Treating myeloma: the future is already here!

In this issue of Blood, Jakubowiak and colleagues report outstanding results from a phase 1/2 study using carfilzomib—a next-generation proteasome inhibitor that selectively and irreversibly binds to the proteasome, targeting chymotrypsin-like activity—in combination with lenalidomide and low-dose dexamethasone in newly diagnosed multiple myeloma patients. The study shows excellent response rates, deep and durable responses, continued responses during treatment, and limited severe toxicities.¹ 

Newly diagnosed multiple myeloma patients 35 to 81 years old (43% older than 65 years), independent of eligibility status for high-dose melphalan (HDM) followed by an autologous stem cell transplantation (ASCT), received carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) induction therapy in 28-day cycles for up to 8 cycles. Transplant- eligible patients achieving at least a partial remission (PR) could proceed to stem cell collection any time after cycle 4 but then were to resume CRd treatment with an option to proceed to HDM/ASCT. The decision to proceed to HDM/ASCT was not mandated and was left to the discretion of the patient and treating physician. After 8 cycles, patients received maintenance-CRd (cycles 9-24). Individual study drugs were continued at the same dose level as cycle 8; lenalidomide and dexamethasone were continued at the same dosing schedule, while carfilzomib was administered less frequently. After completion of 24 cycles, single-agent lenalidomide was recommended off protocol.

Median follow-up was 13 months (range: 4-25 months) with all 53 patients evaluable for response. Phase 1 dosing cohorts included 4 patients at carfilzomib 20 mg/m², 13 patients at 27 mg/m², and 18 patients at 36 mg/m². An additional 18 patients enrolled as part of the phase 2 expansion at the maximum planned dose level of 36 mg/m². Ten patients discontinued treatment during induction: 1 due to CRd toxicity at dose level 3 (pulmonary edema), 7 proceeded to HDM/ASCT, and 2 due to patient/investigator preference. Thirty-six patients proceeded to maintenance CRd with 1 patient discontinuing treatment due to progressive disease and 1 patient preferring to discontinue treatment while in very good partial remission (VGPR), who subsequently progressed.

At the end of cycle 1, the mean M-protein level was reduced by 67% from baseline, and at the end of cycle 2, the mean level was reduced by 81% from baseline. Prolonged treatment with CRd increased the proportion of patients in at least near complete remission (nCR). At the end of 4 cycles, 38% of patients were in at least nCR with 6% in stringent complete remission (sCR). In patients who received 8 or more treatment cycles, 78% achieved at least nCR, with 61% in sCR. In the subset of patients who did not proceed to transplantation (n = 46), 67% achieved at least nCR (48% sCR), 83% at least VGPR, and 100% at least PR after a median of 12 cycles (range: 1-25). In 22 patients with CR or suspected CR, there was no evidence of minimal residual disease (using flow cytometry) in 20 (91%). ISS stage and presence of unfavorable cytogenetics did not impact rate or depth of responses. In addition, the durations of the responses were equally as impressive. With median follow-up of 13 months (range: 4-25), 24-month progression-free survival estimate was 92%.

Overall, the CRd regimen was well tolerated during induction; dose modifications were limited (31%), and > 50% of patients remained on originally assigned doses. Grade 3/4 nonhematologic adverse events (AEs) included hypophosphatemia (25%), hyperglycemia (23%), deep vein thrombosis/pulmonary embolism (9%), rash (8%), and elevated liver function test (8%). Hematologic grade 3/4 toxicities included anemia (21%), thrombocytopenia (17%), and neutropenia (17%). Importantly, peripheral neuropathy was limited to grades 1 (17%) and 2 (6%). There were no grade 3 or 4 peripheral neuropathy toxicities reported. As a comparison, in the bortezomib-based frontline RVD phase 1/2 study,²  the rate of sensory neuropathy was 80% for all grades and 2% for grade 3 with rates of 18% and 2%, respectively, for motor neuropathy after only 4 cycles.

Beyond the observed promising results, the above study addresses a few existing fundamental questions that are critical to the current landscape of myeloma paradigms. For example, as pointed out by the authors, only 7 of the 35 transplant-eligible patients proceeded to HDM/ASCT and the depth and duration of responses were noninferior for remaining patients. This supports, albeit based on small numbers, the application of delayed HDM/ASCT in newly diagnosed multiple myeloma patients treated with CRd. The concept of delayed HDM/ASCT is currently being evaluated in ongoing trials using bortezomib in combination with lenalidomide and low-dose dexamethasone (www.ClinicalTrials.gov/NCT01191060) and in a study using a sequence of combination regimens (www.ClinicalTrials.gov/NCT01208766). Another fundamental question is: in the era of well-tolerated potent therapy, what is truly the optimal timing for treatment initiation in myeloma (ie, wait until symptomatic disease and possible debilitating pathologic fractures occur or not)? To address this issue, CRd is currently being assessed in a trial (www.ClinicalTrials.gov/NCT01572480) open for patients with “early myeloma” (ie, smoldering myeloma with features of high-risk for transformation to symptomatic multiple myeloma³ ). Lastly, a new and controversial fundamental question may be to challenge the scientific basis behind the current risk-adapted treatment paradigm commonly used in the standard-of-care situation (ie, using FISH and other markers to identify groups of high risk and standard risk and then modify treatment accordingly). Indeed, compared with conventional treatment strategies, the concept of applying all available therapeutic agents in Total Therapy (TT) clinical trials for newly diagnosed multiple myeloma⁴ —with the intent of developing curative treatment—has reported its greatest improved clinical outcomes in gene expression profiling (GEP)–defined low-risk disease. In contrast, patients with GEP-defined high-risk designation, pertinent to almost 20% of patients, continue to have poor clinical outcomes even when treated with TT.⁵  As extrapolated from these facts,^4,5  one may conjecture that CRd, given that the observed deep and durable responses with manageable toxicities¹  will be validated in future studies, could have its largest impact in standard-risk patients (ie, GEP-defined low-risk), while patients whose tumors demonstrate high-risk biology need something completely different, perhaps using an approach with targeted “smart” drugs (ie, defining molecular pathways that can be targeted therapeutically, such as MEK/ERK and TP53) rather than attempting to eradicate/control the disease with “more of the same.”^4,5  The ongoing ASPIRE trial (www.ClinicalTrials.gov/NCT01080391) for patients with relapsed multiple myeloma will allow comparisons of CRd with Rd, stratified by standard-risk versus high-risk disease patients. Importantly, the definition of the optimal treatment strategy (eg, for high-risk vs standard-risk multiple myeloma) is complex and varies from patient to patient based on depth and duration of response, survival, costs, quality of life, and other aspects.³ 

In summary, Jakubowiak and colleagues report exceptional and bold results that bring hope and excitement to myeloma patients and treating physicians.¹  The rate for any grade of peripheral neuropathy was only 23% with no grade 3 events, suggesting carfilzomib as an alternative proteasome inhibitor option for patients with peripheral neuropathy without compromising efficacy.¹  Another ongoing trial for newly diagnosed multiple myeloma patients (www.ClinicalTrials.gov/NCT01402284) with similar design and more focus on advanced molecular monitoring will build on results reported by Jakubowiak et al and give new insight into depth of responses at the genetic level. In addition, long-term follow-up of the current study's patients will help to better characterize the durability of the response with the CRd regimen, and the relationship of response to progression-free survival and overall survival, as well as long-term tolerability. Overall, this study gives us instant access to the future for multiple myeloma treatment. In the coming years, we will have several new antimyeloma agents available as oral formulations. It is an exciting and very promising time to treat myeloma patients with unprecedented outcomes!