iiDiii]
  5. In 511 previously untreated patients not eligible for transplant and older than 65 years, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance used bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone (with no maintenance) and showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.
    • With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01), and 5-year OS was 59% versus 46% (P = .04).[49][Level of evidence: 1iiA] Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during induction or by the use of maintenance therapy with bortezomib and thalidomide.
  6. In 827 previously untreated patients, a randomized comparison of bortezomib plus doxorubicin plus dexamethasone followed by high-dose melphalan plus autologous SCT plus bortezomib maintenance for 2 years versus vincristine plus doxorubicin plus dexamethasone followed by the same SCT consolidation plus thalidomide maintenance showed superiority of the arm with bortezomib during induction and maintenance.[50][Level of evidence: 1iiDiii]
    • With a median follow-up of 41 months, the median PFS was 35 months versus 28 months in favor of the bortezomib arm (P = .002) with no significant difference in OS.[50]

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[10,51] In several retrospective, nonrandomized comparisons, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (2%–8% vs. 13%–28%) with no loss of efficacy compared with standard biweekly administration.[52,53]

In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11).[54] After a median follow-up of 1 year, grade 3 to 4 neurologic toxicity was reduced from 16% to 6% (P = .026) using the subcutaneous route, with no perceived loss of efficacy in terms of response. However, this study was not powered for noninferiority of response. New clinical trials are employing these changes of weekly treatment and subcutaneous route to improve the safety profile of bortezomib-containing regimens. In this trial, the bisphosphonates were continued until the time of relapse.

Carfilzomib

Evidence (carfilzomib):

  1. A phase II trial of 257 patients who were heavily pretreated with bortezomib and lenalidomide showed a response rate of 24% and a median duration of response of 8 months.[55][Level of evidence: 3iiiDiv] Combinations of carfilzomib with lenalidomide and dexamethasone showed a 62% complete response (CR) or near CR in untreated patients.[56][Level of evidence: 3iiiDiv] Response rates around 50% were seen in 129 bortezomib-naïve patients wtih multiply-relapsed or refractory myeloma.[57][Level of evidence: 3iiiDiv]

Conventional-dose chemotherapy

Evidence (conventional-dose chemotherapy):

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[58-61][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 CR rate.
  • An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[62,63][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.[64] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[64-66]

Combinations, such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[67-70][Level of evidence: 1iiA]

A meta-analysis of studies comparing MP with drug combinations concluded that both forms of treatment were equally effective.[64][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.[71][Level of evidence: 1iiA]

Combination therapy

Evidence (combination therapy):

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: Bortezomib + dexamethasone versus lenalidomide + bortezomib + dexamethasone.[72]
  • SWOG-S0777: Lenalidomide + dexamethasone versus lenalidomide + bortezomib + dexamethasone.
  • EVOLUTION (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 (NCT00602641): Thalidomide + melphalan + prednisone versus lenalidomide + melphalan + prednisone.

Options for combination regimens:

  1. Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[72,73]
  2. Lenalidomide + dexamethasone (as demonstrated in SWOG-S0777).[6,33,34]
  3. Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-S0777, EVOLUTION trial, and the U.S. Intergroup/IFM trial).[72-74]
  4. Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[75,76]
  5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[77]
  6. Lenalidomide + cyclophosphamide + dexamethasone.[78]
  7. Bortezomib + melphalan + prednisone.[43]
  8. Bortezomib + liposomal doxorubicin +/- dexamethasone.[46,79]
  9. Melphalan + prednisone + thalidomide.[19,27]
  10. Melphalan + prednisone.[19,27]

Consolidation Chemotherapy

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

Evidence (high-dose chemotherapy: autologous bone marrow or peripheral stem cell transplantation):

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.[80]
  • 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.[5]
  • Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.[81-83]
  • 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.[84] New monoclonal gammopathies of an isotype (heavy and/or light chain) distinct from the original clone can emerge in long-term follow-up.[85]

Single autologous bone marrow or peripheral stem cell transplantation

Evidence (single autologous bone marrow or peripheral stem cell transplantation):

While some prospective randomized trials, such as the U.S. Intergroup trial (SWOG-9321 [NCT00602641]), showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[86-88][Level of evidence: 1iiA] other trials have not shown any survival advantage.[89-92][Level of evidence: 1iiA]

Two meta-analyses of almost 3,000 patients showed no survival advantage.[93,94][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.[86-88,95] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[96,97]

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).[98-102]

Evidence (tandem autologous bone marrow or peripheral stem cell transplantation):

  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).[103][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.[88]
    • 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).[88][Level of evidence: 1iiA]
  3. Five 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.
  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).[109][Level of evidence: 1iiA]
  5. Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity allogeneic SCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity allogeneic SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[110,111][Level of evidence: 1iiA]

A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[112] None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.

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

Evidence (high-dose chemotherapy: allogeneic bone marrow or peripheral stem cell transplantation):

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.[113]

Favorable prognostic features included the following:

  • Low tumor burden.
  • Responsive disease before transplant.
  • Application of transplantation after first-line therapy.

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.[113-115]

The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[115] Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of autologous stem cell transplantation (SCT) versus autologous SCT and nonmyeloablative allogeneic (SCT) in 260 untreated patients showed no difference in PFS or OS.[116][Level of evidence: 3iiiA] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[106,117][Level of evidence: 3iiiA] 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.[115,118]

Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity allogeneic SCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity allogeneic SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[110,111][Level of evidence: 1iiA]

Maintenance Therapy

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. No clinical trial has directly compared a consolidation approach with a maintenance approach to assess which is better in prolonging remission and, ultimately, survival.[119] Most clinical trials employ one or both. Maintenance trials with glucocorticosteroids [16,120] and with interferon [121] showed very minor improvements in remission duration and survival but with toxicities that outweighed the benefits. The efficacy and tolerability of thalidomide, lenalidomide, and bortezomib in the induction and relapse settings has made these agents attractive options in maintenance trials.[119]

Thalidomide maintenance therapy

After ASCT, six randomized, prospective trials showed benefit in PFS for maintenance thalidomide (30–36 months vs. 20–26 months), but only three showed benefit in OS (11–19 months in median OS).[18,25,122-125] No survival benefit could be consistently seen for thalidomide maintenance after induction chemotherapy alone; interpretation of some trials was confounded by thalidomide use during induction.[19,124,126-130] Several trials suggested particularly poor outcomes using thalidomide for patients with poor-risk cytogenetics.[25,124] The lowest active dose for thalidomide is 50 mg daily with a duration of at least 1 year.

Lenalidomide maintenance therapy

After ASCT, two randomized, prospective trials showed benefit in median EFS (40–43 months vs. 23–27 months),[131,132] one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; P = .03).[131][Level of evidence: 1iiA] For elderly patients not eligible for transplantation, a randomized, prospective trial of lenalidomide maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide showed a 66% reduction in the rate of progression (HR, 0.34; P < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[133][Level of evidence: 1iiDi] All three trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.

Bortezomib maintenance therapy

For 178 elderly, untreated patients with an induction combination regimen including bortezomib, maintenance using bortezomib plus thalidomide versus bortezomib plus prednisone was not significantly different in PFS or OS, but both resulted in median PFS of 32 to 39 months and a 5-year OS over 50%.[134][Level of evidence: 1iiDiv]

In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance using bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.

With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01) and 5-year OS was 59% versus 46% (P = .04).[49][Level of evidence: 1iiA] Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.

Management of lytic bone lesions with bisphosphonates

Bisphosphonate therapy

Evidence (bisphosphonate therapy):

  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).[135][Level of evidence: 1iDiii] (Refer to the PDQ summary on Pain for more information on bisphosphonate therapy.)
  2. 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.[136][Level of evidence: 1iDiv]
  3. A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications (both were given for 2 years).[137][Level of evidence: 1iDiii]
  4. A randomized, prospective trial of 1,970 patients compared intravenous zoledronate versus oral clodronate in newly diagnosed patients receiving induction chemotherapy with or without consolidation.[138] With a median follow-up of 3.7 years, zoledronate improved median OS from 44.5 months to 50.0 months (HR, 0.84; CI, 0.74–0.96, P = .0118).[138][Level of evidence: 1iiA] In this trial, both bisphosphonates were continued until time of relapse. As expected, skeletal-related events were also reduced in the zoledronate group (27% vs. 35%; P = .004).[139,140]
  5. The improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[141][Level of evidence: 1A]
  6. Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[142,143] (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation 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.[144] 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.[79,145] The aforementioned randomized trial,[139] which showed OS advantage, continued bisphosphonates monthly until time of relapse.

Radiation therapy for bone lesions

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

  1. If they are associated with an extramedullary (paraspinal) plasmacytoma.
  2. If a painful destruction of a vertebral body occurred.
  3. If computed tomography or MRI scans present evidence of spinal cord compression.[146]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (Refer to the PDQ summary on Pain 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.[147]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[135]

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. 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.

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, Anderson K: Multiple myeloma. N Engl J Med 364 (11): 1046-60, 2011. [PUBMED Abstract]
  4. Palumbo A, Rajkumar SV: Treatment of newly diagnosed myeloma. Leukemia 23 (3): 449-56, 2009. [PUBMED Abstract]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. Alexanian R, Dimopoulos MA, Delasalle K, et al.: Primary dexamethasone treatment of multiple myeloma. Blood 80 (4): 887-90, 1992. [PUBMED Abstract]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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.
  21. 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.
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. Sacchi S, Marcheselli R, Lazzaro A, et al.: A randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant. Leuk Lymphoma 52 (10): 1942-8, 2011. [PUBMED Abstract]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. Palumbo A, Cavo M, Bringhen S, et al.: Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 29 (8): 986-93, 2011. [PUBMED Abstract]
  32. Delforge M, Bladé J, Dimopoulos MA, et al.: Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11 (11): 1086-95, 2010. [PUBMED Abstract]
  33. 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]
  34. 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]
  35. 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]
  36. Larocca A, Cavallo F, Bringhen S, et al.: Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 119 (4): 933-9; quiz 1093, 2012. [PUBMED Abstract]
  37. Dimopoulos MA, Richardson PG, Brandenburg N, et al.: A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 119 (12): 2764-7, 2012. [PUBMED Abstract]
  38. 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]
  39. Rossi A, Mark T, Jayabalan D, et al.: BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood 121 (11): 1982-5, 2013. [PUBMED Abstract]
  40. Lacy MQ, Allred JB, Gertz MA, et al.: Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood 118 (11): 2970-5, 2011. [PUBMED Abstract]
  41. Leleu X, Attal M, Arnulf B, et al.: Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood 121 (11): 1968-75, 2013. [PUBMED Abstract]
  42. Richardson PG, Siegel D, Baz R, et al.: Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 121 (11): 1961-7, 2013. [PUBMED Abstract]
  43. San Miguel JF, Schlag R, Khuageva NK, et al.: Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 31 (4): 448-55, 2013. [PUBMED Abstract]
  44. 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]
  45. Dimopoulos MA, Mateos MV, Richardson PG, et al.: Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol 86 (1): 23-31, 2011. [PUBMED Abstract]
  46. 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]
  47. Cavo M, Pantani L, Petrucci MT, et al.: Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 120 (1): 9-19, 2012. [PUBMED Abstract]
  48. Garderet L, Iacobelli S, Moreau P, et al.: Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 30 (20): 2475-82, 2012. [PUBMED Abstract]
  49. Palumbo A, Bringhen S, Rossi D, et al.: Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients. [Abstract] Blood 120 (21): A-200, 2012.
  50. Sonneveld P, Schmidt-Wolf IG, 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 30 (24): 2946-55, 2012. [PUBMED Abstract]
  51. Dimopoulos MA, Terpos E, Chanan-Khan A, et al.: Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28 (33): 4976-84, 2010. [PUBMED Abstract]
  52. 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]
  53. Mateos MV, Oriol A, Martínez-López J, et al.: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11 (10): 934-41, 2010. [PUBMED Abstract]
  54. Moreau P, Pylypenko H, Grosicki S, et al.: Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12 (5): 431-40, 2011. [PUBMED Abstract]
  55. Siegel DS, Martin T, Wang M, et al.: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120 (14): 2817-25, 2012. [PUBMED Abstract]
  56. Jakubowiak AJ, Dytfeld D, Griffith KA, et al.: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120 (9): 1801-9, 2012. [PUBMED Abstract]
  57. Vij R, Wang M, Kaufman JL, et al.: An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 119 (24): 5661-70, 2012. [PUBMED Abstract]
  58. 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]
  59. 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]
  60. 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]
  61. 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]
  62. 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]
  63. 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]
  64. 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]
  65. 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]
  66. 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.
  67. 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]
  68. 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]
  69. 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]
  70. 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]
  71. 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]
  72. 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]
  73. 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]
  74. 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.
  75. 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]
  76. 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.
  77. Khan ML, Reeder CB, Kumar SK, et al.: A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br J Haematol 156 (3): 326-33, 2012. [PUBMED Abstract]
  78. Kumar SK, Lacy MQ, Hayman SR, et al.: Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 86 (8): 640-5, 2011. [PUBMED Abstract]
  79. 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]
  80. Bladé J, Vesole DH, Gertz Morie: High-dose therapy in multiple myeloma. Blood 102 (10): 3469-70, 2003. [PUBMED Abstract]
  81. 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]
  82. 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]
  83. 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]
  84. 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]
  85. Wadhera RK, Kyle RA, Larson DR, et al.: Incidence, clinical course, and prognosis of secondary monoclonal gammopathy of undetermined significance in patients with multiple myeloma. Blood 118 (11): 2985-7, 2011. [PUBMED Abstract]
  86. 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]
  87. 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]
  88. 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]
  89. 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]
  90. 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]
  91. 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]
  92. 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]
  93. 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]
  94. 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]
  95. 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]
  96. 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]
  97. Harousseau JL: Hematopoietic stem cell transplantation in multiple myeloma. J Natl Compr Canc Netw 7 (9): 961-70, 2009. [PUBMED Abstract]
  98. 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]
  99. 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]
  100. 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]
  101. 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]
  102. 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]
  103. 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]
  104. 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]
  105. 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]
  106. Björkstrand B, Iacobelli S, Hegenbart U, et al.: Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 29 (22): 3016-22, 2011. [PUBMED Abstract]
  107. 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]
  108. Krishnan A, Pasquini MC, 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 12 (13): 1195-203, 2011. [PUBMED Abstract]
  109. 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]
  110. Armeson KE, Hill EG, Costa LJ: Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 48 (4): 562-7, 2013. [PUBMED Abstract]
  111. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al.: Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 6: 2, 2013. [PUBMED Abstract]
  112. Naumann-Winter F, Greb A, Borchmann P, et al.: First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 10: CD004626, 2012. [PUBMED Abstract]
  113. 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]
  114. 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]
  115. 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]
  116. Lokhorst HM, van der Holt B, Cornelissen JJ, et al.: Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 119 (26): 6219-25; quiz 6399, 2012. [PUBMED Abstract]
  117. Giaccone L, Storer B, Patriarca F, et al.: Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 117 (24): 6721-7, 2011. [PUBMED Abstract]
  118. Moreau P: Death of frontline allo-SCT in myeloma. Blood 119 (26): 6178-9, 2012. [PUBMED Abstract]
  119. Ludwig H, Durie BG, McCarthy P, et al.: IMWG consensus on maintenance therapy in multiple myeloma. Blood 119 (13): 3003-15, 2012. [PUBMED Abstract]
  120. 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]
  121. 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]
  122. 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]
  123. 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]
  124. Morgan GJ, Gregory WM, Davies FE, et al.: The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 119 (1): 7-15, 2012. [PUBMED Abstract]
  125. Barlogie B, Pineda-Roman M, van Rhee F, et al.: Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 112 (8): 3115-21, 2008. [PUBMED Abstract]
  126. Palumbo A, Bringhen S, Caravita T, et al.: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367 (9513): 825-31, 2006. [PUBMED Abstract]
  127. Wijermans P, Schaafsma M, Termorshuizen F, et al.: Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 28 (19): 3160-6, 2010. [PUBMED Abstract]
  128. Waage A, Gimsing P, Fayers P, et al.: Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 116 (9): 1405-12, 2010. [PUBMED Abstract]
  129. Beksac M, Haznedar R, Firatli-Tuglular T, et al.: Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 86 (1): 16-22, 2011. [PUBMED Abstract]
  130. Kagoya Y, Nannya Y, Kurokawa M: Thalidomide maintenance therapy for patients with multiple myeloma: meta-analysis. Leuk Res 36 (8): 1016-21, 2012. [PUBMED Abstract]
  131. McCarthy PL, Owzar K, Hofmeister CC, et al.: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366 (19): 1770-81, 2012. [PUBMED Abstract]
  132. Attal M, Lauwers-Cances V, Marit G, et al.: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366 (19): 1782-91, 2012. [PUBMED Abstract]
  133. Palumbo A, Hajek R, Delforge M, et al.: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366 (19): 1759-69, 2012. [PUBMED Abstract]
  134. Mateos MV, Oriol A, Martínez-López J, et al.: Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 120 (13): 2581-8, 2012. [PUBMED Abstract]
  135. 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]
  136. 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]
  137. 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]
  138. Morgan GJ, Davies FE, Gregory WM, et al.: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376 (9757): 1989-99, 2010. [PUBMED Abstract]
  139. Morgan GJ, Child JA, Gregory WM, et al.: Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol 12 (8): 743-52, 2011. [PUBMED Abstract]
  140. Morgan GJ, Davies FE, Gregory WM, et al.: Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood 119 (23): 5374-83, 2012. [PUBMED Abstract]
  141. Mhaskar R, Redzepovic J, Wheatley K, et al.: Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 5: CD003188, 2012. [PUBMED Abstract]
  142. 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]
  143. 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]
  144. 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]
  145. 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]
  146. 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]
  147. 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]
  • Updated: June 24, 2014