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Treatment Options for Lenalidomide-Exposed R/R Multiple Myeloma

Simoneaux, Richard

doi: 10.1097/01.COT.0000554585.76804.c9
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multiple myeloma

multiple myeloma

The immunomodulatory drug lenalidomide, which is an analog of thalidomide, has been increasingly utilized as a standard therapy for newly diagnosed multiple myeloma patients. With greater use in first-line treatment and as part of maintenance, there has been a corresponding increase in the number of multiple myeloma patients having disease that is refractory to treatment with this agent.

In addition, those with lenalidomide-refractory multiple myeloma represent both the largest group of patients at first relapse in the U.S., as well as a growing population worldwide. The effective management of these patients' disease has been poorly studied, and thus, optimal choices when lenalidomide has failed prove difficult.

To address this clinical need, the phase III OPTIMISMM clinical trial (NCT01734928) was undertaken. This was a multi-center, international, global study comparing the use of the potent immunomodulatory drug pomalidomide plus the proteasome inhibitor bortezomib and low-dose dexamethasone (PVd arm) with bortezomib and low-dose dexamethasone (Vd arm) in relapsed or refractory multiple myeloma patients. The lead investigator for this trial is Paul G. Richardson, MD, Dana-Farber Cancer Institute.

“The rationale for this trial was to evaluate the real-world triplet combination in a patient population that all had prior lenalidomide exposure, and a significant portion of whom had undergone disease progression while on lenalidomide-containing therapy,” Richardson noted. “One crucial facet to the real-world aspect of this study was to utilize a regimen that would be of utility to multiple myeloma patients globally from both a cost and availability perspective.”

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Study Background

The next-generation immunomodulatory drug pomalidomide has shown significant clinical benefit in the treatment of patients with lenalidomide-refractory relapsed or refractory multiple myeloma, even including those who have had several prior treatment lines. In the phase III MM-003 study (NCT01311687), pomalidomide plus low-dose dexamethasone was compared with high-dose dexamethasone monotherapy (Lancet Oncol 2013;14;1055-1066).

In that trial, the investigators found that the median progression-free survival (PFS) for those receiving pomalidomide plus low-dose dexamethasone was 4.0 months (95% CI: 3.6-4.7 months) versus 1.9 months (95% CI: 1.9-2.2 months) with high-dose dexamethasone, giving a hazard ratio (HR) of 0.48 (95% CI: 0.39-0.60; p<0.0001).

In a phase II study (NCT00833833), the safety and efficacy of pomalidomide was evaluated alone or in combination with low-dose dexamethasone (Blood 2014;123:1826-1832). This study included heavily pre-treated patients with a median of five prior therapies (range: 1-13 prior therapies). The primary endpoint was PFS. The median PFS was 4.2 months for the pomalidomide plus low-dose dexamethasone patients and 2.7 months for the pomalidomide monotherapy patients, giving an HR of 0.68 (p=.003).

The use of lenalidomide plus bortezomib and low-dose dexamethasone was assessed in patients with relapsed or relapsed/refractory multiple myeloma in a phase II clinical study (NCT00378209). The results obtained in that study showed that nearly two-thirds of the relapsed/refractory participants attained a partial response or better (Blood 2014;123:1461-1469). Also of note was the significant activity obtained by the triplet therapy despite the poor prognosis that characterized the patients' disease.

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Methodology

Among the inclusion criteria for this study were the following: adult (i.e., aged 18 years or older); confirmed multiple myeloma diagnosis with measurable disease (serum and urine protein electrophoresis); at least one but not more than three lines of prior therapy; prior treatment with lenalidomide which included at least 2 consecutive treatment cycles of this immunomodulatory drug; and confirmed disease progression during or after last anti-myeloma treatment.

Patients were excluded from participation in this clinical trial if any one of the following conditions were met: documented disease progression during or within 60 days after the last dose in a bortezomib-containing therapy below the 1.3 mg/m2 dose twice weekly dosing schedule; peripheral neuropathy of grade 4, grade 3, or grade 2 with pain within 14 days before randomization; non-secretory multiple myeloma; inadequate kidney function that required dialysis; or prior pomalidomide-containing therapy.

Patients were randomized in a 1:1 ratio to either the pomalidomide and bortezomib plus low-dose dexamethasone regimen (PVd arm) or the bortezomib plus low-dose dexamethasone regimen (Vd arm).

For the PVd regimen, the dosing schedule was as follows for each 21-day treatment cycle: pomalidomide-4 mg (oral) days 1-14; bortezomib-1.3 mg/m2 (subcutaneous) days 1, 4, 8, and 11 for cycles 1-8 and days 1 and 8 of cycles 9 or greater; dexamethasone 20 mg/day [75 years or younger] or 10 mg/day [older than 75 years] (oral) on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and days 1, 2, 8, and 9 of cycles 9 or greater.

For the Vd arm, the dosing schedule was as follows for each 21-day dosing schedule: bortezomib-1.3 mg/m2 (subcutaneous), days 1, 4, 8, and 11 for cycles 1-8 and days 1 and 8 of cycles 9 or greater; dexamethasone 20 mg/day [75 years or younger] or 10 mg/day [older than 75 years] (oral) on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and days 1, 2, 8, and 9 of cycles 9 or greater.

The primary endpoint for this study was PFS, while secondary study endpoints included the following measures: overall survival, objective response rate (ORR), duration of response, and adverse events (AEs).

“As of the cutoff date [of Oct. 26, 2017], the survival data were not mature,” Richardson noted.

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Intent-to-Treat Population Data

A total of 559 patients were enrolled in this study and randomized in a 1:1 fashion to either the PVd arm (n=281) or the Vd arm (n=278). “These patients comprised the intent-to-treat (ITT) population,” Richardson stated. The median ages for the PVd and Vd patients were 67 years and 68 years accordingly.

Lenalidomide-refractory disease was present in 71 percent and 69 percent of the PVd and Vd patients, respectively; in addition, 72 percent of the PVd arm and 73 percent of the Vd arm had prior bortezomib-based therapies. Patients having disease that was refractory to their last therapy comprised 70 percent and 66 percent of the PVd and Vd patients, respectively. Patients in the ITT had a median of two therapies, while 40 percent of the PVd arm and 41 percent of the Vd arm had one prior line of therapy.

Among the ITT population, the median PFS was 11.2 months for those in the PVd arm and 7.1 months for those in the Vd arm, affording an HR of 0.61 (95% CI: 0.49-0.77, p< .0001). In this same patient population, the ORR (i.e., those showing a partial response or better) was 82.2 percent and 50.0 percent in the PVd and Vd arms. For the ITT population, a total of 52.7 percent of the PVd arm and 18.7 percent of the Vd arm showed very good partial response (VGPR) or better.

The most commonly observed grade 3 or 4 treatment-emergent adverse events (TEAEs) in this population were neutropenia (PVd-42% and Vd-9%), infections (PVd-31% and Vd-18%), and thrombocytopenia (PVd-27% and Vd-29%). “These AEs were not wholly unexpected, as similar patterns had been previously observed in other pomalidomide-containing regimens, but as before, these effects were easily managed,” Richardson explained.

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Patients as Second-Line Therapy

Of the 559 patients enrolled, 226 were treated in this study as their second line of therapy. These patients were randomized in the following manner: 111 to the PVd arm and 115 to the Vd arm. The median time to follow-up for these second-line patients was 16.4 months.

For patients receiving their second line of therapy in this study, the median PFS was 20.73 months for the patients in the PVd arm and 11.63 months for those in the Vd arm; this gave an HR of 0.54 (95% CI: 0.36-0.82; p=.0027). The ORR was 90.1 percent and 54.8 percent for the PVd and Vd patients, respectively. Those patients displaying a VGPR were 61.3 percent and 22.6 percent of the PVd and Vd arms, accordingly.

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Lenalidomide-Refractory Disease

Among the second-line patients, 129 (57.1%) were lenalidomide refractory; of these, 64 and 65 patients were present in the PVd and Vd arms, respectively. The remaining 97 second-line patients (42.9%) were deemed lenalidomide-nonrefractory; of these, 47 and 50 patients were assigned to the PVd and Vd arms correspondingly.

In the second-line, lenalidomide-refractory patients assigned to the PVd arm, the following characteristics were noted: median age-68 years; gender-57.8 percent male; and prior bortezomib therapy-56.3 percent. The corresponding second-line Vd-assigned lenalidomide-refractory patients had the following characteristics: median age-69 years; gender-58.5 percent male; and prior bortezomib therapy-47.7 percent.

In second-line patients who were nonrefractory to lenalidomide, the PVd patients displayed the following characteristics: median age-66 years; gender-63.8 percent male; and prior bortezomib therapy-66 percent. Correspondingly, the Vd arm of these patients displayed the following characteristics: median age-65.5 years; gender-38 percent male; and prior bortezomib therapy-72 percent.

In lenalidomide-refractory second-line therapy recipients, the median PFS was 17.8 months (95% CI: 12.2 months–not estimable) for the PVd arm and 9.5 months (95% CI: 6.3-16.2 months) for those in the Vd arm, giving an HR of 0.55 (95% CI: 0.33-0.94). Second-line lenalidomide-refractory patients, attained an ORR of 85.9 percent in the PVd arm and 50.8 percent in the Vd arm (p<.001).

The most common grade 3 or 4 TEAEs observed in second-line lenalidomide-refractory patients were neutropenia (PVd-35.9% and Vd-12.9%), thrombocytopenia (PVd-17.2% and Vd-22.6%), and anemia (PVd-17.2% and Vd-8.1%). In addition, grade 3 or 4 infections occurred in 29.7 percent and 21.0 percent of the PVd and Vd patients. The median durations of therapy for second-line lenalidomide-refractory patients were 9.7 and 6.1 months for the PVd and Vd arms.

Lenalidomide-nonrefractory second-line therapy patients had median PFS values of 22.0 months (95% CI: 14.7 months–not estimable) for the PVd arm and 12.0 months (95% CI: 7.9-21.1 months) in the Vd arm, affording an HR of 0.54 (95% CI: 0.29-1.01). For the second-line lenalidomide-nonrefractory patients, the ORR values were 95.7 percent and 60.0 percent in the PVd and Vd arms, respectively (p<.001).

In second-line lenalidomide-nonrefractory patients, the most common grade 3 or 4 TEAEs were neutropenia (PVd-36.2% and Vd-6.3%) and thrombocytopenia (PVd-23.4% and Vd-18.8%). “As with the other patient populations,” Richardson observed, “grade 3 or 4 infections were more prevalent in second-line lenalidomide-nonrefractory patients in the PVd arm (27.7%) relative to those in the Vd arm (8.3%).” The median durations of therapy for the lenalidomide-refractory patients were 13.6 months (PVd arm) and 6.6 months (Vd arm).

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Discussion

“To date, OPTIMISMM is the only phase III triplet study to report significantly improved PFS in patients with relapsed or relapsed and refractory multiple myeloma who were entirely lenalidomide-exposed and in whom over 70 percent were lenalidomide refractory,” Richardson noted. “Significant improvement was noted for the PVd arm in the ITT (4.1 months greater) and especially in second-line patient populations (9.1 months greater).

“The greatest difference in median PFS values,” he stated, “were in those second-line PVd patients who had lenalidomide-nonrefractory disease, who had a median PFS value that was over 10 months longer than their counterparts in the Vd arm.

“The study results indicated an improved benefit for the subgroup of patients who had had only one prior line of therapy. The safety profile for the PVd regimen was consistent with previous studies and was generally well-tolerated with manageable toxicities.”

When asked about the next steps for evaluating the PVd combination, Richardson replied, “A logical next step is the addition of monoclonal antibodies to the PVd regimen, such as the CD38-targeting daratumumab or the SLAMF7-directed elotuzumab, and studies are planned or already completed with this approach. Whatever additions are made to the PVd regimen, two important factors for global use will be cost-effectiveness and availability.”

Richard Simoneaux is a contributing writer.

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A Conversation on the OPTIMISMM Study

Krina Patel, MD, MSc

Krina Patel, MD, MSc

Recently, Krina Patel, MD, MSc, Assistant Professor in the Department of Lymphoma/Myeloma of Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, shared her thoughts on the impact of the phase III OPTIMISMM clinical trial for patients with multiple myeloma.

  • What is your general background at MD Anderson?

Roughly 90 percent of my cases are multiple myeloma patients.

  • What is your most common starting therapy for these multiple myeloma patients?

At MD Anderson, most frequently, we initiate our multiple myeloma patients on the next-generation proteasome inhibitor carfilzomib. We tend to use carfilzomib initially, as that drug has shown significant activity in myeloma patients whose disease is resistant or refractory to lenalidomide or bortezomib (the first-in-class proteasome inhibitor) therapy. Additionally, the newer proteasome inhibitor doesn't have the peripheral neuropathy that is associated with bortezomib therapy.

  • Given your use of carfilzomib, what are your thoughts on the recently presented results for the phase III OPTIMISMM clinical trial?

In general, the pomalidomide-bortezomib-low-dose dexamethasone (PVd) triplet regimen is a great option relative to the doublet therapy of bortezomib plus low-dose dexamethasone (Vd). This was shown by the improved progression-free survival data across all subgroups.

  • What do you consider the main impact of this clinical trial?

One important aspect for this study was the requirement for lenalidomide exposure, even including a large percentage of patients who had lenalidomide-refractory disease. Additionally, these results also lend support for the use of triplet therapy for multiple myeloma patients. Realistically, many myeloma patients only receive doublet therapy for their disease; this trial gives good evidence of the benefits for using the PVd combination. Importantly, these results also provide physicians with another viable option for treating their multiple myeloma patients.

  • What do you feel are some of the strengths of OPTIMISMM?

The subgroup analysis that was done in this study was excellent. A clear benefit was shown in those patients for whom the clinical trial regimen was their second-line therapy. These patients were then also stratified by the disease status, i.e., lenalidomide-refractory or lenalidomide-nonrefractory.

  • What do you consider to be the pros and cons for some prominent myeloma therapies?

For carfilzomib, the proteasome inhibitor which we most frequently use, it does not exhibit the neuropathy associated with bortezomib, however, there is an increased risk for cardiovascular effects. Bortezomib, which was the first-in-class proteasome inhibitor, is now off-patent, which means that the costs for this drug are now less and in the future there may be the option of generic bortezomib.

Additionally, bortezomib is administered subcutaneously, which is much less difficult than IV administration which is often necessary for drug delivery. As previously stated, bortezomib has an adverse event profile that is often characterized by peripheral neuropathy. Regarding the PVd regimen utilized in OPTIMISMM, there was a clear benefit for patients relative to those receiving the Vd doublet therapy that served as a comparison. This advantage in PFS was most pronounced in those patients for whom their second-line therapy was in the clinical trial. Although the AE profile was generally manageable, there was still an increased presence of myelosuppression and infections in the PVd arm of this study.

  • What do feel are the most relevant outcomes of the OPTIMISMM trial?

I think that these results add to the body of knowledge for effectively treating multiple myeloma patients. Another important aspect is the fact that patients having lenalidomide-refractory disease were successfully treated using the PVd combination. This provides important documentation for using an immunomodulatory drug-containing regimen in those patients that have shown prior disease resistance to that class of compounds (IMIDs).

Wolters Kluwer Health, Inc. All rights reserved.
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