Multiple Myeloma and Plasma Dyscrasia

Despite the introduction of many new therapeutic agents over the past two decades, there is still no confirmed curative approach. Major controversies have resulted regarding the framework for both future trials and current therapeutic recommendations. Unresolved questions in multiple myeloma include the following:
1. Does a high-dose alkylator-induced immune reset after induction therapy (i.e., autologous stem cell transplant [ASCT] consolidation) result in long-term benefits that outweigh potential toxicities such as the emergence of resistant clones or second malignancies? Some clinicians in the United States and many in Europe consider ASCT to be the backbone after induction therapy or after trials introducing new agents into induction therapy. Other clinicians think that combinations of new agents and the availability of other agents provide the ability to avoid ASCT.

2. In choosing initial induction therapy, should new triple-drug regimens (e.g., lenalidomide, bortezomib, and dexamethasone) be employed to achieve the best response and most durable remission? Or should active agents be used in singlets and doublets in a sequential fashion, using the same approach as for an indolent lymphoma? Should this decision be made in a risk-adaptive way, with favorable-prognosis patients employing the sequential approach? Or should all new patients receive triple-drug regimens? In fit patients, triple-drug regimens that include bortezomib are considered standard treatment in the absence of a clinical trial. The most commonly used triplets include:
    • VRd: lenalidomide + bortezomib + dexamethasone.
    • CyBorD: cyclophosphamide + bortezomib + dexamethasone.

3. As newer agents, such as carfilzomib and pomalidomide, move upfront into triplets, and with the introduction of the anti-CD38 monoclonal antibody daratumumab and the monoclonal antibody targeting SLAMF7 (signal lymphocyte activating molecule F7) elotuzumab, will the stringent complete remissions equal or surpass ASCT with less long-term toxicities?

4. Maintenance therapies are under active clinical evaluation; the prolonged remissions and improved progression-free survival (PFS) have not translated into established overall survival (OS) benefits in most trials. (Refer to the Maintenance Therapy section of this summary for more information.) How will this approach augment induction and consolidation therapies?

5. How do we incorporate the newer agents such as daratumumab and elotuzumab upfront creating four or five drug regimens? Or can we find a more personalized targeted approach to create a smaller cocktail?

6. The assessment of minimal residual disease is mandatory for the assessment of efficacy in clinical trials. Does this testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing about selection or duration of therapy?

7. How do we deal with the financial toxicity of all these advances?

Several questions are raised when therapy is chosen for a patient with symptomatic myeloma at first presentation:

1. Is the patient eligible for a clinical trial? The sequence and combinations of new and older therapies can be determined only by prospective clinical trials.

2. Does the patient have comorbidities? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as ASCT.

In summary, clinicians utilize a clinical trial or one of the following strategies for a newly diagnosed patient with multiple myeloma:

1. A risk-adapted approach using single agents or doublets sequentially and re-using previous successful regimens before proceeding to newer agents (the indolent lymphoma-leukemia approach). Maintenance therapy can be implemented along the way.

2. Induction using a triple-drug approach to maximize durable response first and then to implement new agents on protocols (avoiding ASCT). Maintenance therapy can be implemented along the way.

3. Induction using a doublet or triplet or using new drugs in an investigative setting en route to ASCT consolidation followed by maintenance therapy.

There are regional geographic variations to the approaches listed. Clinical trials and future discoveries may help to explicate the best therapeutic strategy. Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved OS. While this interim marker may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy.

Induction therapy agents

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

• Steroids (e.g., dexamethasone and prednisone).

• Immunomodulatory drugs (IMiDs).
    • Lenalidomide.
    • Pomalidomide.
    • Thalidomide.

• Proteasome inhibitors.
    • Bortezomib.
    • Carfilzomib.
    • Ixazomib.

• Monoclonal antibodies.
    • Daratumumab (monoclonal antibody targeting CD38).
    • Elotuzumab (monoclonal antibody targeting SLAMF7).

• Alkylating agents (e.g., melphalan and cyclophosphamide).

• Other cytotoxic drugs (e.g., vincristine, doxorubicin, and liposomal doxorubicin).

• Histone-deacetylase inhibitors.

Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity.

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.
2. Bortezomib and/or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned. (Refer to the Lenalidomide and Bortezomib sections of this summary for more information; also refer to the Therapeutic Overview section of this summary for a discussion about the controversy of using doublets or triplets.)
3. The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration.
    • Bortezomib is given subcutaneously and can cause neuropathic toxicities. Bortezomib is preferred in the setting of renal impairment.
    • Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT), requiring additional prophylactic medication.
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. (Refer to the Therapeutic Overview section of this summary for a discussion about the controversy of using a risk-adapted approach in some cases.)
5. Patients with high-risk disease might receive triple-drug induction therapy until best response, followed by consolidation therapy with allogeneic or ASCT.

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. Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[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 OS (median survival times, 32 months–40 months).[Level of evidence: 1iiA]
• The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints.

There has never been a randomized trial comparing single-agent oral dexamethasone at a traditional high dose (40 mg qd 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 [NCT00002678]).
• 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.
• In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial (ECOG-E4A03 [NCT00098475]).
• The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone. (Refer to the Lenalidomide section of this summary for more information.)
On the basis of these trials, almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents: 40 mg dexamethasone (oral [PO] or intravenous [IV]) weekly in younger patients or fit older patients or 20 mg dexamethasone (PO or IV) in less-fit older patients.

IMiDs (immunomodulatory drugs)

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.
    • 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).[Level of evidence: 1iA]
    • The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).

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).[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).
    • 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 PFS.[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).[Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.

4. A prospective, randomized study of 1,623 transplant-ineligible, untreated patients compared lenalidomide and low-dose dexamethasone when given until progression with a 72-week induction regimen with melphalan plus prednisone plus thalidomide (MPT) for 72 weeks.
    • With a median follow-up of 46 months, this trial showed improved OS for patients on the continuous lenalidomide plus dexamethasone (52% vs. 38% for MPT at 4 years; HR, 0.72; 95% CI, 0.54–0.96; P = .02).[Level of evidence: 1iiA]
    • Although median PFS was 5 months longer for continuous lenalidomide plus dexamethasone versus 72 weeks of the same regimen (HR, 0.71; 95% CI, 0.61–0.83; P < .001), there was no difference in OS.[Level of evidence: 1iiDiii]

5. 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.[Level of evidence: 3iiiA]

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT. A randomized, prospective trial of 342 previously untreated patients receiving lenalidomide-containing regimens compared aspirin (100 mg/qd) with enoxaparin (40 mg/qd); the 2% incidence of venous thromboembolic events was similar for both interventions. 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 meta-analysis of 3,254 individual patients from seven randomized trials showed that lenalidomide was associated with an increased risk of hematologic second primary malignancies (3.1% in patients who received lenalidomide vs. 1.4% in those who did not; HR, 3.8; 95% CI, 1.15–12.62; P = .029). This risk was confined to the combination of lenalidomide and melphalan (HR, 4.86; 95% CI, 2.79–8.46, P = .0001) but was not higher for lenalidomide with either cyclophosphamide or dexamethasone.

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. 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 qd; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis). Uncontrolled trials, including NCT00151203, have added clarithromycin (500 mg bid) to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach.

Pomalidomide
Evidence (pomalidomide):
1. Several trials in heavily pretreated patients after bortezomib and lenalidomide showed a response rate ranging from 26% to 63%.[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.

2. For 302 patients with relapsed or refractory disease, a pomalidomide and low-dose dexamethasone regimen was compared with high-dose dexamethasone in a randomized, prospective trial; after a median follow-up of 10.0 months, the PFS favored the pomalidomide arm by 4.0 to 1.9 months (HR, 0.48; 95% CI, 0.39–0.60; P < .0001).[Level of evidence: 1iiDiii]

Pomalidomide was approved for patients who relapse after two previous regimens, which must have included bortezomib and lenalidomide. Although some myelosuppression and increased risk of thromboembolic events are noted as with lenalidomide and thalidomide, very little peripheral neuropathy is noted in comparison with the other agents.

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.
• 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.
• A meta-analysis of 1,685 patients from six of the randomized trials confirmed that thalidomide added to MP improves the median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; P = .004).[Level of evidence: 1iiA]
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.

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

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

Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses. By utilizing a low dose (50 mg PO qd), significant sedation, constipation, and neuropathy may be avoided. Prophylaxis to avoid thrombosis with aspirin, warfarin, or low molecular–weight heparin is required; the choice of therapy depends on pre-existing risk factors.

Proteasome inhibitors

Bortezomib
Evidence (bortezomib):
• 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.
• With a median follow-up of 60 months, the median OS favored the bortezomib arm (56.4 vs. 43.1 months, P < .001).[Level of evidence: 1iiA]
• 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.[Level of evidence: 1iiA]
• Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.
• A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.
• 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).[Level of evidence: 1iiA]

1. A prospective, randomized trial of 260 newly diagnosed patients aged 65 years and older compared bortezomib plus melphalan plus prednisone (VMP) with bortezomib plus thalidomide plus prednisone (VTP).
    • With a median follow-up of 72 months, the median OS favored the VMP arm, 63 months versus 43 months (HR, 0.67; 95% CI, 0.49–0.91; P = .01).[Level of evidence: 1iiA]

2. In 511 previously untreated patients who were not eligible for transplant and older than 65 years, 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 the superiority of the arm with thalidomide and bortezomib during induction and maintenance.
    • With a median follow-up of 54 months, 3-year PFS was 35% versus 25% (P < . 001), and 5-year OS was 61% versus 51% (P = .01).[Level of evidence: 1iiA] Because of the 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.

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment. 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.

In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11). 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.

More than 6 months after completion of bortezomib induction therapy, bortezomib can be applied again with a 40% overall response rate, according to a meta-analysis of 23 phase II studies.[Level of evidence: 3iiiDiv]

Carfilzomib
Evidence (carfilzomib):
1. In a prospective, randomized trial [NCT01568866] of 929 patients with relapsed or refractory multiple myeloma, carfilzomib and dexamethasone were compared with bortezomib and dexamethasone.[Level of evidence: 1iiA] With a median follow-up of about 37 months, the median OS was 47.6 months (95% CI, 42.5–not evaluable [NE]) for the carfilzomib combination compared with 40.0 months (95% CI, 32.6–42.3) for the bortezomib combination (HR, 0.79; 95% CI, 0.65–0.96; P = .020).

2. A prospective, randomized study of 792 relapsed patients compared carfilzomib plus lenalidomide plus dexamethasone with lenalidomide plus dexamethasone.[Level of evidence: 1iiA]
    • With a median follow-up of 32 months, the median PFS was improved with the addition of carfilzomib: 26.3 months versus 17.6 months (HR, 0.69; 95% CI, 0.57–0.83; P = .0001).
    • The 24-month OS favored the addition of carfilzomib 73% versus 65% (HR, 0.79; 95% CI, 0.63–0.99; P = .04).

3. In two phase II trials of newly diagnosed patients, aged 65 years and older, carfilzomib combined with cyclophosphamide and dexamethasone in 58 patients or with MP in 68 patients achieved at least a partial response in 95% of the patients and a near-complete response (nCR) in 90% of the patients.[Level of evidence: 3iiiDiv]

4.In two trials of 53 and 45 patients with newly diagnosed disease, carfilzomib combined with lenalidomide and dexamethasone achieved an nCR or stringent complete response in 62% of the patients in both trials and an 18- to 24-month PFS of 92%, also in both trials.[Level of evidence: 3iiiDiv]

Ixazomib
Evidence (ixazomib):
1. In a prospective, randomized trial involving 722 patients with refractory or resistant myeloma, the oral proteosome inhibitor ixazomib combined with lenalidomide and dexamethasone was compared with a placebo with lenalidomide and dexamethasone only.[Level of evidence: 1iDiii]
    • With a median follow-up of 2 years, the median PFS favored the ixazomib group, 20.6 months to 14.7 months (HR, 0.66; 95% CI, 0.47–0.93; P = .016).
    • Ixazomib is approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide and dexamethasone for patients with relapsed disease.
    • No grade 3 or 4 neuropathy was seen in any patient treated with ixazomib.

Monoclonal antibodies

Daratumumab
Daratumumab is a monoclonal antibody targeting CD38 that is now FDA approved for use as a single agent or in combination therapy after failure of the previous regimen.

Evidence (daratumumab):
1. In a prospective, randomized trial, 498 previously treated patients were randomly assigned to receive daratumumab plus bortezomib plus dexamethasone or bortezomib plus dexamethasone.
    • With a median follow-up of 7.4 months, the median PFS was not reached in the daratumumab group and was 7.2 months in the control group (HR, 0.39; 95% CI, 0.28‒0.53; P < .001).[Level of evidence: 1iiDiii]

2. In a prospective, randomized trial, 569 previously treated patients were randomly assigned to receive daratumumab plus lenalidomide plus dexamethasone or lenalidomide plus dexamethasone.

    • With a median follow-up of 13.5 months, the 1-year PFS was 81.5% in the daratumumab group versus 59.0% in the control group (HR, 0.37; 95% CI, 0.27‒0.52; P < .001).[Level of evidence: 1iiDiii]

3. Several phase I and phase II trials evaluated the CD38-targeting monoclonal antibody daratumumab as a single agent for relapsed or refractory multiple myeloma.[Level of evidence: 3iiiDiv]
    • With a median follow-up of 12 to 17 months, the overall response rate was 31% and 36%, with minimal response or stable disease in about 40% of patients. Responders had an 80% OS at 2 years. The minimal response or stable disease patients had a 40% OS at 2 years.

4. A phase I/II study of 45 patients with relapsed myeloma studied daratumumab in combination with lenalidomide and dexamethasone.
    • With a median follow-up of 15.6 months, the 18-month PFS was 72% (95% CI, 51.7%‒85.0%), and OS was 90% (95% CI, 73.1%‒96.8%).[Level of evidence: 3iiiDiii]

5. In a phase II trial (NCT01998971) of 103 patients with relapsed and/or refractory myeloma, daratumumab was studied in combination with pomalidomide and dexamethasone.
    • With a median follow-up of 13.1 months, the median PFS was 8.8 months (95% CI, 4.6–15.4), and the median OS was 17.5 months.[Level of evidence: 3iiiD]

Elotuzumab
Elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7) that is now FDA approved for use in combination therapy after failure of one previous regimen.

Evidence (elotuzumab):
1. In a prospective, randomized trial of 646 patients with relapsed or refractory myeloma, elotuzumab, was combined with lenalidomide and dexamethasone and compared with lenalidomide and dexamethasone alone.[Level of evidence: 1iiA]
    • With a median follow-up of 2.8 years, the group receiving elotuzumab had a superior 3-year PFS of 26% versus 18% (HR, 0.73; 95% CI, 0.60–0.89; P = .0014) and improved 3-year OS of 44% versus 39% (P = .0257).

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%.[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.[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. The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.

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

Histone deacetylase inhibitors

Evidence (panobinostat):
Panobinostat is a potent pan-deacetylase inhibitor that combines with proteosome inhibition to block removal of overproduced, misfolded proteins from the myeloma cell, which impairs myeloma cell survival.

1. A prospective, randomized study of 768 patients with relapsed or relapsed and refractory myeloma compared panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone.[Level of evidence: 1iDiii]
    • With a median follow-up of 6 months, the median PFS was longer in the panobinostat group, 12 months versus 8 months (HR, 0.63; 95% CI, 0.52–0.76; P > .0001).

Combination therapy

Evidence (combination therapy):
Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials is 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.
• Bortezomib, lenalidomide, and dexamethasone (VRd) versus lenalidomide and dexamethasone (Rd). In a prospective, randomized trial in 474 newly diagnosed patients with myeloma, VRd was compared with Rd.[Level of evidence: 1iiA]
• With a median follow-up of 55 months, the VRd group had superior PFS (median PFS, 43 months vs. 30 months; HR, 0.71; 95% CI, 0.58–0.95; P = .013) and superior OS (median OS, 75 months vs. 64 months; HR, 0.79; 95% CI, 0.52–0.97; P = .025).

• 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.

Options for combination regimens:
1. Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-S0777, EVOLUTION trial, and the U.S. Intergroup/IFM trial).
2. Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).
3. Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).
4. Lenalidomide + dexamethasone (as demonstrated in SWOG-S0777).
Triplets including either melphalan or cyclophosphamide combined with lenalidomide and dexamethasone were compared with a doublet of lenalidomide and dexamethasone in 662 patients; there were no differences in outcome for PFS or OS, but the doublet showed less toxicity.
5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).
6. Carfilzomib + cyclophosphamide + dexamethasone.
7. Carfilzomib + lenalidomide + dexamethasone.
8. Carfilzomib + pomalidomide + dexamethasone.
9. Pomalidomide + cyclophosphamide + dexamethasone.
10. Melphalan + prednisone + thalidomide.
11. Melphalan + prednisone.

Autologous bone marrow or peripheral stem cell transplantation

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

Single autologous bone marrow or peripheral stem cell transplantation

Evidence (single autologous bone marrow or peripheral stem cell transplantation):
1. While some prospective, randomized trials showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[Level of evidence: 1iiA] other trials have not shown any survival advantage.[Level of evidence: 1iiA]

2. Between 2010 and 2012, 700 newly diagnosed patients, aged 65 years or younger, were randomly assigned to receive VRd for three cycles followed by ASCT consolidation and two more cycles of VRd versus VRd alone for eight cycles, with maintenance lenalidomide given to both groups. At relapse, patients on the chemotherapy-only arm were re-induced and offered transplantation if they were still responding. This trial compared ASCT at first induction with transplant at relapse.
    • With a median follow-up of 44 months, the median PFS favored early transplantation (50 months vs. 36 months; HR, 0.65; 95% CI, 0.53–0.80; P < .001), but the 4-year OS was unchanged (81% vs. 82%; HR, 1.16; 95% CI, 0.80–1.68; P = .87).[Level of evidence: 1iiDiii]

3. Two meta-analyses of almost 3,000 patients showed no survival advantage.[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. The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates. Consequently, there is no clear consensus on whether to do transplantations early, or to give chemotherapy and do transplantations at the time of relapse.

Tandem autologous bone marrow or peripheral stem cell transplantation followed by autologous or allogeneic 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).

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).[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.
    • 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).[Level of evidence: 1iiA]

3. Five different groups have compared single or 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 SCT 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).[Level of evidence: 1iiA]

5. Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with 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.[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. 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.

Allogeneic bone marrow or peripheral stem cell transplantation

Evidence (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.

Favorable prognostic features included the following:
• Low tumor burden.
• Responsive disease before transplant.
• Application of transplantation after first-line therapy.

Myeloablative ASCT 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. In one anecdotal series of 60 patients who underwent ASCT, six of the patients relapsed between 6 and 12 years, suggesting that late relapses still occur with this type of consolidation.

The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse. Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of ASCT versus autologous SCT and nonmyeloablative allogeneic SCT in 260 untreated patients showed no difference in PFS or OS.[148][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.[138,149][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 ASCT should be offered in the first-line setting outside the context of a clinical trial.

Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity ASCT 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 ASCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[Level of evidence: 1iiA]

Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation

After relapsing more than 24 months after ASCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage ASCT or oral weekly cyclophosphamide. With a median follow-up of 52 months, the median OS was superior for salvage ASCT: 67 months (95% CI, 55–NE) versus 52 months (42–60); HR, 0.56 (0.35–0.90, P = .017).[Level of evidence: 1iiA]

Lenalidomide maintenance therapy

After ASCT, three randomized, prospective trials showed benefit in median EFS or PFS (40–43 months vs. 21–27 months), one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; P = .03).[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.[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%.[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).[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.

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).[Level of evidence: 1iDiii]

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.[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).[Level of evidence: 1iDiii]

4.A randomized, prospective trial of 1,970 patients compared intravenous zoledronate with oral clodronate in newly diagnosed patients receiving induction chemotherapy with or without consolidation. 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).[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).

5.The improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[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. These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident. 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. The aforementioned randomized trial, showed OS advantage, continued patients on bisphosphonates monthly until time of relapse.

7. A clinical trial of zoledronate given once a month compared with zoledronate given every 12 weeks showed noninferiority for the 12-week regimen in 1,822 patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma. However, this study included only 278 myeloma patients, and evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen.

Radiation therapy for bone lesions

Lytic lesions of the spine generally require radiation 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.

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy.

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

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

There are two main types of refractory myeloma patients:
• Primary refractory patients who never achieve a response and progress while still on induction chemotherapy.
• Secondary refractory patients who do respond to induction chemotherapy but do not respond to treatment after relapse.

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients. When the stable nature of the disease becomes established, these types of patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy. (Refer to the Treatment for Multiple Myeloma section of this summary for more information.)

The myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, for patients who respond to their initial therapy increases progressively with each subsequent relapse, and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally, the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed.

A cellular therapy for refractory myeloma has been introduced that consists of autologous T-cells transduced with an anti-CD19 chimeric antigen receptor (so-called CAR T-cells) after myeloablative chemotherapy and autologous stem cell transplantation, with anecdotal responses. Other molecular targets and expanded clinical approaches are being investigated.[Level of evidence: 3iiiDiv]