Advances in the Treatment of Multiple Myeloma: Next-Generation Proteasome Inhibition

Online First
Alice Goodman

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, with more than 64,000 people living with this disease and about 21,700 new cases diagnosed each year.1,2 The disease is due to an abnormality in plasma cells that causes them to proliferate in the bone marrow. This can lead to osteolytic lesions and bone destruction in a significant number of patients.3 Over the past decade, the development and implementation of several targeted therapies has revolutionized the treatment of myeloma. These include the first-in-class proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide. In addition to these therapies, numerous investigational agents are now being studied in clinical trials for MM. One such agent is carfilzomib, a next-generation proteasome inhibitor that selectively and irreversibly binds to its target; this results in sustained proteasome inhibition without the off-target effects that occur with bortezomib.4-6

Table 1
Table 1. Phase 2 Clinical Trials of Single-Agent Carfilzomib Use in Multiple Myeloma

As a single agent, intravenous (IV) carfilzomib has undergone extensive phase 2 evaluation for the treatment of relapsed and/or refractory myeloma (Table 1). Investigators are also assessing its safety and efficacy when combined with other agents, both in newly diagnosed and pretreated patients. At the 53rd Annual Meeting of the American Society of Hematology (ASH), held December 10-13, 2011, in San Diego, California, poster and oral presentations focused on encouraging results from clinical trials of carfilzomib use in MM.

Single-Agent Carfilzomib

Dose-response relationship in relapsed and/or refractory MM

Squifflet and colleagues presented findings from a pooled analysis of 430 patients from two phase 2 clinical studies in which carfilzomib was given as a single agent for the treatment of relapsed and/or refractory MM.7 A rigorous, multivariate analysis  demonstrated a highly significant dose-response relationship with carfilzomib across efficacy end points that included overall response rate (ORR, the primary end point), duration of response (DOR), time to progression, progression-free survival (PFS), and overall survival (OS) (P <.001 for all end points). A dose-response relationship was also observed in the depth of response (partial response [PR] or better) across the study population. Although a corresponding dose-toxicity analysis has not been completed, thus far, carfilzomib has been shown to have a similar tolerability profile at doses of 20 mg/m2 and 27 mg/m2.

This analysis was based on nonrandomized trials, and the investigators indicated that it therefore may be subject to bias, some of which can be accounted for by multivariate modeling. Clinical trials are currently under way to evaluate carfilzomib in higher dosing regimens. 

Safety of carfilzomib in relapsed and/or refractory MM

Early trials have reported acceptable tolerability with carfilzomib, including low rates of peripheral neuropathy (PN).8  Singhal and colleagues presented updates of a pooled analysis of 526 pretreated patients with relapsed and/or refractory MM who received single-agent carfilzomib in four phase 2 studies (003-A0, 003-A1, 004, 005) to further evaluate the safety of this agent.6

Discontinuation of therapy due to toxicities occurred in 15% of patients. Grade 3 and 4 adverse events (AEs) were mostly reversible and primarily hematologic. Neuropathy was generally mild to moderate and did not require dose adjustments. In addition, the rate of this toxicity was low: PN of all grades was reported in 73 patients (14%), with 1 treatment discontinuation (<1%) attributed to PN. Less than 1% of patients discontinued carfilzomib due to renal toxicity, and 87% had stable renal function while on therapy. Cardiac events were reported in 7% of all patients (regardless of causality), but fatal cardiac events possibly related to carfilzomib occurred in less than 2% of the study population. Treatment discontinuations attributed to cardiac events included congestive heart failure (2%), cardiac arrest (1%), and myocardial ischemia (<1%).

The investigators concluded that it was not possible to determine the extent to which these AEs could be attributed to comorbidities present at baseline, toxicity from prior chemotherapies, effects of myeloma, carfilzomib, or a combination of any or all of these factors. However, the rates and causes of death were consistent with those previously reported in pretreated patients with end-stage MM.

Impact of cytogenetics on carfilzomib therapy

Specific genetic abnormalities in patients with MM can result in poor response to therapy and shorter survival.9 According to results of a study reported by Jakubowiak and colleagues, carfilzomib appears to be effective despite the presence of high-risk cytogenetics associated with poor prognosis.10

An analysis of the 003-A1 study found that unfavorable cytogenetic characteristics did not adversely impact response to single-agent carfilzomib in heavily pretreated patients with relapsed and/or refractory MM. However, median OS was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities (11.9 months vs 19.2 months). A similar trend was observed for median PFS (3.6 months vs 4.6 months). Of 234 evaluable patients, 75 had ≥1 unfavorable cytogenetic abnormalities including deletion of chromosome 13 (del 13) or hypodiploidy (detected by metaphase cytogenetic analysis) and/or deletion of chromosome 17p13, t(4;14), or t(14;16) (by fluorescence in situ hybridization [FISH]).

The presence of unfavorable cytogenetics did not significantly impact DOR or response rates of patients in this study. ORR was 23% in those with normal cytogenetics versus 30% in those with unfavorable cytogenetics. A trend was observed toward higher response rates in the presence of t(4;14) and lower response rates for t(14;16), but the numbers of patients were too small in these subgroups for statistical significance.

The investigators concluded that the trend toward shorter PFS and OS in the presence of cytogenetic abnormalities in this trial may reflect the lack of effective alternative therapies available after carfilzomib treatment, resulting in a higher discontinuation rate among patients with unfavorable cytogenetics, or the poor prognosis in these patients despite improvement in response with carfilzomib. The role of cytogenetics continues to be evaluated in ongoing clinical trials of carfilzomib. 

Rapid response to single-agent carfilzomib

A separate exploratory analysis of two phase 2 studies (003-A1 and 004) by Wang and colleagues showed that rapid responses are achieved with single-agent carfilzomib in patients with relapsed and/or refractory MM. Specifically, they found that minimal response (MR) or better occurs within a median of 0.5 to 1 month.11 This analysis included 257 response-evaluable, heavily pretreated patients from the 003-A1 trial, and 161 response-evaluable patients (bortezomib-naive and bortezomib-treated) from the 004 trial. 

When examining the cohorts separately, the investigators found that the heavily pretreated patients in study 003-A1 achieved PR or better at a median of 1.9 months and MR or better at a median of 1 month. In study 004, the bortezomib-naive patients achieved PR or better at a median of 1.7 months and MR or better at a median of 0.5 month and the bortezomib-treated patients achieved PR or better at a median of 1.4 months and MR or better at a median of 1 month.

When results were analyzed according to specific baseline characteristics, a trend was observed toward longer time to clinical benefit rate (MR or better) in patients treated with a greater number of previous therapeutic regimens, although prior autologous stem cell transplant (ASCT) did not appear to affect this rate.

The investigators concluded that the data compare favorably to historical data for agents frequently used in the treatment of relapsed and/or refractory myeloma, including bortezomib, dexamethasone, lenalidomide, liposomal doxorubicin, and thalidomide. In addition, this preliminary analysis represents the first focused evaluation of the dynamics of response to single-agent carfilzomib, and further investigation in the setting of ongoing and future trials is merited.

Safety and efficacy of prolonged carfilzomib infusion

Updated results of the phase 1b/2 007 trial reported by Papadopoulos and colleagues suggest that single-agent carfilzomib can achieve excellent response rates in heavily pretreated patients with relapsed and/or refractory MM.12 The study included 33 patients who progressed on at least 2 prior lines of therapy. Carfilzomib was administered via 30-minute IV infusions in “stepped up” doses at 4 different levels: 20/36 mg/m2, 20/45 mg/m2, 20/56 mg/m2, and 20/70 mg/m2. ORR was 60% with the 20/56 mg/m2 dose of carfilzomib (maximum tolerated dose), which the investigators described as “noteworthy” for a heavily pretreated population.

The safety profile for carfilzomib was acceptable. The most common grade 3 or 4 AEs in the 20/56-mg/m2 cohort were thrombocytopenia (38%), anemia (21%), hypertension (13%), and pneumonia (13%). The majority of AEs were grade 1 and 2. One patient in the 20/56-mg/m2 cohort experienced grade 1 PN. 

The investigators concluded that the pharmacokinetic and pharmacodynamic results of this trial reinforce preclinical data showing a dose-response relationship and suggest that longer infusion times allow higher doses of carfilzomib and more robust proteasome inhibition. These findings suggest that higher dosing of carfilzomib may improve efficacy with acceptable safety. 

Carfilzomib use in bortezomib-naïve patients

Vij and colleagues reported final results of study 004, a multicenter, nonrandomized, open-label, phase 2 trial of 164 patients with relapsed and/or refractory MM who were treated with 1 to 3 prior lines of therapy.13 Cohort 1 consisted of 59 bortezomib-naive patients treated with carfilzomib 20 mg/m2 (35 bortezomib-treated patients were also included in cohort 1, but results were reported previously).14 Cohort 2 included 70 bortezomib-naive patients treated initially with carfilzomib 20 mg/m2 (cycle 1), then escalated to 27 mg/m2 for all treatment cycles thereafter.

Median age of patients in this study was 65 years, and median time to diagnosis was 3.6 years. Approximately 80% of patients had favorable cytogenetics, and 94% had an Eastern Cooperative Oncology Group performance status of 0-1. Patients received a median of 6 or 7 cycles. Approximately 30% of cohort 1 and 40% of cohort 2 received the full planned cycles of therapy.

Response to carfilzomib treatment (time to achieve PR) was rapid at a median of 1 month for cohort 1 and 1.9 months for cohort 2. Median PFS was 8.1 months for cohort 1 and not yet reached at the time of reporting for cohort 2. ORR (the primary end point of the trial) was 42% in cohort 1 and 52% in cohort 2, and the clinical benefit rate was 59% and 64%, respectively. Median DOR was 13.1 months in cohort 1 and not yet reached in cohort 2.

Table 2
Table 2. Number of Cycles Completed and Reasons for Treatment Discontinuation

Toxicities in this trial were mainly hematologic. Notable AEs were fatigue, nausea, anemia, and dyspnea. The rates of grade 3 and 4 toxicity were acceptable. Treatment-emergent PN was reported in 15% of cohort 1 and 19% of cohort 2, but this did not lead to treatment discontinuation. Overall, AEs led to discontinuation in approximately 15% of patients (Table 2). 

During an oral presentation at ASH, Dr Ravi Vij, from Washington University School of Medicine, St Louis, Missouri, stated that if carfilzomib gains approval for relapsed and/or refractory MM, he envisions that the drug will continue on for use in combination regimens and in the frontline setting. “We still don’t know what the best dose of carfilzomib is. Studies have escalated the dose up to 56 mg/m2,” he stated. “Tolerability may be improved by slow infusion, especially at doses above 20 mg/m2 (PX-171-007).”

Multidrug Carfilzomib-Based Therapy

Carfilzomib with other agents in relapsed and/or refractory MM

Usmani and colleagues presented results of a phase 2 study of 81 heavily pretreated patients with relapsed and/or refractory MM who were participating in the UARK Compassionate Use Protocol.15 Patients in this trial received carfilzomib as a single agent at 20 mg/m2 for days 1 and 2 of the first cycle, then the dose was escalated to 27 mg/m2 for the rest of that cycle; dexamethasone 4 mg was given with each dose. From cycle 2 onward, patients who failed to achieve PR or better on cycle 1 could receive escalated carfilzomib doses of 36, 45, and 54 mg/m2 plus dexamethasone 20 mg. In the absence of PR from cycle 2 onward, additional antimyeloma drugs could be added with subsequent cycles.

Of the 81 patients, 79 had prior ASCT; 60 had at least 2 transplants. All patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan, or steroids. During the study, 71 patients discontinued therapy due to progression, death, or toxicity.

At 12 months, OS and PFS rates were 41% and 5%, respectively. In univariate and multivariate analyses, an OS benefit was observed in patients receiving at least 3 cycles of carfilzomib (P <.001). Myelotoxicity (grade 3 or higher) was observed in the majority of patients (anemia, 79%; leukopenia, 83%; and thrombocytopenia, 100%). Grade 1 and 2 PN was present at baseline in 53% of patients; grade 3 or higher PN was seen in 7% of patients after cycle 1 and in 8% after cycle 5. Surprisingly, worsening or new neuropathy was not observed in the majority of patients.

The investigators concluded that combining carfilzomib with other antimyeloma agents on a compassionate-use basis allowed them the opportunity to make observations regarding potential clinical synergy of particular combinations. Specifically, the combination of carfilzomib plus dexamethasone with lenalidomide and vorinostat was shown to be promising in a subset of relapsed and/or refractory MM patients.

Carfilzomib, lenalidomide, and low-dose dexamethasone in newly diagnosed MM

In a phase 1/2 trial by Jakubowiak and colleagues, treatment with a regimen of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) was shown to be safe and effective for newly diagnosed patients with MM.16 These investigators presented more mature data from their study, which confirmed that CRd was highly active and well tolerated in this population of patients.17

Patients in this trial were placed on 1 of 3 treatment dosing schedules and received 20 mg/m2, 27 mg/m2, or 36 mg/m2 of carfilzomib to determine the maximum tolerated dose. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for 8 cycles. They also received lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly for cycles 1 to 4 and 20 mg weekly for cycles 5 to 8. 

Transplant-eligible patients who achieved a PR or greater could proceed to stem cell collection (SCC) with growth factor support alone after 4 cycles. There was no difficulty in harvesting stem cells from patients treated with CRd; 100% of attempted stem cell harvests were successful in the 24 patients in whom harvest was attempted.

All patients received 4 more cycles of CRd, with transplant-eligible patients having the option to proceed with ASCT. Patients who continued therapy beyond 8 cycles received maintenance CRd (carfilzomib on days 1, 2, 15, 16; lenalidomide on days 1-21; and dexamethasone weekly) in 28-day cycles at the doses tolerated at the end of 8 cycles. 

Median age of patients was 59 years; 43% were aged 65 years or older. One third had unfavorable cytogenetics: del 13 (by meta­phase) or hypodiploidy or t(4;14), t(14;16), or del 17p (by FISH).

Table 3
Table 3. Best Responses to a Frontline Regimen of Carfilzomib, Lenalidomide, and Dexamethasone.

Responses to CRd were rapid. Of the 49 response-evaluable patients, 46 achieved PR or better after 1 cycle with 100% achieving PR or better after 4 cycles, 100% achieving very good partial response (VGPR) or better after 12 cycles, and 79% achieving complete response (CR)/near-CR after 12 cycles. Responses to CRd were also durable and were not affected by stage or cytogenetics (Table 3). At 9.5 months of follow-up, only 1 patient had progressed and all patients were still alive.

The CRd regimen was also well tolerated. Grade 3/4 thrombocytopenia was reported in ~10% of patients, anemia in ~18%, and neutropenia in ~12%. No grade 3/4 PN was reported.

The investigators concluded that the responses seen with CRd compared favorably to the best frontline regimens currently used for MM. This combination provided rapid response, and DOR increased with longer duration of treatment. Toxicities were manageable and there was a limited need for dose modification.

Carfilzomib, thalidomide, and dexamethasone as induction prior to high-dose melphalan in newly diagnosed MM

A phase 2 trial from the Erasmus Medical Center and the European Myeloma Network evaluated an induction regimen of carfilzomib, thalidomide, and dexamethasone (CARTHADEX) in patients with newly diagnosed MM who were candidates for high-dose therapy.18

Sonneveld and colleagues reported on 45 patients enrolled in this trial who were evaluable for response and safety. Patients received induction therapy with 4 cycles of carfilzomib at 20/27 mg/m2, plus thalidomide 200 mg, and dexamethasone 40 mg on a 28-day cycle. SCC was performed with cyclophosphamide 2 g/m2 and growth factor support. After high-dose melphalan (200 mg/m2) and ASCT, consolidation therapy was given with 4 cycles of carfilzomib 27 mg/m2, thalidomide 50 mg, and dexamethasone 40 mg.

SCC was successful in 100% of patients (N=16) at the time of the report. Four patients discontinued therapy: 2 who developed progressive disease and 2 who experienced severe AEs in cycle 1. After induction therapy, the ORR was 84% (CR, 16%; VGPR, 29%; PR, 39%).  

Grade 1 and 2 PN was reported in 24% of patients, mostly related to thalidomide; 4% had grade 3 tumor lysis syndrome. Grade 1 and 2 gastrointestinal toxicity was observed in 4% of patients, and grade 3 in 4%. Grade 1 and 2 infection was reported in 4%, and grade 3 in 4%. 

During an oral presentation, Dr Pieter Sonneveld, from Erasmus Medical Center, Rotterdam, stated, “Thus far, bortezomib has been the most effective regimen prior to high-dose therapy in transplant-eligible patients with MM. Bortezomib, thalidomide, and dexamethasone (VTD) produces the highest CR rate after induction and after high-dose melphalan and ASCT. VTD is also effective consolidation therapy, which further improves response. CARTHADEX builds on VTD, re­placing bortezomib with carfilzomib. Our study showed that this induction regimen is feasible and tolerable. The response after induction is rapid and equals that seen with VTD.” 

Conclusion and Future Directions

There has been remarkable progress in the treatment of MM over the past several years, and it is clear that the use of newer, targeted therapies has contributed substantially to this reality. The next generation of antimyeloma agents offers the promise of improving outcomes even further. As shown in recent phase 2 studies, carfilzomib is safe and effective as a single agent and in combination regimens. In particular, it produces less PN than bortezomib, and other toxicities appear manageable. 

Carfilzomib is now being studied in two phase 3 trials. The ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and DexamethaSone for the treatment of PatIents with Relapsed Multiple MyEloma, PX-171-009)  trial is an international, randomized phase 3 trial that is evaluating the safety and efficacy of the combination of lenalidomide and low-dose dexamethasone, with and without carfilzomib, in patients with MM treated with 1 or more prior therapies.19 The FOCUS (CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study, PX-171-011) trial is evaluating single-agent carfilzomib in patients with relapsed and/or refractory MM who have received 3 or more prior therapies versus best supportive care.20

References

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  3. Newly diagnosed patients: what is multiple myeloma - definition. Multiple Myeloma Re­search Foundation Web site. http://www.themmrf.org/living-with-multiple-myeloma/newly-diagnosed-patients/what-is-multiplemyeloma/definition.html. Accessed January 12, 2012.
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  7. Squifflet P, Michiels S, Siegel DS, et al. Multivariate modeling reveals evidence of a dose-response relationship in phase 2 studies of single-agent carfilzomib. Poster presentation at: the 53rd Annual Meeting of the American Society of Hema­tology (ASH); December 10-13, 2011; San Diego, California. Abstract 1877.
  8. O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15:7085-7091. 
  9. Newly diagnosed patients: genetic abnormalities in multiple myeloma. Multiple Myeloma Research Foundation Web site. http://www.themmrf.org/living-with-multiple-myeloma/newly-diagnosed-patients/what-is-multiple-myeloma/genetic-abnormalities.html. Accessed January 12, 2012.
  10. Jakubowiak AJ, Siegel DS, Singhal S, et al. Unfavorable cytogenetic characteristics do not adversely impact response rates in patients with relapsed and/or refractory multiple myeloma treated with single-agent carfilzomib on the 003 (A1) study. Poster presentation at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 1875.
  11. Wang L, Siegel DS, Jakubowiak AJ, et al. The speed of response to single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma: an exploratory analysis of results from 2 multicenter phase 2 clinical trials. Poster presentation at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 3969.
  12. Papadopoulos KP, Lee P, Singhal S, et al. Phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma: updated efficacy and tolerability from the completed 20/56mg/m2 expansion cohort of PX-171-007. Poster presentation at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 2930.
  13. Vij R, Kaufman JL, Jakubowiak AJ, et al. Final results from the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Oral and poster presentations at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 813.
  14. Vij R, Siegel DS, Kaufman JL, et al. Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J Clin Oncol. 2010;28(15s). Abstract 8000.
  15. Usmani S, Szymonifka J, Sexton R, et al. Phase II study of carfilzomib (CFZ) combined with other anti-myeloma agents in relapsed-refractory multiple myeloma (RRMM): updates on the UARK compassionate use protocol. Poster presentation at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 2947.
  16. 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 (ASH Annual Meeting Abstracts). 2010;116: Abstract 862.
  17. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). Poster presentation at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 631.
  18. Sonneveld P, Hacker E, Zweegman S, et al. Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan (HDM) in newly diagnosed patients with multiple myeloma (MM): a trial of the European Myeloma Network (EMN). Oral and poster presentations at: the 53rd Annual Meeting of the American Society of Hematology (ASH); December 10-13, 2011; San Diego, California. Abstract 633.
  19. ClinicalTrials.gov. Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Versus Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma. www.clinicaltrials.gov/ct2/show/NCT01080391. Accessed January 17, 2012.
  20. ClinicalTrials.gov. A Study of Carfilzomib vs Best Supportive Care in Subjects With Relapsed and Refractory Multiple Myeloma (FOCUS). www.clinicaltrials.gov/ct2/show/NCT01302392?term=focus+carfilzomib&rank=1. Accessed February 17, 2012.
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Last modified: May 21, 2015