Literature Review

For many years, first-line treatment for younger multiple myeloma (MM) patients has involved high-dose chemotherapy as well as autologous stem-cell transplantation (ASCT). The more recent use of lenalidomide, thalidomide, and bortezomib as induction and consolidation therapy has changed the way we approach patients with relapsed and refractory MM, according to Donna E. Reece, MD, from the Princess Margaret Hospital, Toronto, Canada. Dr Reece reviewed the use of innovative therapies before and after ASCT, focusing on phase 3 trial results.

Use in Induction Therapy Before Undergoing ASCT.

Newer combinations have been compared with older induction regimens before ASCT in various phase 3 studies, stated Dr Reece. However, outcomes comparisons are challenging, because many of the trials used different maintenance or consolidation treatments, and the induction regimens themselves varied. In phase 3 trials, induction regimens included:

• Lenalidomide and dexamethasone

• Thalidomide and dexamethasone

• Bortezomib and dexamethasone

• Bortezomib, thalidomide, and dexamethasone

• Bortezomib, adriamycin, and dexamethasone

• Vincristine, carmustine, melphalan, cyclophosphamide, doxorubicin, and prednisone

The trials used varying doses of these agents. Dr Reece stated that each of the therapy combinations using novel agents offer benefits over conventional chemotherapy in terms of remission rates. However, only 1 trial not using lenalidomide reported a statistically significant overall survival (OS) rate—when bortezomib was used both before and after ASCT during the HOVON MM-65/GMMG-HD4 study, which enrolled 613 participants and used the induction treatment of bortezomib, adriamycin, and dexamethasone. In this trial, the bortezomib combination was compared with the conventional chemotherapy combination of vincristine, doxorubicin, and dexamethasone, and resulted in a progression-free survival (PFS) at 3 years of 48% and a median 3-year OS of 78% for the study drug combination.

The induction regimen of lenalidomide and dexamethasone was examined by Dr Reece. A phase 3 trial compared lenalidomide plus either highdose dexamethasone (40 mg on days 1-4, 9-12, and 17-20 on a 28-day schedule) or a weekly low dose (40 mg) for 4 cycles in patients just diagnosed with myeloma. After 4 cycles, the overall response rate for the lenalidomide plus high-dose or low-dose dexamethasone groups was 79% versus 68%, with a “very good partial remission,” nearly complete remission, or complete remission rate of 42% versus 24%, respectively. A 92% survival at 3 years was achieved for patients who underwent ASCT. However, she pointed out a possible bias for the ASCT patients due to the design of the study: The individuals undergoing ASCT may have been younger and healthier or high-risk patients who were not presumed to do well with a continued administration of the lenalidomide combination regimen. The data do show, according to Dr Reece, that the combination therapy was well-tolerated and stem-cell collection was not compromised when patients were given chemotherapy and hematopoietic growth factors.

Source: Reece DE. Post-transplantation maintenance therapy and optimal frontline therapy in myeloma. Hematology Am Soc Hematol Educ Program. 2011;2011:197-204.

The Total Therapy programs developed by the University of Arkansas are also noteworthy, stated Dr Reece. Newly diagnosed patients were treated with induction therapy consisting of 2 cycles of dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (D-PACE) in the Total Therapy 2 trial, before tandem ASCT, further D-PACE consolidation, and maintenance with IFN for 1 year and dexamethasone until the disease advanced. They were then randomized to either receive thalidomide or not. Patients in the thalidomide group experienced higher remission rates before and after ASCT and a significantly longer progression-free survival (PFS). The next study, Total Therapy 3, added bortezomib, thalidomide, and dexamethasone (VTD) as VTD-PACE, which patients received before and after ASCT. This regimen led to a further improvement in the response rate, OS, and PFS for newly diagnosed patients with lowrisk disease, but Dr Reece noted that approximately 15% had early treatment failure and death. Therefore, it is still a challenge to find optimal treatment for this subset of patients.

All of the various study regimens using novel agents were proved to be superior in attaining higher response rates after induction therapy, according to Dr Reece.

Maintenance Therapy.

The most frequently studied maintenance drugs are lenalidomide and thalidomide. Seven randomized trials of post-ASCT thalidomide therapy were analyzed by Dr Reece. They were different with regard to use of induction regimen, single or tandem transplantation before starting maintenance therapy, thalidomide dose and duration, corticosteroid use, and comparison with various regimens. Even so, a PFS benefit was consistently seen with thalidomide therapy (OS benefit was not always observed).

The optimal use of thalidomide maintenance is still unclear, Dr Reece admitted, because of different criteria used when classifying patient subgroups even after several investigators attempted to identify which patient groups would most likely benefit from this therapy. Nevertheless, thalidomide

maintenance therapy has not been widely accepted outside of clinical trials even with the longer PFS, said Dr Reece, largely owing to its toxicity.

Maintenance therapy with lenalidomide has also recently been studied. The CALGB-100104 study in North America and the IFM 2005-02 trial in France compared low doses of lenalidomide (10-15 mg/day) with placebo after ASCT. Both studies demonstrated a median PFS of 42 months in the lenalidomide groups.

Unexpectedly, a fairly small increase in the frequency of secondary cancers, such as secondary myelodysplastic syndromes and/or acute myelogenous leukemia, was observed in both studies, Dr Reece pointed out, but the risk is “quite small and is likely counterbalanced by the strong antimyeloma efficacy of this drug when used in the maintenance setting.”

Consolidation Therapy.

Three recent phase 3 trials examined consolidation therapy use after ASCT. Some of the best outcomes of a transplantation program so far, according to Dr Reece, were from an Italian trial that used the bortezomib-thalidomide-dexamethasone regimen, also given for induction for 2 cycles after transplantation while a control group did not receive bortezomib for 2 months. In the IFM- 2005-02 trial, patients were given a full therapeutic consolidation dose of lenalidomide (25 mg for 2 cycles) followed by a lower maintenance dose until disease progression. The ASCT patients in the Nordic Myeloma Study Group were randomized to receive bortezomib treatment or no therapy. Both of those groups had a 90% OS. Each innovative agent can postpone disease progression, noted Dr Reece, as demonstrated in these post-ASCT maintenance and/or consolidation studies even when OS benefits have not been found.

Novel agents used at the induction phase followed by maintenance with lenalidomide after ASCT have the best PFS results so far, concluded Dr Reece. She added that the role of a second ASCT or consolidation therapy to lenalidomide maintenance is still to be clarified by clinical trials.

Source: Reece DE. Post-transplantation maintenance therapy and optimal frontline therapy in myeloma. Hematology Am Soc Hematol Educ Program. 2011;2011:197-204.

Benefits of Lenalidomide Dose Reduction for Patients With Multiple Myeloma

A combination of lenalidomide and dexamethasone is indicated for use in patients suffering from relapsed or refractory multiple myeloma (MM) who had tried at least 1 previous treatment. This approval was based on the results of 2 phase 3 clinical trials, which also showed that continuing, longterm therapy assures patients the best chance for success. However, the evidence supporting the optimal dose of lenalidomide in patients with recurrent or refractory MM is vague. Full dosing (25 mg/day) is associated with common adverse effects, which can result in delays in or interrupted treatment. Clinicians from Greece and the United States sought to determine from the 2 pivotal trials whether reduced doses of lenalidomide had a negative effect on progression-free survival (PFS).

The study group included only subjects who did not progress and were still being treated with lenalidomide 12 months after starting therapy. Of the 177 patients in the MM-009 trial receiving lenalidomide and dexamethasone and 176 from the MM-010 trial, 116 were included in the analysis. A total of 52 patients (45%) had no dose reductions, 39 (34%) had their lenalidomide dose reduced before 12 months, and 25 (22%) had their lenalidomide reduced at least 12 months after starting therapy.

All 3 subgroups achieved similarly high response rates. However, a significantly longer PFS was seen in patients with dose reductions after 12 months than

those with dose reductions before 12 months or those with no dose reductions. For those with dose reductions 12 months or beyond, PFS was not yet reached. In comparison, for those without any dose reduction, median PFS was 36.8 months (P = .039). None of the 3 subgroups reached median overall survival.

After adjusting for patient characteristics, a Cox regression analysis of PFS found that an independent predictor of PFS continued to be lenalidomide dose reductions after 12 months (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98). Twelve-month levels of serum albumin, M-protein, and neutrophils were other independent predictors of PFS.

The patients who had lenalidomide dose reductions after at least 12 months of full-dose lenalidomide experienced a significantly higher median PFS as well as overall survival than those who had dose reductions earlier, the researchers commented. Therefore, they added, the data suggest if the patient can tolerate the treatment, it is important that the full-dose lenalidomide therapy should continue for at least 12 months.

Source: Dimopoulos MA, Hussein M, Swern AS, et al. Impact of lenalidomide dose on progressionfree survival in patients with relapsed or refractory multiple myeloma. Leukemia. 2011;25:1620-1626.

Can Reduced Lenalidomide Doses in Refractory or Recurrent Multiple Myeloma Patients Produce Positive Outcomes?

Lenalidomide combined with dexamethasone has proved to be an effective treatment for many patients with refractory or recurrent multiple myeloma (MM). German researchers noted, however, that adverse effects seen with the approved doses (25 mg/day for 21 days of each 28-day cycle) may result in suboptimal cancer outcomes in some individuals.

They evaluated the efficacy of a reduced lenalidomide dose on 10 patients with recurrent MM who had difficulty adhering to standard dosing because of leukopenia (4 patients), muscle cramps (1), polyneuropathy (1), renal insufficiency (1), or thrombocytopenia (1). In 1 case, the patient requested the reduced dose and in another, the patient was given lenalidomide as reduced-dose continuous therapy (1). Two patients began the trial with a reduced dose while 8 had their dose reduced during the therapy. Seven patients had undergone autologous stem-cell transplant, and all had had at least 2 previous MM treatments.

Initially, 8 subjects received the full 25-mg per day lenalidomide dose on days 1 to 21 every 28 days plus dexamethasone at a mean dose of 17.6 mg per day on days 1 to 4, 9 to 12, and 17 to 20, with the dose first reduced a mean of 4.8 months after beginning treatment. After dose reduction, lenalidomide averaged 14.1 mg per day. Treatment duration with lenalidomide averaged 15.1 months.

One study participant achieved a complete response, 6 attained a partial response, and 1 had a minimal response. Time to first response after starting lenalidomide was a median 41.1 days. The dose each patient was taking at the time of their best response was 25 mg per day in 7 patients (1 complete response, 5 partial responses, 1 progressive disease), 15 mg per day in 1 patient (partial response), 10 mg per day in 1 patient (who experienced progressive disease), and 5 mg per day in another (who experienced minimal response only). Therefore, most of the patients in this small series experienced best response before their dose was reduced; however, they continued to do well after the dose reduction.

The time-to-progression (TTP) mean values and progression-free survival (PFS) rates are noted in the Figure. Both were 8.7 months. Since all patients were still alive at the end of the study, a mean overall survival could not be calculated.

All patients experienced some level of anemia (grade 3/4, 2 patients), and leukopenia was observed in 8 (grade 3, 3 patients), thrombocytopenia in 7 (grade 3, 3 patients). When the lenalidomide dose was decreased, thrombocytopenia, anemia, and leukopenia became stable or diminished. Non-hematologic toxicities included back pain (5 patients), polyneuropathy (3), muscle cramps (2), pruritus (1), and severe constipation (1).

The researchers concluded that in patients who experienced recurrent or refractory MM and who could not tolerate a standard dose of lenalidomide, dose reductions still proved to be a safe and effective alternative.

Source: Schwamborn K, Gorschluter M, Glasmacher A, et al. Efficacy of dose-reduced lenalidomide in patients with refractory or recurrent multiple myeloma. GMS Ger Med Sci. 2011;9:doc26.

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