Pomalidomide in lenalidomide-refractory multiple myeloma and carfilzomib in refractory and newly diagnosed multiple myeloma

From the Oncologist's Perspective - Evolving therapies for multiple myeloma

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Pomalidomide in lenalidomide-refractory multiple myeloma and carfilzomib in refractory and newly diagnosed multiple myeloma

Pomalidomide and carfilzomib represent active and well-tolerated new options in combination regimens.

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Matt Stenger, MS

What's new, what's important

Treatment of multiple myeloma is evolving rapidly. It is tough to keep up with the rapid pace of new drugs, updates, and changes in the standard of care. In this issue of Community Oncology we bring to you two new exciting drugs on the horizon, pomalidomide and carfilzomib. In addition to introducing these two new drugs, we have asked Dr. Noopur Raje to explain how she treats a newly diagnosed patient with multiple myeloma.

Pomalidomide, a thalidomide (Thalomid) analog, is a promising myeloma drug with encouraging responses in relapsed/refractory myeloma patients. Carfilzomib is a novel proteasome inhibitor. When combined with lenalidomide (Revlimid) in the first-line setting, it produced a 100% response rate. Phase III studies are in progress or being completed. It will be exciting to see the final results of these studies.

With this issue we are changing the format of Community Translations to incorporate the mechanism of action or pathophysiology of some of these new advances so that a clinician can relate to them in a clinical setting.

--Jame Abraham, MD, Editor

Two of the most promising drugs on the horizon for patients with multiple myeloma (MM) are pomalidomide and carfilzomib. Both agents have shown significant single-agent activity in clinical trials. They seem to work in patients whose MM is resistant to other treatments and are being studied in combination regimens.

Pomalidomide

Pomalidomide is a new immunomodulatory drug (IMiD) with high in vitro potency. In initial experience with pomalidomide and low-dose dexamethasone in relapsed MM, Lacy and colleagues found an overall response rate of 63% and observed responses in some patients who were refractory to lenalidomide (Revlimid), suggesting an absence of cross-resistance between pomalidomide and other IMiDs. In a recently reported phase II study,¹ these investigators assessed the combination of pomalidomide and low-dose dexamethasone in patients with lenalidomide-refractory MM, finding the combination to be highly active and well tolerated.

In this study, 34 patients with lenalidomide-refractory MM were treated with oral pomalidomide (2 mg daily) and dexamethasone (40 mg once weekly) in 28-day cycles. Patients had a median age of 61.5 years, 68% were male, 85% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and 41% were categorized as high risk. The median time from diagnosis was 62 months. The median number of prior chemotherapy regimens was four. In addition to lenalidomide, 58% of patients had received prior thalidomide (Thalomid), and 59% had received prior bortezomib (Velcade); 68% of patients had undergone prior autologous stem cell transplantation, and 53% had prior radiation therapy. Twenty patients (59%) had peripheral neuropathy at baseline.

Patients received a median of 5 cycles (range, 1−14) of pomalidomide plus low-dose dexamethasone. Prophylaxis for venous thromboembolism was given in 204 of 209 treatment cycles (aspirin in 150 cycles and warfarin in 54 cycles). Treatment responses consisted of a very good partial response in 9%, a partial response in 23%, and a minimal response in 15%, for an overall clinical benefit rate of 47%; 35% of patients had stable disease, and 18% had disease progression. The median time to response was 2 months. Response was observed in 8 of 14 (57%) high-risk patients, in 8 of 19 (42%) who received previous thalidomide treatment, and in 9 of 20 (45%) who were given previous bortezomib treatment. In eight patients with stable disease, the pomalidomide dose was increased to 4 mg/d, with one patient improving to a partial response. The median duration of response in 11 patients with a partial response or better was 9.1 months. The median progression-free survival was 4.8 months, and progression-free survival did not differ between high-risk and standard-risk patients. The median overall survival was 13.9 months. During follow-up, treatment was stopped due to disease progression in 23 patients, 3 withdrew from the study due to patient/physician discretion, and 8 continued to receive treatment. Seven patients died, all due to disease progression. The median follow-up of patients remaining alive was 8.3 months.

Pomalidomide/dexamethasone treatment was well tolerated. Toxicity consisted mostly of myelosuppression. Grade 3 or 4 hematologic toxicity at least possibly related to treatment occurred in 38% of patients, including neutropenia in 29%, anemia in 12%, and thrombocytopenia in 9%. The most common grade 3/4 nonhematologic toxicity was fatigue, which occurred in 9% of patients (all grade 3); grade 3 pneumonitis, edema, pneumonia, and folliculitis were each observed in one patient. Nine patients (26%) had neuropathy during treatment (six grade 1, three grade 2); they included six patients with neuropathy at baseline, three of whom had a worsening of grade.

Carfilzomib

Carfilzomib is a highly selective epoxyketone proteasome inhibitor with minimal affinity for nontarget proteases. In a recent phase II trial in patients with relapsed/refractory MM, reported at the 2010 American Society of Hematology (ASH) meeting, carfilzomib produced durable responses and was well tolerated.² An ongoing phase I/II trial assessing carfilzomib, lenalidomide, and dexamethasone in newly diagnosed MM, also reported at the 2010 ASH meeting, has shown good activity and tolerability of the regimen.³ A phase III trial comparing carfilzomib plus lenalidomide and low-dose dexamethasone versus lenalidomide and low-dose dexamethasone in relapsed MM has been initiated.

Relapsed/refractory MM

In the trial in patients with relapsed/refractory MM, 266 patients with multiply relapsed MM who had disease refractory to their last treatment received carfilzomib (20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16) every 28 days for the first cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles.2 Prior therapies included bortezomib, either lenalidomide or thalidomide, and an alkylating agent. Patients had a median duration of MM of 5.4 years and had received a median of 5 prior lines of chemotherapy and a median of 13 antimyeloma treatments; prior treatments included bortezomib in 99.6% of patients (a median of two prior regimens containing bortezomib), lenalidomide in 94%, thalidomide in 74%, corticosteroids in 98%, alkylating agents in 91%, and stem cell transplantation in 74%. Overall, 65% of patients were refractory to bortezomib prior to study entry.

At the time of reporting, 79 patients (30%) had completed at least 6 cycles of study treatment, approximately 11% had completed 12 cycles (with most entering an extension phase of the study), and 15 patients remained on study (all with more than 10 cycles of study treatment). Among 257 patients evaluable for response, 0.4% (one patient) had a complete response, 4.7% had a very good partial response, and 19% had a partial response, for an overall response rate of 24%; an additional 12% of patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease for at least 6 weeks was achieved in 32%. Among patients with a partial response or better, the median duration of response was 7.4 months. Among patients with a minimal response, the median duration of response was 6.3 months, indicating durable minor responses.

Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 8%, and anemia in 7%.⁴ Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.²

Newly diagnosed MM

In an ongoing phase I/II trial, patients with newly diagnosed MM are receiving carfilzomib, lenalidomide, and dexamethasone.³ Carfilzomib is started at 20 mg/m2 (dose level 1) and increased to 27 mg/m2 (dose level 2) and 36 mg/m2 (dose level 3) given IV on days 1, 2, 8, 9, 15, and 16 in 28-day cycles. Lenalidomide is given at 25 mg/d on days 1−21 in each cycle, and dexamethasone is given weekly at 40 mg during cycles 1−4 and at 20 mg during cycles 5−8. Patients with a partial response or better are eligible to proceed to stem cell collection and autologous stem cell transplantation after at least 4 cycles and can continue study treatment after transplantation. After completion of 8 cycles, patients are to receive maintenance cycles consisting of carfilzomib on days 1, 2, 15, and 16; lenalidomide on days 1−21; and weekly dexamethasone at doses tolerated at the end of 8 cycles. A planned 36 patients are to be treated at the carfilzomib maximum tolerated dose.

At the time of reporting, 24 patients had been enrolled, 4 at dose level 1, 14 at dose level 2, and 6 at dose level 3. Toxicity data were available for 21 patients, including 19 who completed at least 1 cycle of treatment. A single dose-limiting toxicity event was observed, consisting of nonfebrile neutropenia in a patient at dose level 2. The maximum tolerated dose had not yet been reached. Grade 3/4 hematologic toxicities consisted of neutropenia in three patients, thrombocytopenia in three patients, and anemia in one patient. Grade 3 nonhematologic toxicities included five cases of elevated blood glucose levels, deep vein thrombosis during aspirin prophylaxis in one patient, and fatigue in one patient. Emergent peripheral neuropathy was observed in two patients, who developed grade 1 neuropathy.

At the time of reporting, 23 patients continued on treatment, with 20 having no need for dose modifications. After a median of 4 months of treatment (range, 1−8 months), the preliminary response rate in 19 evaluable patients completing at least 1 cycle was 100% with at least a partial response, including 63% with a very good partial response and 37% with a complete response or near-complete response. Partial responses were observed in 17 of 19 patients after 1 cycle, with responses improving in all patients with continuing treatment. Seven patients had proceeded to stem cell collection using growth factors only after a median of 4 cycles, and all resumed study treatment after stem cell collection. No disease progression had been observed in any of the evaluable patients, and all remained alive.

References

1. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010;24:1934−1939.

2. Siegel DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

3. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood 2010;116:862.

4. Singhal SB, Siegel DSD, Martin T, et al. Pooled safety analysis from phase 1 and 2 studies of carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (MM). Blood 2010;116:1954.

Body

Noopur Raje, MD, Massachusetts General Hospital Cancer Center; Division of Hematology and Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Although multiple myeloma (MM) remains an incurable bone marrow

cancer, survival rates have improved markedly over the past decade. An

understanding of MM pathobiology (Figure 1) and improvement in stem cell

transplantation, better supportive care, and novel therapies with

higher efficacy and lower toxicity are all responsible for this

improvement. The availability of a rich pipeline of novel agents

undergoing early-phase clinical trials in MM is an exciting and active

area of research.¹

Current treatment

Over the past several years, five therapeutic strategies have

received US Food and Drug Administration (FDA) approval either as

monotherapy or in combination for treating MM, with thalidomide

(Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) as

important backbone drugs in these approaches. In the upfront setting,

thalidomide with dexamethasone² and bortezomib in combination with melphalan and prednisone³

increased the overall response rate and significantly prolonged time to

disease progression and are FDA approved. For treatment of relapsed MM,

bortezomib alone⁴ and in combination with pegylated liposomal doxorubicin (Doxil),⁵ as well as lenalidomide/dexamethasone,⁶

have been approved. Results of a recent phase III randomized clinical

trial suggest that lower doses of dexamethasone provide a survival

advantage, at least in the upfront setting, mainly due to the increased

toxicity of high doses of dexamethasone.⁷

The availability of these novel agents has not only provided us

with several treatment options but has had an important impact on the

overall survival of our patients. To improve upon current outcomes,

optimal combinations of bortezomib, thalidomide, and lenalidomide are

currently under evaluation in phase II/III clinical trials.

Novel approaches

The preceding review refers to recent data on pomalidomide, the

newest immunomodulatory drug (IMiD) analog, which has shown single-agent

activity in phase I studies and was subsequently tested in a phase II

trial in combination with low-dose dexamethasone in patients with

relapsed or refractory MM. Pomalidomide/dexamethasone was found to be

highly active and well tolerated, providing a clinical benefit in 47% of

patients and no grade 3 neuropathy. These findings have led to a large

phase II study, which has completed accrual and is awaiting analysis.

Another promising agent discussed here is the novel proteasome

inhibitor carfilzomib. Although bortezomib is an effective agent in MM,

about 20% of newly diagnosed patients are resistant to bortezomib, and,

ultimately, all patients relapse and develop resistance to the drug.

Carfilzomib irreversibly blocks chymotrypsin-like activity and in phase I

studies achieved more than 80% proteasome inhibition. Encouraging data

presented at the 2010 annual meeting of the American Society of

Hematology demonstrated that it was well tolerated and had an overall

clinical benefit rate of 36% in relapsed/refractory MM.⁸ In the upfront setting, carfilzomib combined with lenalidomide led to a 100% response rate.⁹

This combination with low-dose dexamethasone is currently

undergoing testing in a phase III registration trial. These data,

therefore, provide important therapeutic options among the armamentarium

of current and future antimyeloma therapies, helping transform MM into

an even more chronic disease than it is today and ultimately leading to a

cure.

References

1. Cirstea D, Vallet S, Raje N. Future novel single agent and combination therapies. Cancer J 2009;15:511-518.

2. Rajkumar

SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind,

placebo-controlled study of thalidomide plus dexamethasone compared

with dexamethasone as initial therapy for newly diagnosed multiple

myeloma. J Clin Oncol 2008;26:2171-2177.

3. San

Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and

prednisone for initial treatment of multiple myeloma. N Engl J Med

2008;359:906-917.

4. Richardson

PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose

dexamethasone for relapsed multiple myeloma. N Engl J Med

2005;352:2487-2498.

5. Orlowski

RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of

pegylated liposomal doxorubicin plus bortezomib compared with bortezomib

alone in relapsed or refractory multiple myeloma: combination therapy

improves time to progression. J Clin Oncol 2007;25:3892-3901.

6. Dimopoulos

MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival

from the MM-009 and MM-010 phase III trials of lenalidomide plus

dexamethasone in patients with relapsed or refractory multiple myeloma.

Leukemia 2009;23:2147-2152.

7. Rajkumar

SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose

dexamethasone versus lenalidomide plus low-dose dexamethasone as initial

therapy for newly diagnosed multiple myeloma: an open-label randomised

controlled trial. Lancet Oncol 2010;11:29-37.

8. Siegel

DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label,

single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with

relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

9. Jakubowiak

AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and

dexamethasone in newly diagnosed multiple myeloma: initial results of

phase I/II MMRC trial. Blood 2010;116:862.

Dr. Raje can be reached at [email protected].

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