Lenalidomide in multiple myeloma

Best Practice & Research Clinical Haematology Vol. 20, No. 4, pp. 717–735, 2007 doi:10.1016/j.beha.2007.09.002 available online at http://www.sciencedirect.com

9 Lenalidomide in multiple myeloma Sheeba K. Thomas

MD

Assistant Professor

Tiffany A. Richards

MS, ANP, AOCNP

Nurse Practitioner

Donna M. Weber *

MD

Associate Professor The University of Texas M.D. Anderson Cancer Center, Department of Lymphoma and Myeloma, 1515 Holcombe BLVD, Box 429, Houston, TX 77030, USA

For many years the treatment of multiple myeloma was limited to such regimens as melphalan– prednisone, high-dose dexamethasone, and vincristine–doxorubicin–dexamethasone (VAD). These combinations provided response rates of 45–55%, with complete remission rates of up to 10%. With the advent of thalidomide- and bortezomib-based combinations, response rates to induction therapy have risen to 85–95% in previously untreated patients and are associated with complete remission rates up to 25%. However, these agents are associated with such sideeffects as somnolence, constipation and neuropathy. Lenalidomide, a thalidomide analog, was developed with the hope of improving both the efficacy and toxicity profile of thalidomide, and has subsequently shown significant clinical activity in patients with multiple myeloma. We describe the role of lenalidomide in patients with symptomatic multiple myeloma that is newly diagnosed, relapsed and/or refractory to other therapies, or concurrent with primary amyloidosis. Key words: lenalidomide; myeloma; dexamethasone; immunomodulatory agents; thalidomide.

Multiple myeloma is a malignancy characterized by a proliferation of clonal plasma cells that usually produce a monoclonal protein. Prior to 1998, dexamethasone, melphalan–prednisone, VAD (vincristine, Adriamycin, dexamethasone), and other similar anthracycline–akylating agent–steroid combinations were the mainstays of therapy for patients with this disorder.1–4 Overall response rates after treatment with single-agent dexamethasone, or combination chemotherapy (CCT) such as VAD, ranged from 45%

* Corresponding author. Tel.: þ1 713 792 2860; Fax: þ1 713 563 5067. E-mail address: [email protected] (D.M. Weber). 1521-6926/$ - see front matter ª 2007 Published by Elsevier Ltd.

718 S. K. Thomas et al

to 65% in chemotherapy-na€ıve patients, and from 25% to 45% in previously treated patients; complete response (CR) was seen in only approximately 10% of patients treated with CCT alone.1–3 Although high-dose chemotherapy supported by autologous stemcell transplantation (AuSCT) leads to responses in 60% of patients with disease previously unresponsive to CCT, and improves CR rates to 35%, nearly all patients eventually relapse and become resistant to therapy.5,6 Since 1998, the introduction of thalidomide and bortezomib has resulted in new effective treatment options for patients with myeloma. Combinations of these novel agents with alkylating agents, anthracyclines, and steroids have improved overall response rates to 45–65% in resistant or relapsing patients, and 85–95% in previously untreated patients with multiple myeloma.7–24 Complete remission has also been achieved in up to 25% of patients without the addition of AuSCT.14,16–18,22,25,26 Although thalidomide and bortezomib have provided exciting new avenues of treatment for myeloma, side-effects including fatigue, neuropathy, constipation, and thrombotic events have been somewhat troublesome.7,27–33 In an effort to improve the toxicity profile of thalidomide while maintaining or surpassing the efficacy of the drug, the immunomodulatory derivative (IMiD) lenalidomide was developed. Lenalidomide has demonstrated significant clinical activity in both previously treated and newly diagnosed patients with myeloma, as well as in patients with primary systemic amyloidosis.34–45 MECHANISM OF ACTION OF LENALIDOMIDE Lenalidomide is a structural analogue of thalidomide which differs from the parent drug by the addition of an amino group to the fourth carbon of the phthaloyl ring.46 In vitro, the drug is up to 50,000 times more potent than thalidomide in inhibiting the production of tumor necrosis factor a (TNF-a) by stimulated peripheralblood mononuclear cells.46 Other in vitro studies indicated that factors such as anti-angiogenic properties, modulation of host immunity, and apoptosis are likely to play a role in the clinical activity of lenalidomide, but the precise mechanism of action of the drug remains unclear.47 Lenalidomide also has a direct cytotoxic effect on myeloma cell lines. G0/G1 growth arrest appears to be related in part to activation of caspase-8 and down-regulation of anti-apoptotic proteins such as the cellular inhibitor of apoptosis protein 2 (cIAP2) and FLICE inhibitory protein (FLIP).48,49 Inhibition of lipopolysaccharide-mediated induction of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE-2) synthesis may also play a role in the drug’s activity.50 Nuclear factor-kB (NF-kB) is an important regulator of cytokine production, myeloma cell adhesion and anti-apoptosis.51,52 Lenalidomide, and other immunomodulatory drugs, inhibit and down-regulate NF-kB, which may interfere with cytokine-stimulated growth of malignant plasma cells and subsequent adhesion to bone-marrow stromal cells.48 A key regulator of myeloma cell growth and survival is interleukin 6 (IL-6).53 Compared with bone-marrow stromal cells (BMSCs) from patients without myeloma, BMSCs of patients with multiple myeloma release increased levels of IL-6, as well as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are integral to angiogenesis.53 Lenalidomide decreases release of these factors in vitro, resulting in growth inhibition of myeloma cell lines and decreased microvessel density in animal models.53–55 No correlation between clinical response to the parent compound, thalidomide, and a decrease in marrow angiogenesis has been observed, making the role of angiogenesis-mediated activity of the IMiDs unclear.56 Lenalidomide also induces production of IL-2 and interferon g (IFN-g) from cytotoxic T lymphocytes (CTLs).57 It is 50–20,000 times more

Lenalidomide in MM 719

potent than its parent compound in stimulating T-cell proliferation, and 50–100 times more potent in increasing secretion of IL-2 and IFN-g from T cells.47 Increased levels of IL-2 promote natural killer (NK) cell and antibody-dependent cytotoxicity, inducing lysis of multiple myeloma cells in vitro.47 Rational combinations of lenalidomide with other drugs have been predicted by in vitro studies.47 Dexamethasone induces caspase-9 activity, and in combination with lenalidomide, which is known to activate caspase-8, additive, and perhaps synergistic, activity has been observed in myeloma cell lines.49 Similarly, bortezomib and lenalidomide target different pathways and have demonstrated at least additive activity in vitro.47,58,59 The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, may overcome drug resistance when combined with lenalidomide in myeloma cell lines, suggesting a rationale for exploring this combination in future clinical trials.60 TOXICITY PROFILE The toxicity of lenalidomide seems to differ somewhat from that of thalidomide. Since the teratogenic potential of lenalidomide is unknown in humans, precautions must be taken to avoid pregnancy in patients taking lenalidomide and in their partners.61 All patients treated in the United States must be registered on the RevAssist program before lenalidomide can be prescribed and dispensed. Women of childbearing potential (premenopausal and <2 years postmenopausal) must take a pregnancy test, use two effective forms of birth control, and have repeated pregnancy tests every 4 weeks for the duration of treatment with lenalidomide. Men receiving lenalidomide must either abstain from sex or use a latex condom.61 The most frequent side-effect of lenalidomide is myelosuppression. Among patients with refractory or relapsing myeloma, grade 3–4 myelosuppression has ranged from 38–69%, with rates of only 12–21% described in previously untreated patients with this disease.34,36,38–40,43,45 Grade 3–4 neutropenia is noted most frequently in previously treated patients (16.5–69%), but is seen in only 12% of previously untreated patients.34,38,39,43,45,47 Significant (grade 3–4) thrombocytopenia is noted less frequently; it is seen in up to 31–43% of previously treated patients, and is rarely encountered in previously untreated patients.34,38–40,43,45 Neuropathy (grade 3–4) occurs in less than 10% or patients, which is significantly lower than that seen with thalidomide.34,39,43 The impact of daily dosing of lenalidomide was evident in a phase-II study of 102 patients with relapsed, refractory myeloma in which 23% of those who received lenalidomide in a twice-daily dosing schedule (15 mg orally b.i.d.) developed grade 3–4 neuropathy, compared with only 10% of those who received once-daily dosing (30 mg orally daily); myelosuppression was also noted more frequently in patients who received two daily doses, emphasizing the importance of a single daily dose to minimize the toxicity of lenalidomide.38 In the same phase-II study of 102 patients, no patients developed thromboembolic complications when lenalidomide was given as monotherapy. However, among 68 patients in whom dexamethasone therapy was later added, three developed thromboembolic events.38 In the subsequent pivotal phase-III studies (North American and International trials) of lenalidomide–dexamethasone (L–D) versus placebo–dexamethasone (P–D) in patients with relapsed or refractory myeloma, rates of deep vein thrombosis (DVT) were 15% and 8.5% with L–D, respectively for each trial, compared to 3.5% and 4.5% (respectively) with P–D.39,43 Concurrent use of erythropoietin or darbepoetin in these trials was associated with a higher incidence of thromboembolic events.62 In

720 S. K. Thomas et al

contrast, the rate of thrombosis was only 3% in a study of 34 previously untreated patients given aspirin prophylaxis during treatment with L–D.34 Similarly, in a retrospective analysis of 50 patients treated with lenalidomide–melphalan–prednisone (R-MP), who also received aspirin prophylaxis (100 mg daily), only one patient developed a thromboembolic event (2.1%).63 However, in a Southwest Oncology Group (SWOG) study that randomized patients to receive either L–D or P–D, 9/12 patients (75%) treated with L– D had thromboembolic events whereas no patient treated with P–D had an event.64 Subsequently, aspirin prophylaxis (325 mg) reduced the incidence of thromboembolic events, but these still remained high at 19%, suggesting the need to further explore optimal thromboembolic prophylaxis for most patients treated with L–D.65 Preliminary results of patients treated with aspirin prophylaxis and lenalidomide in combination with either low-dose (40 mg once weekly) or high-dose dexamethasone (40 mg/day on days 1–4, 9–12, 17–20) indicate a lower incidence of thromboembolic events with low-dose dexamethasone (22.1 versus 6.1%), suggesting that the potential for these events may be related to the dexamethasone schedule. The need for aspirin prophylaxis for patients treated with the low-dose schedule should be investigated further.66 Recently, the first case report of Coomb’s positive autoimmune hemolytic anemia due to lenalidomide was published, but this appears to be a rare complication.67 Additionally, a variety of rashes (morbilliform, acneiform, urticarial, etc) have been described in approximately 30% of myeloma patients treated with lenalidomide.68 The incidence of rash was considerably higher in patients treated for amyloidosis (43%), although the reason for this difference remains unclear.68 PHARMACOKINETICS Lenalidomide has been shown to reach its maximum concentration at a median of 1–1.5 hours after administration at various dose levels.45 Maximum plasma concentrations (Cmax) decline within 1–8 hours after dose administration in a monophasic pattern. The half-life of lenalidomide is 3–4 hours, with a mean accumulation ratio in plasma of 0.7 to 1, and an area under the curve (AUC) and Cmax of 0.8–1.2 on day 28 compared with day 1. Low to moderate inter-subject variability for (AUC) and Cmax has been noted, as demonstrated by a range of 10.6–51.8% and 3–33% respectively.45 In healthy volunteers, the time to maximum concentration (Tmax) occurred within 35–90 minutes and food did not impair absorption of the drug.69 Lenalidomide appears to be excreted, renally with two thirds of the drug excreted unchanged in the urine. Accordingly, patients with a creatinine >2.5 mg/dL have been excluded from clinical trials.69 In the phase-III trials, patients with impaired kidney function developed more thrombocytopenia than those with normal kidney function.44 This may be related to the 56% greater AUC found in those patients with mild renal impairment compared to those with normal renal function. In patients with impaired hepatic function, pharmacokinetics have not been evaluated. In vitro, lenalidomide does not interfere with CYP450 or warfarin metabolism.69 RELAPSED/REFRACTORY MYELOMA Single agent studies (see Table 1) In a phase-I study by Richardson et al (24 patients), lenalidomide was evaluated in dose levels of 5–50 mg per day.45 The overall response rate (ORR) was 29%, with

Table 1. Single-agent lenalidomide for refractory/relapsing myeloma. Author Richardson et al45

Zangari et al40

Richardson et al38 Richardson et al37 Zangari et al86

Oral dose

Evaluable patients (n)

PR (%)

L 5 mg/d  28 d L 10 mg/d  28 d L 25 mg/d  28 d L 50 mg/d  28 d L 5 mg/d  28 d L 10 mg/d  28 d L 25 mg/d  28 d L 50 mg/d  28 d L 15 mg b.i.d.  21 d, q 28 d versus L 30 mg/d  21 d, q 28 d L 30 mg  21 d, q 28 d L 25 mg  20 d, q 28 d L 50 mg  10 d, q 28 d

3 5 3 13 3 3 3 6 35 67 212 NA

33 20 0 38 0 0 20a 14 12 25a 40 15

CR (%)

0 0 0 0 0 6

EFS/PFS/TTP (median months)

OS (median, months)

% DVT

DVT prophylaxis

NA

NA

0

None

NA

NA

7

None

PFS 2.8 PFS 3 TTP 22.4 weeks EFS 30%a

27 28 NA 61

6 2 0 0

None None None

Lenalidomide in MM 721

PR, partial response; CR, complete response; EFS, event-free survival; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DVT, deep vein thrombosis; L, lenalidomide; NA, not available. a Response for both the 25-mg and 50-mg levels were combined.

722 S. K. Thomas et al

most responses seen at the 25- and 50-mg dose levels. The median time to response was rapid at 2 months, and the median duration of response was 6 months. Based on this study, a maximum tolerated dose (MTD) of 25 mg was defined. These results were confirmed in a second phase-I study by Zangari et al, where a partial response rate of 20% was observed.40 A subsequent phase-II study of 102 patients evaluated a regimen of lenalidomide 30 mg daily, given in either single or divided doses.38 Because patients given doses of 15 mg twice daily had more grade 3–4 myelosuppression and neuropathy, this arm was subsequently closed prematurely. The ORR with lenalidomide monotherapy was 17%. However, an additional 29% of patients achieved an objective response after the addition of dexamethasone 40 mg daily for 4 of every 14 days. The median overall survival (OS) of all enrolled patients was 27 months, and median progression-free survival (PFS) was 4.6 months. These initial studies provided the dose and schedule framework for later trials examining lenalidomide in combination with other effective agents.38 In a second phase-II study, 222 patients received 25 mg of lenalidomide once daily on days 1–21 of a 28-day cycle. The ORR was 25%, with a median time to progression (TTP) of 22.4 weeks.37 Because of sustained response rates and good tolerance, a final dosing regimen of 25 mg by mouth once daily for 21 days of a 28-day cycle is now considered standard. These promising results and in-vitro synergy of lenalidomide with other agents including dexamethasone, bortezomib, polyethylene glycolated (PEGylated) doxorubicin, and melphalan have led to multiple studies of lenalidomide-based combination therapy. Combination studies (see Tables 2 and 3) Two phase-III randomized double-blind placebo-controlled trials of lenalidomide– dexamethasone versus placebo were completed in North America (MM-009) and internationally (MM-010) (Europe, Israel, Australia)39,43; 705 patients with relapsed or refractory myeloma received dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 every 28 days, plus either lenalidomide 25 mg orally on days 1–21 of 28-day cycles or an identical placebo.39,43 Beginning with cycle 5, dexamethasone was reduced to 40 mg daily on days 1–4 only. The overall response rates (ORR) were significantly higher for L–D at 61% (MM-009) and 59% (MM-010), respectively, compared with P–D (21% and 24%, P < 0.001). Median TTP was also significantly longer for patients treated with L–D (11.1 and 11.3 months versus 4.7 and 4.7 months respectively, P < 0.001). In MM-009, the median OS for L–D was 29.6 months compared to 20.5 months in the P–D arm (P < 0.001). Similar results were noted in the MM-010 trial where median OS was not estimable for patients given L–D, and was 20.6 months for patients treated with P–D alone (P < 0.001).43,44 Among patients who had received prior thalidomide, the response rate was lower in those patients who had been resistant to thalidomide (43%) compared with those who were still sensitive to thalidomide (63%).70 L–D was generally well tolerated, although grade 3–4 neutropenia occurred more commonly in patients treated with L–D (16.5 and 24.0% versus 1.2 and 3.5%), as did infections.39 Thrombosis also occurred more frequently in the L–D arm than with P–D: 15% (MM009) and 8.5%(MM-010) versus 3.5(MM-009) and 4.5%(MM-010).39 In subgroup analysis, the incidence of DVT and neuropathy was higher in those who had previously received thalidomide than in those who were thalidomide-na€ıve.70 In patients with impaired renal function, L–D was also superior to P– D in terms of response, TTP, and OS, but grade 3–4 thrombocytopenia was noted

Table 2. Lenalidomide combinations for relapsing/refractory myeloma. Author

Regimen acromyn

Dose

Weber et al44

Len/Dex

L 25 mg/d  21 d D 40 mg/d d 1e4, 9e12, 17e20 (cycles 1e4; >5 cycles  4 d only); repeat every 28 d

354

46

13

TTP 11

NR

Dimopoulos et al43 Knop et al71

Len/Dex RAd

351 31

58 45

3

TTP 13 NA

NR NA

8.5 0

None None

Baz et al72

DVd- R

Same as above L 15 mg/d PO  21 d Do 9 mg/m2/d  4 d CI D 40 mg/d p.o. d 1e4,17e20 PLD 40 mg/m2 i.v. d 1 V 2 mg i.v. d 1 D 40 mg/d  4 d L 10 mg/d  21 d Cycle 1:35 d, cycle 2e5: q 28 d Cy 500 mg p.o. d 1, 8, 15, 21 L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1e4, 12e15 Repeat q 28 d

52

46

29

NA

NA

9

ASA 81 mg/d p.o.

17

65

6

NA

NA

11

Morgan et al75

CRd

Evaluable PR (%) CR (%) PFS/TTP OS (median, % DVT DVT prophylaxis patients (n) (median, months) months) 15

None

PR, partial response; CR, complete response; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DVT, deep vein thrombosis; Len/Dex, lenalidomide/dexamethasone; L, lenalidomide; D, dexamethasone; NR, not reached; Do, doxorubicin; NA, not available; PLD, PEGylated liposomal doxorubicin; V, vincristine; Cy, cyclophosphamide.

Lenalidomide in MM 723

1 patient received prophylactic anticoagulation

724 S. K. Thomas et al

Table 3. Lenalidomide combinations without steroids in relapsed/refractory multiple myeloma. Author

Regimen

Dose

Richardson Len-Bor L 5e15 mg/d et al76 p.o.  14 d B 1e1.3 mg/m2 i.v. d 1, 4, 8, 11 D 40 mg/d p.o. d 1, 2, 4, 5, 8, 9, 11, 12 (added for PD) Repeat q 21 d

Evaluable PR CR EFS/PFS/TTP OS DVT DVT patients (%) (%) (median, (median, (%) prophylaxis (n) months) months) 38

34

3

NA

NA

4

None

PR, partial response; CR, complete response; EFS, event-free survival; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DVT, deep vein thrombosis; L, lenalidomide; B, bortezomib; D, dexamethasone; PD, progressive disease; NA, not available.

more frequently (creatinine clearance (CrCl)  50 mL/min, 13.8%; CrCl > 50 mL/min, 4.6%).44 Neutropenia was not increased in the setting of renal insufficiency.44 In vitro, doxorubicin has shown synergy with L–D, and Knop et al combined these agents (RAd) in a phase-I dose-escalation study of patients exposed to at least three prior lines of therapy.49,71 The MTD of RAd was reached at a lenalidomide dose of 25 mg p.o. on days 1–21, doxorubicin 9 mg/m2 i.v. on days 1–4, and dexamethasone 40 mg p.o. on days 1–4, 9–12, and 17–20. Among 26 evaluable patients, partial response (PR) was achieved in 84%, and CR was achieved in 3%. One patient each experienced neutropenia, renal failure, catheter-related infection, and pneumocystis pneumonia.71 Similarly, Baz et al evaluated a regimen of lenalidomide, liposomal doxorubicin, vincristine, and dexamethasone (DVd-R).72 In this phase-I/II study, 62 evaluable patients received liposomal doxorubicin 40 mg/m2 i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1–4 (DVd), and lenalidomide p.o. on days 1–21, in 28-day cycles. All patients received aspirin 81 mg daily, amoxicillin 250 mg b.i.d., and acyclovir 400 mg b.i.d. for prophylaxis of thrombosis and infections, respectively. The MTD of lenalidomide was reached at a dose of 10 mg in this regimen; nonneutropenic sepsis was the dose-limiting toxicity. A PR rate of 60% was achieved, and 15% of patients attained CR. The median PFS was 12 months, and median OS had not been reached at the time of publication. Grade 3 or 4 neutropenia occurred in 32% of patients, but febrile neutropenia occurred in only 7%. Thromboembolic events still occurred in 9% of these patients who received concomitant aspirin therapy.73 These studies, with response rates of 60–84%, confirm the benefit of lenalidomide combination therapy, particularly with anthracyclines.71,72 Based on the success of thalidomide–cyclophosphamide–dexamethasone (Thal/Cy/ Dex) in previously treated patients with myeloma, cyclophosphamide, has also been combined with L–D (CRD).74 In patients treated with a median of four prior lines of therapy, a regimen of cyclophosphamide 500 mg p.o. on days 1, 8, 15, and 21, lenalidomide 25 mg p.o. on days 1–21, and dexamethasone 40 mg p.o. on days 1–4 and 12–15 was given on a 28-day cycle for a maximum of six cycles.75 Prophylactic acyclovir, trimethoprim–sulfamethoxazole, and proton pump inhibitors were given to all patients. Among 17 evaluable patients, 65% of patients achieved PR and 6% achieved

Lenalidomide in MM 725

CR. Granulocyte-specific colony-stimulating factor (G-CSF) was given to 67% of patients to maintain their neutrophil count. Neutropenic fever was seen in 22% of patients, and DVT occurred in 11%.75 Additional studies are currently under way evaluating cyclophosphamide at a reduced frequency of days 1 and 15. Finally, the toxicity associated with high-dose dexamethasone has prompted evaluation of steroid-sparing regimens. In a phase-I/II study of 36 patients treated with lenalidomide and bortezomib, the MTD was reached at a schedule of lenalidomide 15 mg on days 1–14 and bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 on a 21-day cycle.76 In patients developing progressive disease, dexamethasone 40 mg was added on the day of, and the day after, each bortezomib dose. Initially response rates (PR þ CR) were encouraging, with an ORR of 77%.77 However, as more dose levels were explored, response rates decreased.76 Including all dose levels, the PR rate was 36% and CR occurred in 3% of patients. Toxicities observed included transient hyponatremia, herpes zoster reactivation, grade-4 neutropenia, and DVT. No fatigue or peripheral neuropathy  grade 3 was observed.76 It is not clear how dexamethasone impacted response rates in those patients who had progressive disease; however, studies of the combination are under way in both relapsing/refractory and previously untreated patients. Somewhat paradoxically, it appears that the response rates were higher in the lowerdose cohorts compared to the response seen at the higher dose levels. PREVIOUSLY UNTREATED MYELOMA (SEE TABLE 4) Given the high response rate and improvements in TTP and OS in patients with relapsing or refractory myeloma treated with single-agent and combination lenalidomide therapy, many investigators have begun to evaluate the efficacy of lenalidomide in newly diagnosed patients with multiple myeloma. In a phase-II study of 34 patients, lenalidomide 25 mg p.o. on days 1–21 was combined with dexamethasone 40 mg on days 1–4, 9–12, and 17–20 of each 28-day cycle.34 All patients received aspirin (81 mg or 325 mg daily) as prophylaxis against DVT. Adequate numbers of stem cells were collected from all patients proceeding to autologous stem-cell transplantation. More recently, these data were updated and showed an overall response rate of 91% and complete remission rate of 18%.36 Median TTP, PFS, and OS had not been reached at the time of publication, but 2-year PFS and OS rates were 74% and 91%, respectively. The most common non-hematologic grade 3–4 side-effects seen were fatigue (21%), neutropenia (21%), anxiety (6%), pneumonitis (6%), muscle weakness (6%), and rash (6%). Only 3% of this group of patients treated with aspirin prophylaxis had a thromboembolic event.34,36 This response rate of >90% in previously untreated patients with an oral regimen for myeloma is unprecedented; given the low degree of toxicity, particularly notable for the relative absence of significant neurotoxicity, this regimen (if confirmed) appears ideal for the treatment of newly diagnosed, symptomatic myeloma. In an effort to improve the tolerability and adverse event profile of L–D, a phase-III trial of 445 patients was conducted to evaluate a regimen of lenalidomide 25 mg/d for 21 days with either ‘high-dose’dexamethasone (40 mg/d on days 1–4, 9–12, 17–20) or ‘low-dose’ dexamethasone (40 mg/d once weekly).66 At the time of publication response rates were unavailable, but survival at 1 year was significantly higher in patients who received low-dose dexamethasone (96.5%) compared with counterparts who received high-dose dexamethasone (86%) and lenalidomide. As might be expected, a higher incidence of  grade-4 non-hematologic toxicity was observed in the high-dose dexamethasone

Author

Rajkumar et al34

Regimen

LeneDex

Lacy et al36

Rajkumar et al66

LeneDex (high dose)

(low dose)

Palumbo et al63

R-MP

Roy et al80

R-MP

Niesvizky et al79

BiRD

Dose

Evaluable patients (n)

PR (%)

CR (%)

EFS/PFS/TTP (median, months)

OS (median, months)

% DVT

DVT prophylaxis

L 25 mg/d p.o.  21 d

34

85

6

Projected 2 years 91%

3

Aspirin (81e325 mg)

D 40 mg/d p.o., d 1e4, 9e12, 17e20 Repeat q 28 d L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1e4, 9e12, 17e20 versus L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1, 8, 15, 22 Repeat q 28 d L 5e10 mg/d p.o.  21 d M 0.18e0.25 mg/kg/d p.o.  4 d P 2 mg/kg/d p.o.  4 d Repeat q 4e6 weeks L 10 mg/d p.o.  21 d M 5e8 mg/m2/d p.o.  4 d P 60 mg/m2/d p.o.  4 d Repeat q 28 d Bi 500 mg/d b.i.d. p.o.  28 d L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1, 8, 15, 22 Repeat q 28 d

34

73

18

223

NA

NA

NA

NA

18.4

NA

222

NA

NA

NA

NA

5.4

NA

54

52

23

87% (at 16 months)

NR

6

Aspirin 100 mg/d p.o.

7

57

14

NA

NA

14

Aspirin 325 mg/d p.o.

40

70

25

NA

NA

15

Aspirin 81 mg/d p.o. 3 patients had thromboembolic events when stopped

PFS projected 2 years 74%

PR, partial response; CR, complete response; EFS, event-free survival; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DVT, deep vein thrombosis; L, lenalidomide; ASA, M, melphalan; P, prednisone; Bi, clarithromycin; NA, not available; NR, not reached.

726 S. K. Thomas et al

Table 4. Lenalidomide combinations in previously untreated multiple myeloma.

Lenalidomide in MM 727

arm compared with the low-dose arm (20.3% versus 13.1%). Specifically, rates of infections/pneumonitis (15.7% versus 7.5%), thromboembolic events (22.1% versus 6.1%), and hyperglycemia (9.7% versus 6.7) were higher with the intermittent pulsing (highdose) regimen.66 The incidence of  grade 3 neuropathy, however, was comparable between the two schedules (<1%). A second study explored the use of reduced-frequency dexamethasone combined with clarithromycin (Biaxin), lenalidomide, and once-weekly dexamethasone (BiRD). This was based on previous observations that clarithromycin may augment tumor mass reduction and improve responses in patients receiving low-dose thalidomide and/or dexamethasone.78,79 Among 40 evaluable patients, 29% achieved PR and 28% CR. Thromboembolic events were noted in 15% of patients; of the seven cases that occurred, three were in patients taking aspirin prophylaxis.79 If time to response, TTP, and OS with these low-dose regimens are comparable to treatments with high-dose steroids, these regimens may provide useful alternatives for patients with difficulty in tolerating the side-effects of steroids, particularly for those with diabetes, congestive heart failure (CHF), or other comorbidities that may make high doses of dexamethasone impractical. Finally, the combination of melphalan, prednisone, and thalidomide has provided an ORR of 73%, including CR rates of 18%22, prompting investigators to evaluate the combination of lenalidomide with melphalan and prednisone (R-MP). In a dose-escalation study of 54 patients, participants were enrolled in four cohorts.63 The MTD was reached with a regimen of oral melphalan 0.18 mg/kg/d and prednisone 2 mg/kg/d on days 1–4 and lenalidomide 10 mg/d p.o. on days 1–21. Patients were given prophylaxis for DVT and infections with aspirin and ciprofloxacin respectively, and cycles were repeated at 4–6-week intervals. A median of seven cycles was administered and 52.3% of patients achieved PR and 23% achieved CR. With a median follow-up of 9.6 months, PFS was 87%. No difference in PFS was observed in the subset of patients with deletion 13q by fluorescence in-situ hybridization (FISH); however, karyotype analysis was not available. Grade 3–4 toxicities observed included neutropenia (66%), thrombocytopenia (34%), anemia (17%), and skin eruptions (10%). Three patients developed thromboembolic events; however, two of these patients had discontinued aspirin prophylaxis at the time the event occurred.63 In a similar study of R-MP for patients ineligible for stem-cell transplantation, 82% achieved PR or better at the MTD of melphalan 5 mg/m2 p.o. and prednisone 60 mg/m2 p.o. on days 1–4 with lenalidomide 10 mg/d p.o. on days 1–21.80 Toxicities were similar, although no thromboembolic events were observed with this regimen.80 The potential for myelotoxicity, and the impact on the stem-cell harvest, must be considered prior to using this regimen for induction therapy of myeloma; to date, no randomized studies have demonstrated superiority of these regimens over full-intensity stem-cell-supported therapies that incorporate novel agents for induction or conditioning regimens. MYELOMA WITH CONCOMITANT PRIMARY AMYLOIDOSIS (SEE TABLE 5) Primary amyloidosis is a rare plasma-cell proliferative disorder that occurs in approximately 10% of patients with multiple myeloma.81 The deposition of the amyloid fibrils into tissues can either be localized or more widespread in nature. For many years, low-dose melphalan and prednisone was the standard care, providing a median survival of 16–18 months.82,83 In an attempt to improve outcomes of patients with primary amyloidosis, high-dose melphalan followed by autologous stem-cell transplantation

728 S. K. Thomas et al

Table 5. Lenalidomide for amyloidosis. Author

Regimen

Dose

Evaluable HR (%) patients (n)

OR (%)

EFS/PFS/TTP OS (median, % DVT DVT Prophylaxis (median, months) months)

Sanchorawala et al42 Len/Dex

24

47

41 (renal)

NA

NA

8

None

Dispenzieri et al41

22

40

23

NA

NA

9

None

L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1e4, 9e12, 17e20 (every other cycle if PD after 3 cycles) LeneDex L 25 mg/d p.o.  21 d D 40 mg/d p.o. d 1e4, 15e18 (if SD or PD after 3 cycles)

HR, hematological response, OR, organ response, EFS, event-free survivial; PFS, progression-free survival; TTP, time to progression; OS, overall survival; DVT, deep vein thrombosis; L, lenalidomide; D, dexamethasone; PD, progressive disease; NA, not available; SD, serologically detectable disease.

Lenalidomide in MM 729

has been evaluated. In an 8-year longitudinal study of 701 patients with primary amyloidosis that included 394 patients eligible for high-dose melphalan followed by AuSCT, complete hematologic remission was achieved in 40% of the 312 patients who received AuSCT, and was associated with prolonged survival.84 Unfortunately, most patients with primary amyloidosis are unable to proceed to stem-cell transplantation due to the extensive organ damage sustained from amyloid deposition, and their resultant poor performance status.84 More recently, thalidomide was found to be effective in the treatment of amyloidosis, and when combined with dexamethasone has produced response rates of 50%.85 However, due to the toxicities observed, most patients required discontinuation of therapy.85 Based on the response rates seen after therapy for amyloidosis with thalidomide, trials of lenalidomide for the treatment of this disorder have been initiated and recently reported. In a phase-II trial of 34 patients with AL amyloidosis, patients received lenalidomide 25 mg/d p.o. for 21 out of every 28 days.42 After three cycles, if no hematologic response was observed, dexamethasone was added at doses of 10 mg/d or 20 mg/d on days 1–4, 9–12, 17–20 every other cycle. Organ involvement among those treated included renal (38%) and cardiac deposition (38%), with 20% of patients having more than two organ systems involved. Among patients completing at least three cycles of therapy (24 patients, 70%), 21% achieved hematologic PR and 6% achieved CR with single-agent lenalidomide. However, with the addition of dexamethasone, there was improvement in the overall PR and CR rates (38% and 29%, respectively). Forty-one percent of patients with renal involvement had reduction of total proteinuria by at least 50%. One patient, with cardiac involvement had improvement of symptoms related to congestive heart failure and a concomitant reduction of serum brain natriuretic peptide (BNP). Grade 3 and 4 toxicities included myelosuppression (35%), skin rash (59%), increased serum creatinine (59%), and respiratory infections (50%). Thromboembolic events occurred in three patients. Of these, two received lenalidomide alone (one patient had a cerebrovascular accident after air travel) and one received L–D combination therapy. Two of three were also on concommittant erythropoietin at the time of their thromboembolic event. However, eight other patients receiving concommittant erythropoietin did not develop a thromboembolic event. Due to the rate of thromboembolic events, the study was amended and all subsequent patients received prophylaxis with aspirin (81–325 mg/d).42 In a similar phase-II trial, 23 patients with AL amyloidosis were treated with lenalidomide 25 mg/d p.o. on days 1–21 with a 7-day rest period.41 Patients not achieving a hematologic response after three cycles were given dexamethasone 40 mg on days 1–4 and 15–18. Among study participants, the median number of organs involved (cardiac, liver, renal, and nerve) was two, and 64% of patients had cardiac involvement. Fourteen of 22 evaluable patients achieved a hematologic response based on free light chain measurement. Within 3 months of initiating therapy, ten patients ended treatment due to death (four due to restrictive cardiomyopathy), adverse events (four), other medical problems (one), alternative therapy (one), and disease progression (one). Factors predicting early withdrawal and death included poor cardiac function, higher NT–proBNP level (5925 versus 537 ng/L, P ¼ 0.02), and worse New York Heart Association Class (>II versus I; P ¼ 0.08). After three cycles of therapy, 11 patients had not achieved a hematologic response and required the addition of dexamethasone. While ten of the 22 patients did not continue with therapy, hematologic response was 41% and organ response was 23% (overall response 45%). In those with previously untreated AL amyloidosis, the hematologic response was 44%, with an organ response rate of 33%. The median time to response in patients with amyloidosis was slower

730 S. K. Thomas et al

than for counterparts with myeloma, with median times to hematologic and organ response of 6.2 and 9.4 months respectively. Median time to progression was 18.8 months, with a 12-month progression-free survival of 56%. Grade 3 and 4 toxicities were seen in 83% of patients and included neutropenia (45%), thrombocytopenia (27%), rash (18%), infection (9%), and fatigue (18%). Two patients developed thromboembolic events, one in the absence of dexamethasone. Most patients required some dose reduction, with six patients requiring reductions in the lenalidomide dose to 5–15 mg/d. While this was not designed as a phase-I dose-escalation study, the authors determined the MTD to be 15 mg/d for patients with AL amyloidosis based on the outcomes observed in this study.41 In patients who have concurrent myeloma and amyloidosis, lenalidomide appears to be a rational choice for induction therapy as it provides effective treatment for both diseases. However, depending on the extent of organ involvement by amyloidosis, initial or later dose reduction of lenalidomide due to patient comorbidities and tolerance (compared with counterparts treated for myeloma alone) may be necessary. CONCLUSION Lenalidomide in combination with other active agents has provided high rates of response, including complete remission rates for previously untreated patients with symptomatic myeloma. Additionally, it has increased response rates in patients with relapsed and refractory disease, even after prior therapy with the parent compound thalidomide, and synergy with other effective drugs provides patients with many new options for therapy of multiple myeloma in the relapsed setting. With lenalidomide’s different adverse event profile, including a low rate of treatment-induced neuropathy, patients now have the opportunity to receive a highly effective oral therapy with improved short- and long-term tolerability; however, some form of thromboembolic prophylaxis appears justified. While the role of lenalidomide as maintenance therapy needs clarification, ease of administration, improved tolerability, and efficacy seen with this drug lends itself to such consideration, and currently trials for this use are underway. There is still much to be discovered regarding use of the novel agents, particularly lenalidomide, for myeloma. Well-designed randomized studies including lenalidomide, with or without myeloablative therapy, in combination with novel and conventional chemotherapy, as well as with phase-I targeted therapy, are likely to clarify the role of this immunomodulatory derivative in therapy of multiple myeloma, providing continued hope for improved survival for patients with this disorder. Practice points  lenalidomide is a structural analog of thalidomide, created by the addition of an amino group  the teratogenic potential of lenalidomide is unclear, therefore precautions to avoid pregnancy are mandatory (all patients in the US must be enrolled in the STEPS program)  lenalidomide alone, or in combination, is efficacious in patients with relapsed/ refractory and previously untreated multiple myeloma  myelosuppression is the most frequent grade 3–4 side-effect associated with lenalidomide. It occurs with increased frequency in patients with relapsed/

Lenalidomide in MM 731





   

refractory disease. Blood counts should be monitored weekly for 8 weeks. If no myelosuppression is seen, weekly blood counts may then be discontinued lenalidomide should be held for platelets <30,000 until the platelets increase to >30,000, with a reduction of lenalidomide to 15 mg daily. For an absolute neutrophil count (ANC) <1000 K/UL, lenalidomide should be held until the ANC >1000 K/UL; if no other significant toxicity is present, lenalidomide may be resumed at the same dose level; in patients with concomitant toxicity the dose should be decreased to 15 mg. With each successive drop in platelets or ANC, the dose of lenalidomide should be decreased (usually by 5-mg increments) patients treated with lenalidomide combined with steroids should receive some form of anticoagulation (e.g. aspirin, low-molecular-weight heparin or warfarin) as prophylaxis against thromboembolic events; the ideal program remains unclear concurrent use of erythropoietin or darbopoetin and lenalidomide has been associated with a higher rate of thromboembolic events lenalidomide and steroids, in combination with other agents such as melphalan, cyclophosphamide, PEGylated liposomal doxorubicin, or bortezomib, are safe and well tolerated lenalidomide-based combinations have response rates of 85%, with CR rates of 18–25% in previously untreated patients lenalidomide/dexamethasone produces both organ and hematologic response in patients with amyloidosis

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