Multiple Myeloma Treatment & Management

Updated: May 26, 2017
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Physicians must understand both the natural history of multiple myeloma (MM) and the limitations of current therapy in the treatment of the disease. The objective in therapy is to obtain the deepest response in the first round by choosing the appropriate regimen; this should lead to better overall survival in both transplant and non-transplant patients. In situations with no definite data on therapeutic choices, participation in clinical trials should be encouraged. For a summary of treatment approaches to MM, see Multiple Myeloma Treatment Protocols.

Progression of disease and timing of treatment

An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with MM. [31] This study evaluated 638 consecutive untreated subjects with MM. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of bone disease.

The individuals in this group were designated as either low risk (ie, no bone disease, M protein level <3 g/dL, or Bence Jones protein level <5 g/24 h) or high risk (ie, lytic bone disease and serum M protein level >3 g/dL or Bence Jones protein level >5 g/24 h). Intermediate-risk subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones protein level greater than 5 g/24 h. The patients were evaluated every 2 months.

The median time for disease progression was 10 months in the high-risk group, 25 months in the intermediate-risk group, and 61 months in the low-risk group. [31] At the time of progression, subjects were treated with standard chemotherapy. Their response rates did not significantly differ from those of unselected populations. Median survival time from the institution of chemotherapy did not differ among the groups. Thus, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect treatment efficacy (ie, survival).

A systematic review by He et al demonstrated a reduction in vertebral compressions and time to progression with early systemic treatment for asymptomatic patients, but this study also revealed an increase in acute leukemia in the early treatment group. [32] The failure to demonstrate improved survival may be due to the small number of patients studied.

The 2009 International Myeloma Workshop concluded that detection of any cytogenic abnormality suggests higher-risk disease, including chromosomal 13 or 13q deletion, t(4;14), and del17p and fluorescence in situ hybridization detection of t(4;14), t(14;16), and del17p. [33] Fluorescence in situ hybridization detection of 13q deletion alone is not considered a high-risk feature. International Staging System stages II and II and high serum beta(2)-microglobulin levels are suggestive of higher risk disease.

A study by Klein et al determined that the prognostic significance of t(4;14) may be eliminated or lessened among patients who receive lenalidomide and dexamethasone; however, del(17p13) and +1q21 are still associated with a dismal overall survival. [34] A study by Neben et al concludes that long-term administration of bortezomib in patients with del(17p13) may result in better overall and progression-free survival. [35]

Current therapeutic approaches

Overall, the care of patients with MM is complex and should focus on treatment of the disease process and any associated complications. [3, 4, 5] Although MM remains incurable, several drug therapies are valuable in the treatment of patients with MM, as are autologous stem cell transplantation, radiation, and surgical care in certain cases.

Several studies are evaluating the role of treatment in patients with high-risk smoldering multiple myeloma (SMM). Previous smaller studies evaluating thalidomide did not show a clear evidence of benefit with treatment in patients with SMM; however, these included patients with all risk levels of SMM.

In a phase III trial that was restricted to patients with high-risk SMM, the PETHEMA group found evidence of benefit from treatment with lenalidomide versus observation. After a median follow-up of 40 months, study patients who were randomized to lenalidomide and dexamethasone induction followed by lenalidomide maintenance demonstrated significantly prolonged median time to progression (median not reached vs 21 months) and higher 3-year survival rate (94% vs. 80%). [36] Larger trials are ongoing to validate this benefit. Concern for second primary malignancies (SPMs) with the use of lenalidomide is also a significant issue. Consequently, watchful observation and frequent monitoring remains the standard of care for patients with SMM.

Patients with MM for whom therapy is indicated typically receive chemotherapy. Greater understanding of the cell biology of MM and the ability to identify prognostic factors has led to the increasing individualization of treatment for affected patients. Physicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation.

The 2016 National Comprehensive Cancer Network (NCCN) guidelines for MM list the following combinations as preferred regimens  for primary induction therapy in patients who are not transplant candidates [2] :

  • Bortezomib/dexamethasone
  • Bortezomib/cyclophosphamide/dexamethasome
  • Bortezomib/lenalidomide/dexamethasone (category 1)
  • Lenalidomide/low-dose dexamethasone (category 1)
  • Melphalan/prednisone/bortezomib (MPB) (category 1)
  • Melphalan/prednisone/lenalidomide (MPL) (category 1)
  • Melphalan/prednisone/thalidomide (MPT) (category 1)

Patients should be assessed for response after two cycles of one of the above regimens.

Patients with MM who are treated with lenalidomide or thalidomide are at significantly increased risk for thrombotic events, and many physicians incorporate anticoagulation strategies in their management. A study by Palumbo et al determined that aspirin and low-dose warfarin had similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths in patients with myeloma receiving thalidomide-based regimens compared with low-molecular weight heparin, except in elderly patients. [37]

As monotherapy or in combination, interferon alfa-2b and prednisone modestly prolong the disease-free interval.

A study by the Southwest Oncology Group compared lenalidomide plus dexamethasone to placebo plus dexamethasone in patients with newly diagnosed myeloma. [38] The study determined that lenalidomide plus dexamethasone had superior 1-year progression-free survival, overall response rate, and very good partial response rate, suggesting that it is safe and effective as initial therapy for patients with newly diagnosed myeloma. In February 2015, the FDA approved an expanded indication for MM to included newly diagnosed patients. The original indication was for patients who had received at least 1 prior therapy.

A phase III randomized, open-label trial of 119 patients with high-risk smoldering MM found that early treatment with lenalidomide plus dexamethasone, followed by maintenance therapy with lenalidomide, delayed progression to symptomatic disease and increased overall survival. [39, 40]

Adjunctive therapy for MM includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture, need for surgery, need for radiation). Evidence suggests that it may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence. [41, 42, 43]

Adjunctive therapy may also include any of the following, as appropriate:

  • Erythropoietin
  • Corticosteroids
  • Surgical intervention
  • Plasmapheresis

Bone disease guidelines

In May 2013, the International Myeloma Working Group released practice guidelines for the management of MM-related bone disease. [44] The recommendations, which were based on a review of the literature through August 2012 and a consensus of an interdisciplinary panel of experts, include the following:

  • Consideration of bisphosphonates (BPs) in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography
  • Intravenous (IV) zoledronic acid or pamidronate for preventing skeletal-related events in patients with MM
  • Because of its potential antimyeloma effects and survival benefits, zoledronic acid is preferred in newly diagnosed patients with MM
  • Bisphosphonates should be administered IV every 3 to 4 weeks during initial therapy, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw
  • Zoledronic acid or pamidronate should be continued in patients with active disease and should be resumed after disease relapse
  • Kyphoplasty should be considered for symptomatic vertebral compression fractures
  • Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability
  • Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression
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Chemotherapy and Immunosuppression

In patients with symptomatic MM, chemotherapy is required. In asymptomatic patients with MM, treatment is delayed until disease clinically progresses or until serum or urine levels of M protein substantially increase.

The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction after chemotherapy is used as a sign of response. A 50% reduction in M-component is considered a good clinical response (according to the Chronic Leukemia-Myeloma Task Force). MP induces a response in 50-60% of patients with MM. Disappearance of the M component on electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.

The first step before starting therapy in MM is to determine whether a patient is a candidate for an autologous stem cell transplant. Eligibility depends primarily on the patient’s age and comorbidities. Typically an age of 65 years is used as a cut-off point for transplant eligibility. Thus, treatment for MM is best looked at in terms of the following three categories of patients:

  • Young, newly diagnosed patients who are potential transplant candidates
  • High-risk patients who are potential transplant candidates
  • Newly diagnosed elderly patients who are not transplant candidates

Young, newly diagnosed patients who are potential transplant candidates

Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy has been used to decrease the tumor burden in MM as preparation for transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a central venous catheter for delivery of the infusion. In selected patients, this therapy can be performed in an outpatient setting.

Many researchers feel that the high-dose steroid component of VAD accounts for much of its efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical responses.

Significant concerns with the use of infusion therapy include the risk of soft-tissue injury if the chemotherapy agent infiltrates, the risk of cardiac injury from the doxorubicin, and the risk of infection or hyperglycemia from the high-dose steroids. Some patients also experience adverse central nervous system (CNS) effects from the high-dose steroids. Given these risks, and the higher response rates of new agents (thalidomide, lenalidomide, and bortezomib), VAD is now considered suboptimal treatment.

Thalidomide has proved effective against MM. The superiority of induction regimens containing thalidomide was demonstrated in randomized trials that compared VAD with thalidomide plus dexamethasone [45] ; thalidomide and doxorubicin plus dexamethasone [46] ; and thalidomide plus VAD. [47]

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids in patients with MM. The toxicity of this drug is predominantly sensory neuropathy, and because of the drug’s teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy.

An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of MM therapy. In July 2013, Celgene Corp announced that a phase III trial of lenalidomide (Revlimid) met the main goal of improving progression-free survival in patients with newly diagnosed MM. [48] The drug was already approved for use in previously treated MM, mantle cell lymphoma, and transfusion-dependent anemia caused by myelodysplastic syndromes.

In the late-stage study, treatment with lenalidomide combined with dexamethasome in patients with newly diagnosed MM resulted in a significant improvement in survival without the cancer worsening, compared to treatment with a regimen consisting of melphalan, prednisone and thalidomide (MPT). [48] Evaluation of safety and efficacy is ongoing.

In a randomized, double-blind, placebo-controlled trial, lenalidomide plus high-dose dexamethasone proved superior to high-dose dexamethasone alone as treatment for newly diagnosed MM. [45] The overall response rate was 84% in the lenalidomide plus high-dose dexamethasone group versus 53% in the high-dose dexamethasone group, with 22% of patients achieving complete remission in the lenalidomide plus high-dose dexamethasone arm.

Progression-free survival and overall survival favored lenalidomide plus high-dose dexamethasone, but 12-month survival for both arms was >90%. A very important observation, however, was the high incidence of deep venous thrombosis in the lenalidomide plus high-dose dexamethasone arm. [45]

In another randomized trial of lenalidomide plus high-dose dexamethasone (LD) versus lenalidomide plus low-dose dexamethasone (Ld) in newly diagnosed MM, Rajkumar found that the overall response rate for LD was superior (82%) to that for Ld (70%), with an improvement in the VGPR-or-better rate for LD (44% vs 26%) evaluated after 4 months. [49]

When best overall response was compared, LD again was superior, with an overall response rate of 82% compared with 71% for Ld. However, there was no difference in progression-free survival between the 2 arms. Overall survival continued to favor the Ld arm; however, for patients younger than 65 years, there was no benefit in survival for Ld over LD. [49]

The second interim analysis from Rajkumar et al was completed after 1 year; the data demonstrated that lenalidomide plus low-dose dexamethasone (Ld) was superior to lenalidomide plus high-dose dexamethasone (LD). [50] Overall survival was 96% in the Ld group compared with 87% in the LD group. As a result, the trial was stopped, and patients on high-dose therapy were crossed over to low-dose therapy.

Another trial assessed the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for MM. [51] Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. BiRD was found to be an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed MM.

Patients tolerate lenalidomide therapy well, and nausea is usually minimal. Patients typically experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation) are usually mild. Pancytopenia is expected, but is not severe enough to require hospitalization for infection or transfusion unless the patient also has some other cause of bone marrow suppression.

Bortezomib, a proteosome inhibitor, has shown striking activity against MM. Objective responses as high as 27.7% in patients with relapsed and heavily pretreated MM [52] led to its approval by the US Food and Drug Administration (FDA) in 2003. Subsequent studies reported response rates as high as 80% when bortezomib is combined with melphalan.

A randomized trial compared bortezomib plus dexamethasone with VAD for induction, showing response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD arm. [53] This regimen has been shown to be active not only before but also after transplantation. Following high-dose therapy and autologous transplantation, the rate of very good partial response or better continued to favor bortezomib plus dexamethasone. This benefit was observed independent of beta-2 microglobulin or adverse cytogenetic risk groups.

Similarly, a superior response rate was seen when the combination of bortezomib, thalidomide, and dexamethasone was compared with thalidomide plus dexamethasone in a large phase III study: 93% in the bortezomib-thalidomide-dexamethasone arm versus 80% in the thalidomide-dexamethasone arm, in which patients went on to receive tandem autologous stem cell transplantation. [54] As in other studies, response was independent of adverse prognostic risk factors.

The phase III Velcade as initial standard therapy in MM (VISTA) trial found the combined treatment of bortezomib, melphalan, and prednisone (VMP) significantly prolongs overall survival compared with melphalan and prednisone (MP) after lengthy follow-up and extensive subsequent antimyeloma therapy. [55]

A study by Harousseau et al confirms the role of bortezomib in the initial nonintensive management of MM. [56]

A study by Sher et al found that a combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), known as the VDT regimen, had overall response rate and complete response plus near complete response rates of 78% and 35%, respectively. [57] The study concluded VDT was a tolerable and effective regimen that may induce high response rates among patients considered to be poor candidates for steroid-based treatments.

A notable outcome of this study showed that first-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib-based and other novel agent-based treatment until relapse. [55]

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and renal failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. Despite these results, the exact timing of bortezomib administration in the treatment plan of patients with newly diagnosed multiple myeloma is still evolving through ongoing research.

Varicella-zoster virus reactivation occurs in 10%-60% of patients with MM treated with bortezomib. Antiviral prophylaxis (eg, acyclovir, 400 mg daily) has been found effective for preventing these reactivations. [58]

The FDA approved administration of bortezomib by the subcutaneous route in January 2012. A study by Moreau et al found that the efficacy of subcutaneous bortezomib is not inferior to the efficacy of standard intravenous administration and that the safety profile of the subcutaneous administration is improved. Moreau also observed the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher occurred in 6% when administered SC vs 16% for IV administration. [59] Starting therapy with SC administration may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

A study by Mateos et al found that patients with cytogenetic abnormalities had similar response to bortezomib therapy but shorter survival. The authors concluded that the present treatment schema does not overcome the negative prognosis associated with high-risk cytogenetic abnormalities. [60]

Overall, the data on these novel agents are very encouraging and promising. Nevertheless, oncologists will need further studies to help define the exact timing and role of novel agents in the treatment of MM.

High-risk patients who are potential transplant candidates

High-risk MM patients are those with advanced-stage disease (stage III according to the International Staging System); those with poor cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome 13, inactivation of TP53; and those with a complex karyotype. Patients with very high proliferative rates are also included in this classification.

This group represents about 25% of those with newly diagnosed MM, with an expected median survival of 2 years or less. Although they respond to traditional therapies for induction, these individuals tend to relapse rapidly. Therefore, novel agents should be considered up front for these patients.

The advent of thalidomide, lenalidomide, and bortezomib has substantially improved outcomes in these high-risk groups. In fact, these novel agents appear to overcome the influence contributed by high-risk cytogenetics. [61, 62] Once a response has been achieved, then these patients can be brought to autologous stem cell transplantation.

Newly diagnosed elderly patients who are not transplant candidates

All of the above regimens may be used in patients who are not being considered for autologous stem cell transplantation. The following, however, can only be used in patients not going for transplantation, as they impair stem cell reserve.

The gold standard has been the MP regimen as far back as the 1950s. This regimen typically consists of melphalan 9 mg/m2 and prednisone 100 mg given on days 1-4, with courses repeated at 4- to 6-week intervals for at least 1 year. A meta-analysis of 4930 patients from 20 randomized trials compared MP to other drug combinations and showed a significantly higher response rate (60%) with this combination, with a response duration of 18 months and overall survival of 24 to 36 months. [63]

A three-arm study looked at MP plus thalidomide versus MP versus VAD induction, followed by high-dose melphalan and autologous stem cell transplantation in 447 patients between ages 65 and 75 years. [64] The patients were randomized, with overall survival as the primary endpoint. The response rate in the MP plus thalidomide arm and transplantation arm was similar; the complete response rate was significantly better in the MP plus thalidomide and the transplantation arms than in the MP arm. [64]

MP plus thalidomide is now recommended as first-line treatment. MP plus lenalidomide has also shown promise. [65]

Hulin et al conducted a randomized, placebo-controlled, phase III trial to investigate the efficacy of adding thalidomide to MP in 229 elderly patients (> 75 y) newly diagnosed with MM. [66] During each 6-week cycle, melphalan 0.2 mg/kg/d plus prednisone 2 mg/kg/d was given to all patients on days 1-4 for 12 cycles. In addition, patients were randomly assigned to receive thalidomide 100 mg/d PO (n = 113) or placebo (n = 116), continuously for 72 weeks.

Overall survival was significantly longer in the group that received thalidomide (median, 44 mo) compared with placebo (median, 29.1 mo). [66] Progression-free survival was also significantly prolonged in the thalidomide group (median, 24.1 mo) relative to the placebo group (median, 18.5 mo). However, the investigators noted peripheral neuropathy and neutropenia were significantly increased in the thalidomide group. [66]

A randomized, controlled trial evaluated the addition of thalidomide to standard MP chemotherapy in elderly patients with previously untreated MM. Although no impact on survival was observed, more patients in the thalidomide group achieved an objective response. Of note, thromboembolic events did not increase in the thalidomide group. [67]

A separate study by Fayers et al concluded that thalidomide added to MP therapy improved overall survival and progression-free survival in previously untreated elderly patients with multiple myeloma, extending the mean survival time by an average of 20%. [68]

A study by Gay et al assessed the addition of thalidomide and/or bortezomib to standard oral melphalan-prednisone treatment in 1175 elderly patients with newly diagnosed myeloma. [69] The study found that these novel agents helped achieve maximal response in these patients.

A study by Morgan et al found that cyclophosphamide, thalidomide, and dexamethasone (CTD) produced higher response rates than melphalan and prednisolone among newly diagnosed elderly patients with multiple myeloma; however, CTD was not associated with improved survival outcomes. [70]

Maintenance therapy

In spite of advances in treatment, multiple myeloma remains an incurable disease. To improve overall survival (OS) in these patients, a number of trials have evaluated the role of maintenance therapy in both transplant-eligible and transplant- ineligible patients.

Five large phase III studies have looked at role of thalidomide maintenance after autologous stem cell transplant (ASCT). Three initial studies showed an improvement in both progression-free survival (PFS) and OS. [71, 72, 73] However, two subsequent studies—including one large study with 1970 patients—did not show an improvement in OS with thalidomide maintenance. [74, 75] Long-term use of thalidomide is also associated with significant neuropathy, thus limiting its use in maintenance therapy.

Given its favorable toxicity profile and efficacy at low doses, lenalidomide has also been studied for maintenance therapy. Two large trials, CALGB 100104 and IFM 05-02, have evaluated the role of lenalidomide in maintenance therapy, using slightly different protocols and having somewhat different outcomes. [76, 77] Patients in both studies received induction treatment followed by ASCT. In the IFM 05-02 study, however, all patients received 2 months of consolidation treatment with lenalidomide before being randomized to lenalidomide or placebo.

Both studies showed a significant improvement in time to progression (46 vs 27 months in CALGB study and 41 vs 23 months in IFM study). However, CALGB 100104 study showed significant improvement in OS (85 % vs 77 %), whereas IFM 05-02 did not show an improvement in OS. Both studies showed an increased incidence of hematologic toxicity and second primary malignancies (SPMs), particularly acute myelogenous leukemia/myelodysplastic syndrome in the lenalidomide arm.

The reason for the difference in the two studies in terms of OS benefit is not very clear. Since all the patients in the IFM trial received 2 months of consolidation treatment with lenalidomide following ASCT, it is possible that only short period of maintenance therapy, rather than continuous maintenance therapy, is required to achieve all the OS benefit seen in the CALGB trial.

A meta-analysis shows the benefit of maintenance lenalidomide, with a 51% reduction in the risk of recurrence. [78] This benefit outweighs the risk of SPM seen in the trials of lenalidomide maintenance.

Bortezomib has also been shown to be effective for maintenance therapy in the  HOVON-65/GMMG-HD4 trial. [79] In this trial, patients were randomized to either PAD (bortezomib, doxorubicin [Adriamycin], and dexamethasone) induction followed by bortezomib maintenance or to VAD induction followed by thalidomide maintenance. PFS in the PAD arm was significantly better than in the VAD arm (35 vs 28 months). Patients with high-risk cytogenetics, especially del(17p13) and t(4;14) abnormalities, seemed to benefit more with bortezomib maintenance.

Although several trials have shown the benefit of maintenance therapy after ASCT, the risk of SPM and the need for continuous treatment should be kept in mind. Individual patient characteristics should be taken in consideration before recommending maintenance therapy.

Maintenance therapy has also been evaluated in non–transplant eligible patients. Thalidomide has been studied as maintenance in a number of trials; most of the trials have shown only advantage in PFS, with no advantage in OS. The main problem with thalidomide has been the high incidence of neuropathy in these patients.

A trial of lenalidomide as maintenance therapy after induction with melphalan, prednisone, and lenalidomide showed a significant improvement in PFS (26 vs 7 months) but similar 4-year OS. Patients in the lenalidomide arm had more hematologic toxicity, including neutropenia, thrombocytopenia, and higher risk of second primary malignancy. However, given its overall tolerability, lenalidomide is a good option for induction and maintenance therapy in transplant-ineligible patients. [80]

A number of trials have also evaluated bortezomib in maintenance therapy. All of them have showed benefit in PFS but no clear OS benefit. Bortezomib given once a week in maintenance seems to be better tolerated and associated with lesser neuropathy. [81]

Patients with refractory disease or relapse

Patients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the relapse occurs longer than 6 months after the initial therapy, then the initial regimen can be used again.

Among the other choices for salvage therapy are the following preferred regimens [2] :

  • Bortezomib
  • Bortezomib/liposomal doxorubicin
  • Carfilzomib
  • Carfilzomib/dexamethasone
  • Carfilzomib/lenalidomide/dexamethasone
  • Lenalidomide/dexamethasone
  • Panobinostat/bortezomib/dexamethasone
  • Daratumumab
  • Ixazomib/lenalidomide/dexamethasone
  • Elotuzumab/lenalidomide/dexamethasone

Bortezomib has a well-established role as salvage therapy, based on a phase III randomized trial showing a response rate of 38% versus 18% in patients receiving dexamethasone only. [52] Median progression-free survival was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group.

Panobinostat (Farydak) is a histone deacetylase (HDAc) inhibitor approved in February 2015. It is indicated in combination with bortezomib and dexamethasone for treatment of MM in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. The FDA approval was based on efficacy and safety data in a prespecified subgroup analysis of the phase III PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial, in which patients treated with panobinostat (n = 94) had a median progression-free survival of 10.6 months, compared with 5.8 months for patients in the placebo arm (n= 99) (hazard ratio= 0.52 [95% confidence interval: 0.36, 0.76]). [82]

In 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with MM who have received at least two prior therapies including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of therapy completion. The approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with relapsed multiple myeloma with other therapies. The study assessed for overall response rate (ORR), which was 22.9% over a median duration of 7.8 months. [83]

In 2015, the FDA expanded carfilzomib’s indication for multiple myeloma based on data from the ASPIRE study. In this study, carfilzomib was combined with lenalidomide and dexamethasone (KRd) for patients with relapsed multiple myeloma who had received 1-3 prior lines of therapy. The study showed a significant improvement in progression-free survival (PFS) for patients treated in the KRd arm compared with those treated with lenalidomide and low-dose dexamethasone (Rd) alone. The median PFS was 26.3 months in the KRd arm compared to 17.6 months in the Rd arm. [84]

In January 2016, the FDA approved carfilzomib in combination with dexamethasone for relapsed or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy. Approval was based on the ENDEAVOR study (n=929) where a statistically significant improvement in median progression-free survival was observed with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone in patients with relapsed multiple myeloma (26.3 mo vs 17.6 mo; p=0.0001). Overall survival data are not yet available. [85]

The following three new drugs were approved in November 2015:

  • Daratumumab (Darzalex)
  • Ixazomib (Ninlaro)
  • Elotuzumab (Empliciti)

Daratumumab gained accelerated approval from the FDA for patients with MM who had received at least three prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD. The approval was based on the phase II MMY2002 (SIRIUS) study that showed treatment with single-agent daratumumab resulted in an ORR of 29.2% in patients who received a median of five prior lines of therapy, including a PI and an IMiD. [86]

Stringent complete response (sCR) was reported in 2.8%, very good partial response (VGPR) was reported in 9.4%, and partial response (PR) was reported in 17% of patients. For responders, the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to their last line of therapy, 95% were refractory to both a PI and an IMiD, and 77% were refractory to alkylating agents. [86] These data are supported by similar results from a phase I/II trial. [87]

Ixazomib is a reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. Ixazomib is indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy. Approval was based on data from the phase 3 TOURMALINE-MM1 trial, an international, randomized, double-blind clinical trial of 722 patients with treatment-refractory or recurrent multiple myeloma. It compared ixazomib with placebo the patients who also received lenalidomide and dexamethasone. Median progression-free survival was improved by 35% with ixazomib compared with placebo (20.6 vs 14.7 months; P = 0.012). [88]

Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on myeloma cells and natural killer cells and plasma cells. Elotuzmab facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity. It is indicated for use in combination with lenalidomide and dexamethasone for MM in patients who have received 1-3 prior therapies.

Approval was based on the ELOQUENT-2 trial, a randomized, open-label clinical study that included 646 participants with multiple myeloma who had experienced relapse or who had not responded to previous treatment. The addition of elotuzumab to the combination of lenalidomide and dexamethasone extended progression- free survival to 19.4 months, as compared with 14.9 months seen in patients treated with lenalidomide and dexamethasone (P<0.001). Additionally, the overall response rate (including complete and partial responses) was 78.5%, compared with 60.1% in patients receiving lenalidomide and dexamethasone (P<0.001). [89]

Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm. [90, 91] In a Mayo Clinic study, nearly one third of patients with advanced MM in whom current standard chemotherapy or stem cell transplantation failed were shown to respond to thalidomide for a median duration of nearly 1 year. [92]

An important prospective placebo-controlled trial of the addition of lenalidomide to dexamethasone in relapsed cases of MM demonstrated spectacular results. [93] The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 in the lenalidomide plus dexamethasone group vs 4.7% in the placebo group). Overall survival was significantly improved. [93]

A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory to both lenalidomide and bortezomib. [94] In February 2013, pomalidomide was approved by the FDA for use in patients with MM who have received at least two previous therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy. [7, 8]

This approval was supported by a phase II study comparing pomalidomide plus low-dose dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial response or better, compared with 7.4% in the pomalidomide-alone arm. [7] The median duration of response for the former was 7.4 months; the median had not been reached for the latter.

In a more recent study, Miguel et al found that the combination of pomalidomide with low-dose dexamethasone yielded a longer median progression-free survival (PFS) in 455 patients with refractory or relapsed and refractory MM than high-dose dexamethasone alone. [95] In the open-label, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months), median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in the two groups. [95]

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Transplantation

Using the patient’s own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense therapy for MM. After harvesting the stem cells from the patient, physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then “rescue” the patient by reinfusing the harvested cells. This process of myeloablative therapy, followed by the reinfusion of stem cells, is termed autologous stem cell transplantation.

This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times higher dose than is used in standard therapy. [46] In autologous transplantation, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.

Tandem autologous transplantation has been proposed as a way of overcoming the incomplete response to a single transplant. A 2-arm trial of single versus tandem transplantation revealed no difference in overall survival at 54 months. [96]

Another two-arm study that compared single versus tandem transplants for newly diagnosed MM showed that whereas double autologous stem cell transplantation effected superior complete or near-complete response rates, relapse-free survival, and event-free survival (EFS), it failed to significantly prolong overall survival. [97] Benefits offered by double autologous stem cell transplantation were particularly evident among patients who failed to achieve at least a near-complete response after one autotransplantation.

A review of long-term outcomes of several autotransplantation trials for MM found that tandem transplantations were superior to both single transplantations and standard therapies and that tandem transplantations with thalidomide were superior to trials without thalidomide. [98] However, postrelapse survival (PRS) was superior when initial EFS exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib. [98]

Two randomized prospective studies compared standard chemotherapy with high-dose autologous transplantation. In the first study of 200 subjects, researchers observed better response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated group) and better 5-year event-free survival rates (ie, 28% vs 10%). [99] The second study also showed a significant improvement in event-free survival rates and superior quality of life for subjects treated with the high-dose approach.

In highly selected patients with MM, physicians may use allogeneic (ie, from someone else) transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte antigen (HLA)-identical sibling.

The advantage of this approach over autologous transplantation is that the patient is not at risk of being reinfused with MM cells. In addition, the donor’s immune system may fight the recipient’s cancer (ie, graft vs myeloma effect). Unfortunately, the donor’s immune system may also attack the recipient’s body (ie, graft vs host effect).

Physicians use allogeneic transplantation less often than autologous transplantation in MM patients, for several reasons. First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with multiple myeloma are older than the ideal age for allogeneic transplantation.

Second, the transplantation-related mortality rate is quite high in patients with MM who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to 56% in different case series.

Third, although some survivors experience long-term disease-free results after allogeneic transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation showed a median survival of 34 months for the autologous transplantation group and 18 months for the allogeneic group.

The exception to this rule is the rare patient with a twin donor. In a limited study of 25 transplantations involving twins, outcomes with syngeneic transplantations were superior, with reduced transplantation-related mortality.

The development of a nonmyeloablative preparative regimen for MM allogeneic transplantation is changing the equation. A republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate. [100] Progression-free survival at 18 months was roughly 30%.

A phase II trial of autologous stem cell transplantation followed by a nonmyeloablative matched sibling related donor transplant demonstrated this approach to be feasible, with low treatment-related mortality. [101] Further studies are needed to evaluate relative efficacy.

Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens (mini-allotransplantation) may hold promise for more widely exploiting this feature. [102, 103]

A study by Moreau et al determined that achievement of very good partial response (VGPR) after induction therapy is an important prognostic factor in patients undergoing autologous stem cell transplantation. [104] VGPR was significantly improved with bortezomib-dexamethasone induction therapy.

A study by Harousseau et al also concluded that this combination significantly improved postinduction and posttransplantation complete response/near response rate at at least VGPR rates compared with VAD. [105] Cavo et al also concluded that this combination represents a new standard of care for patients with multiple myeloma who are eligible for transplant. [106]

In MM patients with progressive or relapsing disease following autologous stem-cell transplantation, treatment with the combination of bortezomib, thalidomide and dexamethasone is more effective than treatment with thalidomide and dexamethasone alone, although triple therapy is associated with a greater risk of grade 3 neurotoxicity. [107]

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Interferon Alfa Therapy

Intense research has focused on the use of interferon alfa to treat MM. This drug does not appear to be effective for inducing remission, and a randomized controlled trial showed that patients do not benefit from the addition of interferon to melphalan and prednisone. [108] Interferon alfa does appear to prolong remission in selected patients with MM. For this use, it may be administered after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been completed.

The toxicity of interferon and the availability of alternate interventions have significantly limited the role of interferon alfa.

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Radiation Therapy

MM is extremely sensitive to radiation. Physicians use radiation to treat symptomatic lesions and to stabilize bones at risk for fracture. Physicians also use radiation to treat spinal cord compression. Low-dose, double-hemibody irradiation has been studied as systemic therapy for refractory or relapsed MM, but without dramatic success.

If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated. Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing should be limited for the first 4-6 weeks.

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Bisphosphonate Therapy

Bisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone resorption. They also have a role in the secondary prevention of bony complications in MM, including hypercalcemia, pathologic fracture, and spinal cord compression. Intravenous (IV) pamidronate (Aredia) has been shown to be effective in preventing skeletal complications; zoledronic acid (Zometa) may be significantly more potent than pamidronate. A study by Morgan et al found that the early use of zoledronic acid was superior to clodronic acid in preventing skeletal-related events among patients with newly diagnosed MM, irrespective of bone disease status at baseline. [41]

A randomized placebo-controlled trial of pamidronate in subjects with MM who had experienced one skeletal event demonstrated that the medication reduced the likelihood of a second skeletal event from 41% to 24% after 9 months of therapy. [42] The investigators also noted improvements in pain, narcotic usage, and quality of life scores.

A 2007 systematic review of the use of bisphosphonates in MM confirmed a number-needed-to-treat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was seen. [43]

The American Society of Clinical Oncology (ASCO) issued a clinical practice guideline governing bisphosphonate therapy for MM patients who have lytic destruction of bone or compression fracture of the spine from osteopenia. [43] ASCO recommends IV pamidronate, 90 mg delivered over at least 2 hours, or zoledronic acid, 4 mg delivered over at least 15 minutes every 3-4 weeks. Because the risk for osteonecrosis of the jaw is 9.5-fold greater with zoledronic acid than with pamidronate, patients may prefer pamidronate. [43]

Zoledronic acid doses should be reduced in patients with preexisting mild to moderate renal impairment (estimated creatinine clearance, 30-60 mL/min); the drug is not recommended for use in patients with severe renal impairment. [43] All patients receiving pamidronate or zoledronic acid therapy should be screened every 3-6 months for albuminuria. If unexplained albuminuria (>500 mg/24 hours) is found, ASCO recommends discontinuation of the drug until the renal problems resolve. [43]

A study by Morgan et al revealed the anticancer properties of zoledronic acid in addition to its ability to reduce skeletal-related events in MM. [109]

Osteonecrosis of the jaw

Osteonecrosis of the jaw is a rare but severe adverse effect of bisphosphonate therapy. Level 1 evidence (ie, systematic reviews or randomized controlled trials) indicate that approximately 1% of cancer patients exposed to zolendronic acid develop osteonecrosis of the jaw. [110] Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

A position paper by the American Association of Oral and Maxillofacial Surgeons describes the differential diagnosis, prevention, and treatment of medication-related osteonecrosis of the jaw. Consultation with an appropriate dental professional is advised before prescribing a bisphosphonate. [110]

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Adjunctive Therapy for Complications

Potential complications of MM include the following:

  • Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal cord compression)
  • Infection
  • Anemia
  • Renal failure

Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in MM.

To treat pathologic fractures, physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient’s bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures. [43, 111, 112] (See Surgical Care and Bisphosphonate Therapy.)

Spinal cord compression is one of the most severe adverse effects of MM. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. Patients who may have spinal cord compression need a rapid evaluation, which may necessitate urgent transfer to a center equipped with MRI for diagnosis or a center with a radiation oncologist for urgent therapy.

Patients with spinal cord compression due to MM should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to restore or stabilize neurologic function. Surgery may be indicated. (See Surgical Care.)

Erythropoietin may ameliorate anemia resulting from either MM alone or from chemotherapy and has been shown to improve quality of life. [113] A systematic review failed to demonstrate a survival advantage for the use of erythropoietin agents in the treatment of patients with cancer-related anemia. [114]

Acute renal impairment related to MM is typically managed with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis. [15] Hydration (to maintain a urine output of >3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors. Conventional therapy may take weeks to months to show a benefit.

Renal impairment resulting from MM is associated with a very poor prognosis. A case series demonstrated that patients with renal failure from myeloma may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their renal function with this approach. [115] A report by Ludwig et suggests that bortezomib-based therapy may restore renal function in MM patients with renal failure. [14]

Guidelines on the management of multiple myeloma complications by the European Myeloma Network include the following recommendations [116] :

  • Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus is recommended as the novel standard for the detection of lytic lesions in myeloma.
  • Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate.
  • Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid, but its advantage is not clear for patien ts with no bone involvement on computed tomography or magnetic resonance imaging.
  • In asymptomatic myeloma, bisphosphonates are not recommended.
  • Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use.
  • Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded.
  • Erythropoietic agents should be stopped after 6-8 wk if no adequate hemoglobin response is achieved.
  • For renal impairment, bortezomib-based regimens are the current standard of care.
  • For the management of treatment-induced peripheral neuropathy, drug modification is needed.
  • Vaccination against influenza is recommended; vaccination against Streptococcus pneumoniae and Haemophilus influenzae is appropriate, but efficacy is not guaranteed due to suboptimal immune response.
  • Prophylactic acyclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, or autologous or allogeneic transplantation
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Surgical Care

Surgical therapy for MM is limited to adjunctive therapy. It consists of prophylactic fixation of pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic fractures.

Prophylactic treatment of impending fractures and the treatment of pathologic fractures may involve bracing. In general, bracing is not effective for the long bones, though it may be effective for treating spinal involvement without neurologic compromise.

Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or joint surface is involved, resection of the diseased bone and reconstruction with a total joint or, more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe destruction of the diaphysis may require reconstruction with combinations of methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.

Although surgical decompression of the spinal cord is sometimes appropriate, posterior laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be superior to radiation. This surgical approach is probably best reserved for cases of MM in which radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected into compressed vertebrae, have been shown to improve function with few complications, although the studies reported have been small.

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Dietary Measures

Patients with MM who are receiving bisphosphonate therapy should include adequate calcium in their diet.

The dietary supplement curcumin may slow the progression of smoldering multiple myeloma. [117]

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Physical Activity

Patients with MM should be encouraged to be physically active to the extent appropriate for their individual bone status. Physical activity may help maintain bone strength.

In general, patients with activity-related pain in either the femur or the tibia should be given a walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the target bone. Given that prophylactic treatment of an impending fracture is usually easier than reconstruction of a pathologic fracture, one should have a low threshold for initiating protected weight bearing.

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Prevention of Multiple Myeloma

No preventive measures for MM are known. A study by Chang et al found that routine residential ultraviolet radiation exposure may have a protective effect against lymphomagenesis through mechanisms that may be independent of vitamin D. [118]

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Consultations

Patients with MM often benefit from the expertise of an orthopedic surgeon who is versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

From the orthopedic perspective, because patients with MM have significant systemic comorbidities—including potentially severe hematologic, infectious, and metabolic diseases—the orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in conjunction with the radiation oncologists and the medical oncologists.

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Long-Term Monitoring

Patients with MM may require hospitalization for the treatment of pain or bony pathology.

Patients with MM are at high risk of infection, especially from encapsulated organisms. Vaccinations against pneumococcal organisms and influenza are recommended. Consider vaccinating patients against Haemophilus influenzae type b. Use of the herpes zoster vaccine should be considered.

The following laboratory results are helpful in the follow-up care of patients with MM:

  • Complete blood count (CBC), chemical profile 7 (especially blood urea nitrogen [BUN] and serum creatinine), serum calcium, and serum uric acid, and serum protein electrophoresis (SPEP) findings.
  • M-component level in the serum and/or urine. (This is an indicator of tumor burden; a reduction with chemotherapy is used as a sign of a treatment response.)
  • Serum beta-2 microglobin. (An elevated level indicates a large malignant cell mass, renal impairment, or both.)
  • Serum lactate dehydrogenase (LDH) level. (A high level is predictive of an aggressive lymphomalike course.)
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