Multiple Myeloma and Other Plasma Cell Dyscrasias

Treatment

Exciting advances in the understanding of tumor biology and microenvironment—and their potential interaction—have helped to identify unique targets for rational therapeutic intervention to enhance outcome, which has not improved with conventional chemotherapy over the past 3 decades. Until recently, only 5% to 10% of patients with multiple myeloma lived longer than 10 years, which has now dramatically improved with the introduction of novel therapies; however, cure remains elusive and the outcome for relapsed and refractory patients dismal.

Newly diagnosed patients

Chemotherapy

Dexamethasone/thalidomide Thalidomide(Drug information on thalidomide) has been employed alone and in combination with dexamethasone(Drug information on dexamethasone) as initial therapy in newly diagnosed patients. When employed alone, response (50% reduction in paraprotein) was observed in 36% of patients; when it was used along with dexamethasone, the response rate was higher (72% and 64% in two studies), including a 16% complete response rate in one study.

Thalidomide and dexamethasone is an acceptable induction therapy for newly diagnosed symptomatic myeloma patients. It is superior to vincristine, doxorubicin(Drug information on doxorubicin), and dexamethasone (VAD) chemotherapy as a pretransplant regimen and melphalan(Drug information on melphalan) and prednisone(Drug information on prednisone) (MP) for transplant ineligible patients. Current preferred use of thalidomide would be as a third agent in combination with bortezomib(Drug information on bortezomib) and dexamethasone (VTD) or cyclophosphamide(Drug information on cyclophosphamide), and dexamethasone (CTD) or melphalan and prednisone (MPT). Adequate attention and preventive measures are required for constipation, deep vein thrombosis, bradycardia, and peripheral neuropathy.

TABLE 4Proposed initial treatments for multiple myeloma

Pulse dexamethasone alone as initial therapy no longer is recommended. However, brief therapy with pulse dexamethasone may be warranted under special clinical circumstances (eg, renal failure, hypercalcemia, cord compromise requiring radiation therapy, cytopenia) (Table 4).

MP The combination of melphalan (Alkeran) and prednisone has been used over the past 40 years, and other combinations of multiple alkylating agents have not been found to be superior to MP. Approximately 40% of patients respond to the MP regimen, with a median remission duration of 18 months and an overall median survival of 3 years. The MP regimen should be avoided in patients considered to be transplant candidates. Currently, MP should be combined with a novel agent, such as thalidomide, bortezomib, or lenalidomide, as described below.

MP and thalidomide (MPT) In two large, prospective, randomized trials in patients older than 65, and a third randomized trial in patients over 75 years of age, MPT has been shown to be superior to MP for response rate as well as progression-free and overall survival. Side effects (including constipation, deep vein thrombosis [DVT], and peripheral neuropathy) were more commonly encountered with thalidomide but were found to be manageable. MPT offers a possible alternative for older people who generally are not candidates for high-dose therapy.

MP and Velcade (bortezomib; MPV) Bortezomib is a first-in-class, potent, selective, and reversible small-molecule inhibitor of the proteasome. In a large, international, randomized clinical trial, MPV was shown to be superior to MP for response as well as survival endpoints. MPV induced complete remissions in one-third of the patients, with an overall response rate of 71% and a 2-year overall survival of > 80%. Such high complete responses previously were never seen in this population of patients, where one-third of the patients were over age 75 years. Adverse side effects (eg, peripheral neuropathy, asthenia, fatigue, diarrhea, and constipation) were more frequently encountered on the bortezomib arm. However, the treatment was well tolerated by most patients, with treatment discontinuation due to toxicity noted in only 14% of patients in both arms, and a treatment-related mortality of 1% with MPV (vs 2% in the MP group).

Two large randomized trials support the use of weekly bortezomib to reduce the adverse side effects, especially neuropathy, without compromising efficacy. Furthermore subcutaneous administration of bortezomib has improved the tolerance and reduced toxicity, especially neuropathy, although this approach in combination requires further study.

Rd (lenalidomide, and dexamethasone) Lenalidomide and weekly dexamethasone alone or in combination with clarithromycin(Drug information on clarithromycin) have been shown to be an active induction regimen whether or not the patient is considered for high-dose therapy and stem cell transplantation. Three-year overall survival estimates are approximately 80% in studies to date. Generally, stem cell harvest is recommended after exposure to 4–6 cycles of treatment to avoid compromising stem cell yield. Chemotherapy mobilization or use of plerixafor is recommended.

MPR Lenalidomide can be added to melphalan and prednisone but a dose reduction of melphalan and lenalidomide is required. An international randomized clinical trial has shown that melphalan and prednisone is equivalent to melphalan, prednisone, and lenalidomide given for 9 months, but if it was followed by lenalidomide maintenance, the progression-free survival is improved by almost a year and a half compared with the unmaintained arms.

TABLE 5Other treatment options for multiple myeloma

BD (bortezomib and dexamethasone) Addition of bortezomib to induction regimen has substantially improved the outcome of patients, especially those with adverse genetic risk factors. Randomized phase III trials have shown bortezomib combinations (bortezomib and dexamethasone [VD]; bortezomib, adriamycin, and dexamethasone [PAD]; bortezomib, thalidomide, and dexamethasone [VTD]) to be superior to VAD induction regimen; bortezomib–dexamethasone significantly improved post-induction and posttransplantation complete response and very good partial response rates compared with VAD and resulted in a trend for longer progression-free and overall survival. Bortezomib, lenalidomide, and dexamethasone (RVD) is well tolerated and has the highest overall complete and very good partial response rate of any regimen to date without transplantation in the newly diagnosed setting.

High-dose therapy following induction therapy

Consolidation with high-dose therapy after induction therapy improves the response rate as well as event-free and overall survival, especially in good risk patients. Randomized trials from France and the United Kingdom showed improvement in event-free and overall survival following high-dose therapy compared to conventional chemotherapy alone. Induction with novel agents containing bortezomib and lenalidomide followed by high-dose therapy have further improved the outcome with an expected 3-year survival of about 80%. In a randomized trial reported from Italy, induction with VTD, followed by tandem transplantation, and then consolidation with VTD followed by steroid maintenance, has resulted in a very high complete response rate of 58%, 3-year progression-free survival of 68%, and overall survival of 86%, with clear superiority to thalidomide and dexamethasone (TD) as a comparator. A novel agent induction regimen followed by single transplantation has thus become a new standard of care, with three drugs now generally preferred (eg, RVD or VTD), especially in high-risk patients.

A high-dose alkylating agent, most commonly melphalan at 200 mg/m² with peripheral blood stem cell support, is a standard conditioning regimen. Addition of total-body irradiation (TBI) does not improve the outcome but increases morbidity and results in higher mortality. Interestingly, in a randomized study, Fermand et al have confirmed an equivalent survival benefit between up-front high-dose therapy vs high-dose therapy as a salvage regimen at relapse following initial induction therapy.

Tandem transplants The improved outcome reported after tandem transplants in large cohorts of patients in single-institution studies has not been confirmed. In one mature, randomized study, eleven years after initiation of therapy, there was only a trend in event-free and overall survival in favor of tandem transplants (IFM94). Another randomized trial with a shorter follow-up has confirmed the superior event-free survival (median, 34 vs 25 months) for patients receiving tandem transplants when compared with those given single transplants but not in overall survival. Moreover, the added benefit of the second transplant was not seen in a subset of patients with a complete response or a very good partial response (> 90% paraprotein reduction) after the first transplant in either study. With the advent of novel therapies, the use of tandem transplant has undergone re-evaluation and the need for a second transplant in patients responding to novel agent–based therapy and single transplant appears to have diminished, making this approach less attractive than, for example, a delayed transplant after subsequent relapse.

Radiotherapy

Higher doses of radiotherapy (40–50 Gy) are employed for local control and cure of solitary plasmacytoma involving bone and extramedullary sites. Lower doses (20–30 Gy) may be employed for palliation of local bone pain from tumor infiltration, pathologic fractures, and spinal cord compression. It should be emphasized that excellent pain relief may be obtained by prompt institution of high-dose corticosteroid therapy, especially in newly diagnosed patients.

Radiotherapy should be employed sparingly, as irradiation of multiple sites may impair stem-cell mobilization in patients who are candidates for high-dose therapy. Employment of high doses of radiation to the spine may preclude the subsequent use of TBI as a conditioning regimen for high-dose therapy, although the latter is now rarely used.

Remission maintenance

Maintenance therapy been shown to prolong remission duration after initial treatment with or without high-dose therapy and has become an area of intense clinical research.

Thalidomide

Patients responding to thalidomide and achieving maximal response have received lower-dose thalidomide (50–100 mg) with or without added dexamethasone (40 mg for 4 days every month) as maintenance therapy. In the MPT regimen, continued administration of thalidomide prolonged the duration of remission. Three large randomized trials have shown the prolonged remission and improved survival following thalidomide maintenance therapy after autologous stem cell transplantation, although tolerability of long-term thalidomide use can be a challenge. Upon longer follow-up of one of these trials (IFM 99-02), there was no survival advantage to patients randomized to the thalidomide and pamidronate(Drug information on pamidronate) arm.

Lenalidomide

Typically lenalidomide-dexamethasone induction therapy is followed by continuation of lenalidomide with or without steroids until progression, with discontinuation of steroids preferred with long-term use. Continuation of lenalidomide after MPR regimen has been shown to improve remission duration compared to MP or MPR alone without maintenance (MM-015). In the posttransplantation setting, the French group (IFM 2005-002) and a landmark CALGB study have evaluated the use of lenalidomide as maintenance. All three studies have clearly shown improvement in the progression-free survival by at least 18 months for lenalidomide maintenance compared to placebo. The CALGB trial also demonstrated the benefit in overall survival. There is an increased incidence of second primary malignancy in the lenalidomide maintenance arms in all three studies, with a small effect on the occurrence of various solid tumors and hematological malignancies including myelodysplastic syndrome and acute myeloid leukemia post stem cell transplantation apparent with current follow-up. At the present time, it appears the risk of relapse and dying of myeloma far outweighs the risk of dying from a second primary malignancy. When lenalidomide maintenance is recommended following a melphalan-based regimen, careful observation is recommended and appropriate counseling of the patient should be done regarding these potential risks.

Bortezomib

Bortezomib is currently under study as a maintenance strategy. In the APEX study, bortezomib administered weekly proved efficacious and was well tolerated in responding patients who had successfully completed initial treatment. In another study by the Spanish myeloma group (PETHEMA), following a bortezomib-based induction regimen for patients ineligible for transplantation, maintenance with bortezomib–thalidomide was shown to be superior to bortezomib–prednisone.

Interferon-α

Twenty-four randomized trials have investigated interferon-α as maintenance therapy and neither consistent nor significant benefits have been seen. A large Intergroup trial also reported no benefit of interferon maintenance therapy after conventional therapy and autotransplantation. Side effects, including fatigue and depression, have limited the utility for this approach.

Alkylating agents

Maintenance therapy with alkylating agents has not prolonged survival when compared with no therapy and this approach is no longer recommended.

Steroids for maintenance

Two large, randomized trials have shown that glucocorticoid maintenance prolongs the duration of remission and improves life expectancy although side effects are a concern, particularly with long-term use. The SWOG study used prednisone (50 mg) every other day, whereas the maintenance regimen in the NCI Canada trial contained dexamethasone (40 mg) daily for 4 days every 4 weeks.

Relapsed, and relapsed and refractory disease

The majority of patients progress after initial remission, which usually lasts between 18 months and 5 years. Rapid progress is being made in the management of relapsed disease and many new drugs are being introduced in a succession of promising clinical trials.

Conventional chemotherapy

Alkylating agents, alone or in combination, have been effective in approximately one-third of patients with VAD-refractory disease. Patients relapsing after novel agents often have responded to alkylating agent therapy, especially in combination with novel agents. Patients presenting with high LDH and soft tissue plasmacytoma may respond to combination chemotherapy with cyclophosphamide, etoposide(Drug information on etoposide), cisplatin(Drug information on cisplatin), and dexamethasone (DCEP) with or without doxorubicin, bortezomib, or thalidomide (VDT-PACE). Although this regimen is active, prolonged use is limited by side effects.

High-dose chemotherapy

High-dose melphalan and stem cell rescue should be offered to patients who have deferred the transplant initially. A randomized trial performed in the pre-novel therapy era on early vs late transplantation has shown that an equivalent survival is conferred on patients undergoing salvage, compared with early transplantation.

Novel agents

Thalidomide

Thalidomide has an established role in therapy for refractory/relapsed multiple myeloma, with 30% of patients achieving at least 50% reduction in paraprotein levels. Remissions obtained in responding patients are usually durable. In a large cohort of patients with multiple myeloma receiving thalidomide, 2-year event-free survival rates of ~25% have been observed. Initially, thalidomide was employed in a dose-escalating schedule, starting at 200 mg and achieving a maximal dose of 800 mg. Recently, lower doses have been employed in combination with steroids as well as with other agents and have proved more effective (Table 4).

Lenalidomide

Lenalidomide has greater potency than thalidomide in preclinical studies and is better tolerated, with less neurotoxicity, somnolence, and constipation in clinical trials.

Two large, multicenter, phase III trials of lenalidomide (25 mg daily for 3 weeks with 1 week off) combined with dexamethasone compared with dexamethasone and placebo in patients with relapsed multiple myeloma have been performed. In the US study, there was significant improvement in response rate (partial response, 59% vs 21%, respectively) and time to disease progression (11.1 vs 4.7 months, respectively) in the cohort receiving the lenalidomide combination; the results of the second study from Europe were almost identical. Similar responses were seen in patients relapsing after prior bortezomib or thalidomide exposure. Prophylaxis against DVT and monitoring for myelosuppression are recommended based on the side effects seen, but lenalidomide is generally well tolerated.

Proteasome inhibitors

A large, multi-institution, phase II trial of the proteasome inhibitor bortezomib (given IV at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days) demonstrated remarkable activity in a heavily treated population of patients with relapsed and refractory multiple myeloma, including patients relapsing after transplantation or not responding to thalidomide, with durable responses noted in about 35% (with 10% complete response). Side effects related to the drug were predominantly gastrointestinal (GI) in nature, with neuropathy, fatigue, and reversible cytopenias also noted. Toxicities were generally manageable with supportive care and dose reduction. Patients who did not respond to bortezomib monotherapy (progressive disease after 2 cycles or stable disease after the first 4 cycles) were permitted to receive combination bortezomib and dexamethasone. Combination therapy induced additional responses in 18% of patients.

The large, randomized, phase III APEX trial of bortezomib monotherapy compared with high-dose dexamethasone enrolled 669 patients with relapsed multiple myeloma. This trial showed significant improvement in the median time to disease progression (6.5 vs 3.6 months, respectively; P < .0001) and median overall survival (29.8 vs 23.7 months, respectively; P = .027). Response rates to bortezomib as a single agent were impressive at 43%. The most commonly reported adverse events for bortezomib were neuropathy, GI events, fatigue, pyrexia, and thrombocytopenia; for high-dose dexamethasone, they included fatigue, insomnia, and anemia. Neuropathy was the most important issue with bortezomib, but it proved generally manageable with dose reduction and schedule change. DVT was very rare, and efficacy in patients with significant renal dysfunction was noted. Finally, encouraging responses were noted in patients with adverse cytogenetics as well as in patients with advanced bone disease.

Bortezomib has synergistic activity when combined with pegylated liposomal doxorubicin, thalidomide, melphalan, and lenalidomide, with impressive disease control shown in refractory myeloma. In a randomized, phase III, multicenter, international study in patients with relapsed/refractory myeloma, the combination of bortezomib (1.3 mg/m² on days 1, 4, 8, and 11) and pegylated liposomal doxorubicin (30 mg/m² on day 4) was reported to be superior to bortezomib alone in terms of both overall response (50% vs 42%, respectively; P = .05) and time to disease progression (9.3 months vs 6.5 months, respectively; P < .0001). When bortezomib (1.0 or 1.3 mg/m²) was administered with thalidomide (in doses ranging from 50 to 200 mg starting at cycle 2), 86% of patients with relapsed or refractory disease achieved a complete or partial response. A phase II study combining bortezomib with lenalidomide and dexamethasone (RVD) has also shown promising activity with relatively minimal toxicity.

Promising drugs currently in clinical trials

Pomalidomide (CC 4047) is a new immunomodulatory molecule that has shown activity in patients with relapsed and refractory myeloma. In a phase II trial of 60 patients on pomalidomide and low-dose dexamethasone, complete response was noted in 5% of patients, very good partial responses in 28% of patients, and partial responses in 30% of the patients. Responses were noted in patients with tumors refractory to thalidomide or lenalidomide, and/or bortezomib.

Carfilzomib is a new proteasome inhibitor that does not seem to have significant neurotoxicity. This drug has also been shown to be effective in the treatment of relapsed multiple myeloma as a single agent and in clinical trials with other agents.

Several histone deacetylase inhibitors are currently in phase III clinical trials in multiple myeloma. Both vorinostat (Zolinza) and panobinostat (LBH589) have shown minimal single-agent activity. However, they have been shown to have synergistic activity when combined with bortezomib or lenalidomide. Other small molecules under study include the orally bioavailable agent, perifosine, which targets AKT, JNK, and NFKB. Combinations with bortezomib and lenalidomide have shown encouraging results, and a phase III trial is now underway. Finally, monoclonal antibodies are now becoming an area of active research with one particular example, elotuzomab, which targets CS1, showing great promise in combination with lenalidomide. Comparative studies have begun, with combination trials planned in newly diagnosed multiple myeloma.

Allogeneic stem cell transplantation

For younger patients with resistant relapse or poor-prognosis disease (eg, with deletion of chromosome 13), allogeneic transplantation may be an important option. The role of allogeneic transplant in myeloma should still be considered investigational. High-dose myeloablative therapy with allogeneic stem cell rescue has been abandoned in light of high transplant-related mortality. A nonmyeloablative regimen is ineffective in tumor cytoreduction and, consequently, is related to a high relapse rate. Thus, uniquely in multiple myeloma, high-dose melphalan and stem cell transplant is followed by a nonmyeloablative regimen and allogeneic stem cell transplantation. Two large, randomized trials from France and Italy that compared tandem autologous transplantation with autologous transplantation followed by allogeneic transplantation from matched sibling donors had different outcomes. French investigators noted no improvement in progression-free or overall survival when inclusion criteria were restricted to a high-risk group, whereas Italian investigators noted better event-free and overall survival when no such restriction for patient entry to the study was in place. In addition, chronic graft-vs-host disease inflicts considerable morbidity in excess of 50% of patients post-allograft. Currently, use of allogeneic stem cell transplantation is only recommended in the context of a clinical trial.

Supportive therapy

Various supportive therapies may be beneficial in patients with multiple myeloma (Table 6).

TABLE 6Supportive therapies for multiple myeloma

Chronic anemia

The use of erythropoietic-stimulating agents (ESAs) in myeloma should generally be restricted to patients who are anemic due to concomitant chemotherapy or moderate-to-severe renal failure. The combined use of ESAs and immunomodulatory agents is associated with an increased incidence of venous thromboembolism, but this is not seen with bortezomib. For additional information about the use of ESAs in patients with cancer, visit the US Food and Drug Administration's (FDA) information page on ESAs.

Infection

Serious infection with encapsulated organisms is encountered by patients with myeloma due to their inability to mount successful antibody production (and lack of opsonization). Prompt institution of antibiotics is therefore recommended in the face of systemic infection. Antibiotic prophylaxis is also recommended whenever high-dose glucocorticoids are used for treatment. Patients with recurrent serious infections may benefit from monthly intravenous gamma globulin. Shingles is not uncommon in myeloma patients, and prophylaxis following transplantation and during bortezomib therapy is advised with appropriate antiviral therapy.

Bone pain or imminent fracture

Therapy with bisphosphonates, such as pamidronate or zoledronic acid(Drug information on zoledronic acid), have been shown to reduce skeletal-related events and improve quality of life for patients with multiple myeloma. Bisphosphonates reduce skeletal-related events including bone pain, hypercalcemia, lytic bone disease, and compression fractures. There is reduction in the skeletal-related events within the first year of starting therapy, even in patients presenting with no lytic bone disease. A recent large randomized trial from the Medical Research Council in the UK of newly diagnosed symptomatic myeloma patients has shown continuous therapy with zoledronic acid until progression improves progression-free and overall survival. The risk of osteonecrosis of the jaw was 3% to 5% in this study, and there was no increased incidence of renal impairment.

Zoledronic acid, the more potent amino-bisphosphonate, has comparable efficacy and safety to pamidronate in preventing skeletal lesions. The ease of administration of a 4-mg dose, which reduces the infusion time to 15 to 30 minutes compared with 2 hours for pamidronate, has led to approval of zoledronic acid by the FDA for prevention of bone-related complications in myeloma. Caution should be exercised with long-term use of bisphosphonates, as renal impairment and osteonecrosis of the jaw bones have been reported, as previously mentioned.

Percutaneous vertebroplasty provides pain relief that is not only rapid but sustained, and it also strengthens the vertebral bodies. Kyphoplasty is a safer procedure that involves insertion of a balloon followed by injection of polymethyl methacrylate, the principal component of bone cement, into the balloon. It is performed with the patient under local anesthesia. Transient worsening of pain and fever that may occur is responsive to nonsteroidal anti-inflammatory agents.

Smoldering myeloma

Smoldering, or asymptomatic, myeloma is characterized by the presence of monoclonal Ig > 3 g/dL and/or bone marrow plasmacytosis in excess of 10%. The diagnosis is often made by a chance finding of an elevated serum protein level during a screening examination.

Laboratory features

Features of low tumor mass are usually present, without renal disease, hypercalcemia, or lytic bone lesions (Table 2). Marrow plasma cytosis occurs in less than 30% of patients, and anemia, if present, is mild (hemoglobin value > 10.5 g/dL).

Treatment

Systemic therapy should be withheld until the patient becomes symptomatic. The role of bisphosphonates and lenalidomide in this setting is under investigation, although a series of studies have suggested benefit from reducing the incidence of bone complications and increasing the time to progression with bisphosphonate use. An MRI finding of multifocal plasmacytomas or FDG-PET/CT findings of multifocal osseous lesions would be considered to be evidence of end-organ damage, and should warrant initiation of additional therapy.

Prognostic factors

Smoldering myeloma generally progresses to multiple myeloma at the rate of 10% per year for the first 5 years, 3% per year for the next 5 years, and then 1% for the last 10 years. The initial concentration of serum monoclonal protein > 3.0 g/dL, bone marrow plasmacytosis > 10%, and abnormal serum free light-chain ratio are significant predictors of progression to symptomatic myeloma.