Proceedings From a Post-IMW Roundtable

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Introduction

The 14th International Myeloma Workshop (IMW 2013) held April 3-7, 2013, in Kyoto, Japan, was attended by renowned researchers and thought leaders from around the world. The numerous abstracts and presentations at this workshop demonstrated the outstanding progress that has been made in multiple myeloma (MM) management in the past 10 to 15 years and provided important insights for future clinical practice.

SMOLDERING MYELOMA

Should Smoldering Multiple Myeloma Be Treated?

Smoldering multiple myeloma (SMM) is a precursor to symptomatic myeloma, and is characterized by an excess of monoclonal protein in the blood and urine, in which the patient experiences none of the symptoms (ie, elevated calcium levels, kidney failure, anemia, or bone lesions) typically associated with active disease.1 Overall, the risk for SMM progressing to MM is approximately 10% per year in the first 5 years.¹

Although patients with SMM are at a higher risk for developing active myeloma than the general public, the current standard of care is the so-called “watch and waitâ€� approach, in which they are regularly monitored and treatment only begins once the disease progresses to symptomatic MM. However, certain factors have been shown to be associated with an increased risk of progression in pa­tients with SMM. These include a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10% in the bone marrow; an elevated level of phenotypically abnormal plasma cells in the bone marrow; an abnormal free light chain ratio; the presence of chromosomal abnormalities in plasma cells; and lower than normal levels of one or more types of immunoglobulin.¹

At IMW 2013, María-Victoria Mateos, MD, and Jesús F. San Miguel, MD, discussed the question, “Should we treat smoldering MM?â€�² They began by reviewing the history of studies that investigated the use of melphalan plus prednisone (MP), thalidomide, and/or bisphosphonates in patients with SMM. In the 1980s, a study by Hjorth and colleagues randomized 25 patients to receive MP therapy, started at the time of diagnosis, and another 25 patients to receive deferred therapy, in which MP was started at the time of disease progression. Results showed that no differences in response rate, duration of response (DOR), or survival were observed between treatment groups.³ Due to these findings, and the potential leukemic risk of long-term melphalan, the hematology community decided to dismiss the idea of early treatment and proposed instead that patients with SMM not be treated until they developed symptomatic disease.⁴

Later, when bisphosphonates were added to the MM armamentarium, investigators again decided to explore therapy for SMM. They observed that, although the number of skeletal-related events was lower and bone disease was delayed with these agents, no obvious antitumor effect was observed.⁵

With the advent of novel agents, the idea of early treatment was examined further.⁶ Witzig and colleagues conducted a small trial in which thalidomide plus zoledronic acid was compared with zoledronic acid alone for asymptomatic MM.⁷ Although the thalidomide arm was associated with a delay in time to biologic progression, no effect was seen regarding overall survival (OS) or time to progression (TTP) and the toxicity profile proved challenging. Therefore, the notion of treating SMM with thalidomide was not pursued.

Mateos and colleagues from the Spanish Myeloma Group hypothesized that patients with standard-risk SMM may not benefit from treatment, whereas high-risk patients may desire greater benefit. Therefore, they conducted a study in 125 high-risk patients in which 1 arm received 9 cycles of treatment with lenalidomide plus dexamethasone (Rd), followed by lenalidomide maintenance therapy, whereas the control arm received no treatment until disease progression to active MM.8 The results of this study showed that high-risk patients who received early treatment had significantly better outcomes than patients who did not receive treatment until disease progression. The response rate for the experimental arm was 82%, with 26% complete response (CR). Time to disease progression was longer for the actively treated patients (not yet reached at a median follow-up of 40 months in the experimental arm vs 21 months in the control arm), as was OS at 5 years after diagnosis (94% vs 80%, respectively).

Figure 1

Perspective

“The question, ‘Should we treat SMM?’, has been raised repeatedly over the years, and previous studies indicated that there was no difference in survival between early and deferred treatment. However, none of these previous studies focused on what I think should be the target for treatment in the SMM setting: the high-risk population. When the Spanish Myeloma Group investigated the use of early treatment with Rd in high-risk SMM patients, we found a very similar response rate to what we would expect in symptomatic patients and much higher than the response rates previously reported with thalidomide. In addition, the median TTP has not been reached in the experimental arm, whereas it was 21 months in the control arm.

It is also important to emphasize that tolerability of this orally administered combination therapy was very good. However, probably the most relevant finding of the study is that we have observed a significant benefit in OS with a hazard ratio (HR) of 3.4 with a 3-year OS of 94% in the experimental arm versus 80% in the control arm. I think this is showing for the first time that early treatment could be of clear benefit for patients with high-risk smoldering disease. Additional trials focusing on this SMM population are needed to confirm these results.�

~Jesús F. San Miguel, MD

Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk SMM

On July 20, 2012, the US Food and Drug Administration granted accelerated approval for carfilzomib, a next-generation proteasome inhibitor, for the treatment of patients with MM who had received ?2 prior therapies including bortezomib and an immunomodulatory drug, and demonstrated disease progression on or within 60 days of completion of last therapy.⁹

At IMW 2013, Landgren and colleagues presented preliminary outcomes for 9 evaluable patients with high-risk SMM who were treated with a combination of carfilzomib, lenalidomide, and dexamethasone (CRd) in an ongoing phase 2, single-arm, pilot study.10 Patients received eight 28-day cycles of treatment consisting of carfilzomib (20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16); lenalidomide (25 mg/day on days 1-21); and dexamethasone (20/10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Those who achieved stable disease or better received 12 cycles of lenalidomide maintenance therapy (10 mg/day on days 1-21).

Results showed that all patients responded to CRd therapy. Responses were rapid: the median time to CR/stringent CR, which was achieved in 4 patients, was 107 days. The best response rates (after a median of 5.5 cycles) are shown in Figure 1. Grade 3/4 nonhematologic toxicities included rash/pruritus, heart failure, and liver function abnormalities. Grade 3/4 hematologic toxicities included lymphopenia, anemia, neutropenia, and thrombocytopenia.

Perspective

“In this study, there was an impressive rate of very high-quality responses to CRd, with approximately 80% of patients achieving very good partial response or better (?VGPR). The toxicities observed included hematologic toxicities such as lymphopenia and neutropenia, as well as one case of severe heart failure that required discontinuation of therapy and another case of significant liver dysfunction. To date, none of the evaluable patients have progressed to symptomatic MM. The overall re­sponse rate (ORR) is very encouraging and warrants further study.�

~Paul Richardson, MD

NEWLY DIAGNOSED MM

Cyclophosphamide, Prednisone, and Lenalidomide
vs Melphalan, Prednisone, and Lenalidomide vs Lenalidomide
Plus Dexamethasone

Larocca and colleagues presented the results of a multicenter phase 3 study of cyclophosphamide, prednisone, and lenalidomide (CPR) versus melphalan, prednisone, and lenalidomide (MPR) versus Rd to evaluate the best combination in 663 patients with MM who were not eligible to receive autologous stem cell transplantation (ASCT).11 Results showed that CPR, MPR, and Rd produced response rates in elderly patients (>75 years) that were similar to those seen in the overall population (Figure 2). Grade 3/4 hematologic toxicities were experienced by 62% of patients in the MPR group, 29% of those in the CPR group, and 28% of those in the Rd group. Grade 3/4 nonhematologic adverse events (AEs) were similar in the 3 groups.

Perspective

“I think this is an important trial because it addresses patients who are not eligible for high-dose treatment. The preliminary data indicate that Rd produces good response rates and is much better tolerated than MPR. We are eager to see the impact of this regimen on progression-free survival (PFS) and OS. In addition, it will be important to see what second malignancies are reported. I suspect that fewer secondary malignancies will develop in the group of patients receiving Rd.�

~Meletios A. Dimopoulos, MD

Carfilzomib, Cyclophosphamide, and Dexamethasone

Palumbo and colleagues presented results from a phase 2 study of carfilzomib, cyclophosphamide, and dexamethasone (CCd) in 54 patients with newly diagnosed MM.12 Patients received carfilzomib (20 mg/m2 on days 1 and 2, and 36 mg/m2 on days 8, 9, 15, and 16 in cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 2-9); cyclophosphamide (300 mg/m2 on days 1, 8, and 15); and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for 9 cycles, followed by maintenance with carfilzomib (36 mg/m2 on days 1, 2, 15, and 16) every 28 days until progression.

The median duration of treatment was 5 cycles. Responses improved with the duration of treatment reaching after 9 cycles: 100% partial response (PR), 77% VGPR, and 53% CR/near-complete response (nCR). Responses were rapid, with the median time to PR of 1 month and the median time to CR of 2 months. After a median follow-up of 7.5 months, the 1-year PFS was 87% and the 1-year OS was 88%. Grade 4 hematologic toxicities included neutropenia (5%). Grade 3/4 nonhematologic toxicities were infection (10%), cardiac events (5%), and gastrointestinal complications (2.5%). Five patients (12%) discontinued treatment and 7 patients (17%) required carfilzomib dose reductions due to AEs.

Perspective

“This is an important preliminary study of the frontline use of CCd. The response rate is remarkable. Essentially all patients achieved at least a PR, including approximately 1 in 4 patients who achieved an sCR. In addition, the responses were rapid. The PFS and OS data are excellent, as well. Furthermore, this treatment was well tolerated and the discontinuation rate was low; about 10% of patients discontinued treatment due to toxicities. I believe this is a very interesting combination that requires further evaluation in phase 3 trials.�

~Meletios A. Dimopoulos, MD

Cyclophosphamide, Bortezomib, and Dexamethasone

Areethamsirikul and colleagues presented results from a phase 2 study of induction therapy with the combination of cyclophosphamide (300 mg/m2 weekly); bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11); and dexamethasone (40 mg on days 1-4, 9-12, and 17-20) (CyBorD), given for four 28-day cycles, in newly diagnosed MM patients preparing for ASCT.13 Results showed an ORR of 88%, including 61% who achieved ?VGPR. In an expanded cohort using weekly bortezomib (1.5 mg/m2) and dexamethasone (40 mg once weekly for cycles 3 and 4), similar response rates were attained (ORR 93%; ?VGPR 60%).

To compare the effectiveness of this regimen in the real-world setting, the authors reviewed their institutional experience (N=83) with CyBorD. The median age of these patients was 59 years (range, 37-71 years). MM subtypes included IgG 55%, IgA 20%, light chains only 22%, and other 3%. After a median of 4 cycles, responses were high (ORR 93%; ?VGPR 70%). Grade 3/4 neutropenia (3.6%) and thrombocytopenia (<1%) were uncommon, and there were no cases of grade 3/4 peripheral neuropathy (PN). Dose delays/reductions of any agents were required in 18% of patients. Stem cell mobilization was not compromised. Eighty of 83 patients proceeded to ASCT. The ORR at day +100 post-ASCT was 97% (?VGPR 79%). The authors concluded that weekly CyBorD induction is highly effective in clinical practice, with response and toxicity profiles comparable to phase 2 trial data.

Perspective

“CyBorD is a highly active induction regimen for newly diagnosed patients. The therapy in this study was of particular interest because CyBorD was given weekly. I think it is very encouraging that 70% of patients had manageable toxicities with this approach and that no grade 3/4 neuropathy was reported. In fact, dose reductions were only necessary in 18% of patients and there was no compromise in stem cell collection with this regimen.�

~Paul Richardson, MD

Figure 2

Continuous Lenalidomide Therapy

Palumbo and colleagues reported the results of a phase 3 randomized study (MM-015), in which MPR induction followed by lenalidomide maintenance (MPR-R) was compared with MPR or MP followed by placebo in 459 transplant-ineligible patients with newly diagnosed MM who were ?65 years of age.14 Results previously reported showed that median PFS in the overall population was significantly higher with MPR-R (31 months) than with MPR (14 months; P<.001) or MP (13 months; P<.001). The benefit was observed mainly in patients aged 65 to 75 years.

At IMW 2013, the authors provided updated efficacy and safety data from this 65- to 75-year-old patient population. The proportion of patients in this age group was similar across treatment groups (76% MPR-R, 76% MPR, 75% MP). With a median follow-up of 30 months at final adjudication prior to unblinding, MPR-R significantly prolonged median PFS compared with MPR and MP (31 months vs 15 months vs 13 months, respectively; P<.001). With an updated median follow-up of 53 months, OS was 56 months with MPR-R, 54 months with MPR, and 52 months with MP.

During induction, grade 3/4 neutropenia occurred in 68% (MPR-R), 63% (MPR), and 31% (MP) of patients; thrombocytopenia was reported in 36% (MPR-R), 41% (MPR), and 12% (MP); and febrile neutropenia in 4% (MPR-R), 3% (MPR), and 0% (MP). During lenalidomide maintenance, the most common grade 3/4 newly occurring or worsening AEs (?5% of patients) were thrombocytopenia (8%), anemia (7%), neutropenia (5%), diarrhea (5%), and bone pain (5%). The authors concluded that continuous treatment with lenalidomide is highly effective in transplant-ineligible patients aged 65 to 75 years, and could be considered a standard of care in this population.

Perspective

“This is an update of the MM-015 trial in which the subset of patients 65 to 75 years of age was analyzed. In this elderly population, no difference was seen between the 3 treatment groups in terms of OS; however, a significant improvement in PFS favoring the administration of lenalidomide maintenance was observed. This is the first trial in transplant-ineligible patients that showed an improvement in PFS with lenalidomide maintenance, and I think this information is very important. The ongoing phase 3 MM-020 study (also known as the FIRST study) is investigating Rd versus melphalan, prednisone, and thalidomide in patients with previously untreated myeloma. We expect results from that study to be presented later this year.�

~Meletios A. Dimopoulos, MD

Bortezomib Incorporated Into ASCT

At IMW 2013, Cavo and colleagues presented updated results of the outcomes of 1610 newly diagnosed MM patients, all of whom had available data on the presence or absence of del(13q), t(4;14), and/or del(17p), from the analysis of four phase 3 studies comparing up-front bortezomib (B)-based versus nonbortezomib (NB)-based single or double ASCTs.15 Results showed that, in comparison with NB-ASCTs, B-ASCTs significantly improved PFS in the overall population (HR=0.76), a benefit retained across both low-risk (HR=0.79) and high-risk (HR=0.58) subgroups, with improved OS (HR=0.85) seen with B-ASCTs. In a stratified multivariate analysis, independent variables associated with extended PFS and OS in the overall population included B-ASCTs (HR=0.74 and 0.79), achievement of CR (HR=0.46 and 0.44), and double ASCT (HR=0.44 and 0.31). These variables were also independent predictors for prolonged PFS and OS in patients with t(4;14) and/or del(17p). Patients who carried both of these cytogenetic abnormalities had the poorest prognosis and, in a multivariate analysis, were likely to benefit only from double ASCT (HR=0.13 for PFS and HR=0.28 for OS). The authors concluded that B-ASCTs significantly improved PFS in comparison with NB-ASCTs, but did not completely overcome the adverse prognosis related to the presence of t(4;14) and/or del(17p) and more mature data are needed before definite conclusions regarding the impact of B-ASCTs on OS can be made.

Perspectives

“This analysis was designed to compare outcomes for bortezomib-based induction regimens versus nonbortezomib-based induction regimens in a high-risk population that was defined by the presence of t(4;14) and/or del(17p). The results indicate that independent predictors of longer PFS and OS were bortezomib-based induction regimens, achievement of a CR, and double ASCT. The study showed a significant increase in PFS for bortezomib-treated patients in the overall population, and particularly in the population with high-risk cytogenetics. There was also a trend in favor of OS with bortezomib-based regimens.

Overall, the analysis indicates that the use of bortezomib-based induction regimens improved the outcomes of patients with MM, although it did not completely overcome the detrimental effect of high-risk cytogenetics. Importantly, I think an intriguing result from this analysis was the benefit of double ASCT, particularly in patients with both abnormalities [ t(4;14) and del(17p)].�

~Jesús F. San Miguel, MD

“I thought this was a very interesting presentation on many fronts. First of all, it established that the use of a proteasome inhibitor as part of induction therapy with transplant should be considered a new standard of care given the clinical benefit seen in this comprehensive analysis.

In addition, this analysis provided new information about the use of double transplant in patients with high-risk cytogenetics. Prior to the era of novel therapies, the use of transplant in this high-risk group wasn’t just ineffective, it was actually deleterious, presumably enhancing resistance, particularly in the del(17p) patients. Therefore, these results potentially provide a biological clue that the rebooting of the immunological profile of the patient with ASCT in conjunction with novel therapies may create a new therapeutic paradigm.â€�

~Paul Richardson, MD

Bortezomib, Reduced-Intensity ASCT, Followed by Lenalidomide

Magarotto and colleagues reported the results of a multicenter phase 2 study that evaluated a sequential approach including ASCT in 102 elderly patients with newly diagnosed MM.¹⁶ Patients received 4 cycles of bortezomib, pegylated doxorubicin, and dexamethasone, followed by tandem melphalan (100 mg/m2) and ASCT (MEL100-ASCT), 4 cycles of lenalidomide plus prednisone (LP) consolidation, and lenalidomide maintenance until progression. In an intent-to-treat analysis, the CR rate was 33% after MEL100-ASCT, 49% after LP, and 54% after lenalidomide maintenance. At a median follow-up of 66 months, median TTP was 55 months, median PFS was 48 months, median OS was not reached, and OS at 5 years was 63%. The achievement of CR correlated with longer TTP (median, 70 months), PFS (median, 63 months), and OS (83% at 5 years). Median survival from relapse was 28 months. Overall, the main grade 3/4 toxicities included thrombocytopenia, neutropenia, infections, PN, gastrointestinal AEs, dermatologic toxicity, and thromboembolism. The incidence of second malignancies (skin cancer excluded) was 0.5% per year of follow-up. Deaths related to AEs occurred in 8 of 102 patients (only during induction or transplantation) and were higher in patients >70 years than in younger patients (19% vs 5%; P=.024).

Perspective

“I would like to highlight several points in this interesting trial conducted in early myeloma patients. First, the CR rate is very high; it started at 33% and at the end of the study was 54%. In the maintenance phase, there was a prolonged PFS of 48 months and an OS at 5 years of 63%.

I think this speaks in favor of aggressive treatment in this cohort of patients. Nevertheless, I believe that the major issue was the treatment-related mortality in patients older than 70 years. Therefore, from my point of view, this intensive approach may be a valid alternative for fit patients without comorbidities who are younger than 70 years.�

~Jesús F. San Miguel, MD

Early vs Delayed Transplantation

At IMW 2013, Philippe Moreau, MD, and Paul Richardson, MD, discussed the question, Should ASCT be used early in all eligible patients, or kept in reserve as a salvage treatment at the time of progression for selected patients achieving a high-quality response?¹⁷

In 2009, Stewart and colleagues published an article in which they wrote, “A reasonable goal of MM treatment in younger ‘transplant eligible’ patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control. To achieve this goal we recommend induction therapy with multiagent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteroids) which when employed together elicit frequent, rapid, and deep responses. We recommend consolidation with high-dose melphalan and ASCT in the majority of patients willing and able to undergo this procedure and subsequent maintenance therapy in those failing to achieve a CR or at high risk for early relapse based on prognostic, genetically defined risk factors. Defining genetic risk for early relapse is therefore an important aspect of early diagnostic testing, and attention to minimizing expected toxicities once therapy begins is critical in ensuring the efficacy of modern combination therapy approaches.â€�¹⁸

In 2010, Cavo and colleagues conducted a randomized phase 3 study of bortezomib, thalidomide, and dexamethasone (VTD) compared with thalidomide plus dexamethasone (TD) as induction therapy before, and consolidation therapy after, double ASCT in 480 newly diagnosed MM patients.¹⁹ After induction therapy, CR or nCR was achieved in 31% of patients who received VTD, and 11% of patients who received TD (P<.0001). The authors concluded that VTD induction therapy before double ASCT significantly improves rate of CR or nCR, and represents a new standard of care for patients with MM who are eligible for transplant.

Richardson and colleagues at the Dana-Farber Cancer Institute conducted a phase 1/2 study of lenalidomide, bortezomib, and dexamethasone (RVD) combination therapy in 66 patients with newly diagnosed MM.20 One hundred percent of patients achieved ?PR, with 74% in the phase 2 study and 67% of patients overall achieving ?VGPR. Twenty-eight patients (42%) proceeded to transplantation. With a median follow-up of 21 months, estimated 18-month PFS and OS for RVD with and without transplantation were 75% and 97%, respectively.

In 2011, Moreau and colleagues from the Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib plus dexamethasone (VD) as induction before high-dose therapy and ASCT versus a combination of reduced doses of VTD in 199 newly diagnosed MM patients.²¹ After 4 cycles, the CR rate was the same in both groups (13% in the VTD arm, 12% in the VD arm; P=.74). However, the CR plus VGPR rate was significantly higher in the VTD arm (49% vs 36%; P=.05). After ASCT, the CR plus VGPR rate was 74% in the VTD arm versus 58% in the VD arm (P=.02).

McCarthy and colleagues conducted a study to determine whether lenalidomide maintenance therapy prolongs TTP after ASCT in 460 patients who were younger than 71 years and who had SD or a minimal response (MR), PR, or CR 100 days after undergoing ASCT.²² The study-drug assignments were unblinded when a planned interim analysis showed a significantly longer TTP in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease (PD) or had died (P<.001). Of the remaining 128 patients who received placebo and who did not have PD, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients (37%) who received lenalidomide and 132 of 229 patients (58%) who received placebo had disease progression or had died. The median TTP was 46 months in the lenalidomide group and 27 months in the placebo group (P<.001). More grade 3/4 hematologic and grade 3 nonhematologic AEs occurred in patients who received lenalidomide (P<.001 for both comparisons). Second primary malignancies (SPMs) occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). The authors concluded that lenalidomide maintenance therapy, initiated at day 100 after ASCT, was associated with greater toxicity and secondary cancers but a significantly longer TTP and significantly improved OS.

Attal and colleagues also conducted a phase 3, placebo-controlled trial investigating the efficacy of lenalidomide maintenance therapy in 614 patients <65 years of age who had nonprogressive disease after first-line ASCT.²³ Results showed that the median PFS was 41 months with lenalidomide maintenance therapy versus 23 months with placebo (P<.001). The incidence of SPMs was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=.002). Median event-free survival (EFS) (with events that included SPMs) was significantly improved with lenalidomide (40 months vs 23 months with placebo; P<.001). The authors concluded that lenalidomide maintenance after transplantation significantly prolonged PFS and EFS. Four years after randomization, OS was similar in the 2 study groups but more mature follow-up on these outcomes is eagerly awaited.

Perspectives
“In the comparison of early versus delayed transplant, the data that are available so far are in favor partially of early transplant based on the Siegel study derived from the ECOG trial in which lenalidomide plus high-dose or low-dose dexamethasone were analyzed. One subset of patients continued on primary therapy while another subset received early transplant. The 3-year OS was in favor of the patients who received early transplant.²⁴

We also have data from a randomized trial in which, after 4 cycles of Rd, the patients were randomized to receive either 6 cycles of MPR or MEL-200 and then maintenance or no maintenance.²⁵ So far, the study indicates that high-dose melphalan and autologous transplant is associated with a significant benefit in 2-year PFS, but no difference in OS.

My personal position regarding early versus delayed ASCT is in favor of early transplant until we see results from the ongoing randomized IFM/DFCI2009 trial,²⁶ which is comparing conventional dose treatment using RVD versus high-dose treatment with peripheral ASCT in the initial management of myeloma in patients 65 years or younger. Until this data is available, I prefer early transplant because the patient is more fit upfront to tolerate intensive and repetitive therapies and is also more prepared psychologically for intensive therapies. In addition, I favor early transplant because it is associated with long-term treatment-free intervals during which patients experience an excellent quality of life, and also because, in countries such as Spain, transplant is a less costly approach than those that use novel agents. My final argument for offering my patients early transplant (until the randomized data from the aforementioned trial becomes available) is that, at the time of relapse after MEL-200, patients are very sensitive to novel agents. I don’t know yet what the efficacy of MEL-200 is after long-term exposure to novel agents. This is because most of the data that we have so far with late transplant has been with chemotherapy, not novel agents. Therefore, for these reasons I prefer to be conservative and continue to offer early autologous transplant until data from randomized trials become available.â€�

~Jesús F. San Miguel, MD

“The current data that we have in support of early transplant are based on regimens that do not include a proteasome inhibitor. Because of this, it is still premature to say that early transplant is the standard. I think we recognize that, for a proportion of patients, early transplant may be beneficial. The key question is: Is it beneficial for all patients? In the United States, patients remain quite reluctant to undergo early transplant—particularly with the excellent results now achieved with novel therapy combinations.

I think Dr San Miguel’s point about resistance is well taken but, certainly from a pharmacological standpoint, one might expect the opposite, where resistance after prior conventional chemotherapy with melphalan would be the worry but would not be so with novel therapies. In fact, we didn’t see this in our current studies, suggesting that we wouldn’t expect primary resistance. However, I do agree that the timing of myeloablation and immunological reconstitution is a critical question, and I think this is what we’ll learn from the ongoing randomized trials.

The notion that patients are better able to tolerate a transplant early does certainly apply to a subgroup of patients, but not to all patients. Regarding psychological readiness for transplant, some patients actually find undergoing transplant later in their disease course somewhat easier to come to terms with than they would have soon after diagnosis. In addition, we must be concerned about genotoxic injury in a small subset of patients who are vulnerable to secondary myelodysplasia and leukemia. Therefore, it is very important to identify these patients and potentially spare them from the real risk of such complications both acutely and long term.�

~Paul Richardson, MD

RELAPSED/REFRACTORY MM

Lenalidomide Plus Low-Dose Dexamethasone

At IMW 2013, Gomes presented results of a retrospective study in 7 first-relapse MM patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) who were treated with Rd.27 Results showed an ORR of 71% (5/7 patients). The 2 patients who did not respond had prior exposure to thalidomide. The median DOR was 21 months, and in 4 of 7 patients (57%) the response was longer than 2 years. Forty-three percent of patients experienced renal improvement, and 2 patients continued on dialysis. No serious infections or SPMs were observed.

Perspective

“As we are all aware, the first relapse after initial primary therapy is extremely difficult to treat and we have very little randomized phase 3 data on this population. In addition, while it is difficult to treat patients in this population who have normal renal function, it is even more difficult to treat those patients with impaired renal function. This is especially true because there is a false perception that lenalidomide should not be used in patients with impaired renal function even though adequate guidelines have been published on how to safely use this drug in patients with low CrCl.

The study by Gomes demonstrated that good, durable remissions with an acceptable safety profile could be achieved when Rd was administered to a group of first-relapse patients with severe renal impairment. Although the number of patients was relatively small, these preliminary results suggest that this combination may be helpful for such patients who cannot take bortezomib or for whom carfilzomib is not available.�

~Sergio A. Giralt, MD

Pomalidomide Plus High- vs Low-Dose Dexamethasone

Dimopoulos and colleagues reported updated survival results of a phase 3, multicenter, randomized, open-label study (MM-003) of pomalidomide plus either low-dose dexamethasone (POM+LoDEX) or high-dose dexamethasone (POM+HiDEX) in 455 patients with relapsed/refractory MM.²⁸ Patients must have been refractory to their last prior therapy (ie, they must have developed PD during or within 60 days) and failed lenalidomide and bor­tezomib (alone or in combination) after receiving ?2 consecutive cycles of each. The study design was described previously at ASH 2012.²⁹ Patients had received a median of 5 prior therapies and 72% were refractory to lenalidomide and bortezomib.

Median follow-up was 4 months. PFS and OS were significantly longer in the group that received POM+LoDEX than the group that received POM+HiDEX in the overall population, as well as in patients refractory to lenalidomide and bortezomib, in those with lenalidomide or bortezomib as their last prior therapy, and in both those with normal (CrCl ?60 mL/min) or moderately impaired (CrCl <60 mL/min) renal function. After data evaluation, the Data Monitoring Committee recommended crossover from POM+HiDEX to POM+LoDEX. With updated data, ORRs were 21% for POM+LoDEX and 3% for POM+HiDEX (P<.001). The most frequent grade 3/4 AEs for the low-dose versus high-dose dexamethasone groups were neutropenia (42% vs 15%), anemia (27% vs 29%), and infections (24% vs 23%). The rates of discontinuations due to AEs were low: 7% in the POM+LoDEX group and 6% in the POM+HiDEX group.

Figure 3

Perspective

“I think this randomized, controlled phase 3 trial is very important because it evaluates the role of a novel combination, pomalidomide plus low-dose dexamethasone, in patients with very advanced, refractory myeloma. The control arm received high-dose dexamethasone because patients for whom lenalidomide and bortezomib are not options, and who have no access to clinical trials with novel investigational agents, steroids (such as high-dose dexamethasone) are frequently administered to palliate their disease. The main finding of the study is that the administration of pomalidomide with low-dose dexamethasone improves PFS. In fact, the PFS is doubled with this regimen. In addition, an OS advantage clearly favoring this combination was seen. This regimen was relatively well tolerated, considering the advanced nature of the disease in this population of patients, who have frequent infectious episodes and borderline blood counts. The main toxicity observed was myelosuppression. The main nonhematologic toxicities were infections, which were equally distributed between the 2 groups. It is important to note that no significant deep-vein thrombosis or PN were reported with this regimen.�

~Meletios A. Dimopoulos, MD

Pomalidomide Plus Low-Dose Dexamethasone

Jagannath and colleagues presented the results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide alone versus POM+LoDEX in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.30 The encouraging responses for the overall population are shown in Figure 3. The median DOR (for patients who achieved ?PR) was 45 months in the POM+LoDEX group and 31 months in the pomalidomide alone group. Results of a subanalysis based on age (?65 years vs <65 years) showed that age had no impact on the duration or depth of response. The median PFS for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received pomalidomide alone. The most common grade 3/4 AEs were neutropenia (41%), anemia (22%), thrombocytopenia (19%), and pneumonia (22%). Tolerability was similar across the different age groups.

The authors concluded that, in patients with relapsed and refractory MM who have received multiple prior treatments including lenalidomide and bortezomib, pomalidomide (with or without low-dose dexamethasone) was clinically effective and generally well tolerated. Response rates were encouraging and consistent, as well as durable regardless of age.

Table

Perspective

“In our intent-to-treat analysis, we found that efficacy outcomes for the overall population of the subgroups were very promising in such a heavily treated population. In the patients who were younger than 65 years, the ?PR rate for POM+LoDEX was 31%, and the ?MR rate was 47%. These rates were similar in the older patients (37% and 43%, respectively). The median DOR rates were also similar between groups. The results of this analysis show that patients with relapsed and refractory MM respond well to POM+LoDEX, irrespective of age.�

~Paul Richardson, MD

Pomalidomide, Bortezomib, and Low-Dose Dexamethasone

Richardson and colleagues presented results of a phase 1 multicenter, dose-escalation study (MM-005) of pomalidomide, bortezomib, and low-dose dexamethasone in 15 patients with relapsed and/or refractory MM.31 Patients were divided into 5 cohorts in a 3 + 3 design for 21-day cycles, as shown in the Table, followed by an expansion cohort. They were evaluated every 21 days and followed for 5 years. Patients with 1 to 4 prior antimyeloma therapies, PD during a lenalidomide-containing treatment or within 60 days of last dose, and proteasome inhibitor exposure (but not bortezomib-refractory) were eligible to participate. All 15 patients had prior lenalidomide and bortezomib exposure; 73% of patients had progressed on lenalidomide as their last prior regimen. As of October 15, 2012, no dose-limiting toxicities (DLTs) were observed. Confirmation of the maximum tolerated dose is ongoing. Grade 3/4 AEs included thrombocytopenia (27%) and neutropenia (27%). Grade1/2 PN (none painful) occurred in 4 patients. No thromboembolism occurred. Three patients discontinued therapy, but none due to AEs. At the data cutoff, 73% of patients had achieved ?PR, including 27% VGPRs (Figure 4). Responses were also observed in patients with adverse cytogenetic profiles.

Perspective

“In this trial, patients had to have received 1 to 4 prior anti-myeloma therapies; it was required that they were refractory to lenalidomide but had to be responsive to bortezomib. The ORR was 73% at data cutoff, with a rapid median time to response and very favorable tolerability. This regimen will now provide a platform for an ongoing phase 3 trial of pomalidomide 4 mg, bortezomib 1.3 mg/m2, and dexamethasone 20 mg (according to the schedule described) versus bortezomib, dexamethasone, and placebo administered on the classic schedule (D 1, 4, 8, 11 every 21 days).�

~Paul Richardson, MD

Figure 4

MLN9708

At IMW 2013, Kumar and colleagues reported the safety and pharmaco­kinetic results of early studies of MLN9708, administered alone in relapsed/refractory MM patients or in combination with lenalidomide and dexamethasone in newly diagnosed MM patients.^32-34 In the ongoing phase 1 single-agent study in relapsed/refractory MM patients, DLTs included grade 3 rash and gastrointestinal AEs. Common drug-related AEs included thrombocytopenia (45%), diarrhea (37%), and nausea (35%); grade ?3 AEs included thrombocytopenia (33%), diarrhea (17%), and neutropenia (17%). Grade 1/2 PN was observed in 10% of patients, with no grade ?3 PN observed. Pharmacokinetic data showed rapid absorption, a terminal half-life of 4 to 12 days, and a proportional increase in plasma area under the curve with dose (0.8-3.95 mg/m2). Thus, single-agent MLN9708 appeared generally well tolerated; the long terminal half-life supports weekly dosing.³³

In an ongoing phase 1/2 study of MLN9708 plus lenalidomide and dexamethasone in newly diagnosed patients, common AEs included rash (68%), fatigue (48%), nausea (42%), and PN (32%; 3% grade 3). MLN9708 pharmacokinetic data showed no apparent differences between single-agent and combination dosing, suggesting no pharmacokinetic interaction with lenalidomide or dexamethasone.³⁴

Data from these studies provide the rationale for weekly dosing of MLN9708 at 4.0 mg combined with lenalidomide and dexamethasone in an ongoing phase 3 trial in relapsed/refractory MM. MLN9708 in combination with lenalidomide and dexamethasone is also being evaluated in another phase 3 study in patients with newly diagnosed MM who are not candidates for transplant.

Perspective

“MLN9708 has been referred to as ‘the oral bortezomib.’ We were all impressed regarding the response rates in patients with relapsed/refractory myeloma as well as in the upfront setting. I think we are going to see a new generation of anti-myeloma agents that have new mechanisms of action (eg, monoclonal antibodies) and oral agents that will make treatment much easier to administer.�

~Sergio A. Giralt, MD

References
1. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347–1349.
2. Mateos MV, San Miguel J. Should we treat smoldering multiple myeloma? Haematologica. 2013;13(suppl 1):S20-S21. Abstract S11-3.
3. Hjorth M, Hellquist L, Holmberg E, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993;50:95-102.
4. San Miguel JF, Bladé Creixenti J, García-Sanz R. Treatment of multiple myeloma. Haematologica. 1999;84:36-58.
5. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer. 2008;113:
1588-1595.
6. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008;112:3122-3125.
7. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013;27:220-225.
8. Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance therapy with Len alone vs no treatment. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 991.
9. Krypolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.
10. Landgren CO, Manasanch E, Kwok M, et al. Phase II study: carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) in high risk SMM (early myeloma). Haematologica. 2013;13(suppl 1):S39-S40. Abstract O-6.
11. Larocca A, Magarotto V, Offidani M, et al. Lenalidomide-dexamethasone vs melphalan-prednisone-lenalidomide vs cyclophosphamide-prednisone-lenalidomide in NDMM. Haematologica. 2013;13(suppl 1):S113-S114. Poster P-146.
12. Palumbo A, Bringhen S, Petrucci MT, et al. A phase II trial of carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma patients. Haematologica. 2013;13(suppl 1):S112-S113. Abstract P-145.
13. Areethamsirikul N, Masih-Khan E, Chu CM, et al. CyBorD induction therapy for multiple myeloma in clinical practice. Haematologica. 2013;13(suppl 1):S140. Abstract P-202.
14. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide therapy in patients with newly diagnosed MM aged 65-75 years: MM-015 update. Haematologica. 2013;13(suppl 1):S152. Abstract P-227.
15. Cavo M, Sonneveld P, Moreau P, et al. Impact of bortezomib incorporated into auto transplantation on outcomes of myeloma patients with high-risk cytogenetics. Haematologica. 2013;13(suppl 1):S158-S-159. Abstract P-241.
16. Magarotto V, Gay F, Rossi G, et al. Bortezomib, reduced-intensity transplantation followed by lenalidomide for newly diagnosed elderly MM patients. Haematologica. 2013;13(suppl 1):
S119-S120. Abstract P-158.
17. Moreau P, Richardson P. Debate: early or delayed transplantation for multiple myeloma in the era of novel therapies: does one size fit all? Haematologica. 2013;13(suppl 1):S17. Abstract S9-4.
18. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114:5436-5443.
19. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.
20. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;
116:679-686.
21. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:
5752-5758; 5982.
22. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781.
23. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.
24. Siegel DS, Jacobus S, Rajkumar SV, et al; on behalf of the Eastern Cooperative Oncology Group. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 38.
25. Palumbo A, Cavallo F, Hardan I, et al. A phase III study to compare melphalan, prednisone, lenalidomide (MPR) versus melphalan 200 mg/m2 and autologous transplantation (MEL200) in newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 3573.
26. ClinicalTrials.gov. Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years (IFM/DFCI2009). http://clinicaltrials.gov/ct2/show/NCT01191060.
27. Gomes FR. Lenalidomide in the treatment of first relapsed multiple myeloma patients with severe renal impairment. Haematologica. 2013;13(suppl 1):S95. Abstract P-108.
28. Dimopoulos MA, Weisel KC, Moreau P, et al. Progression-free survival (PFS) and overall survival (OS) advantages with pomalidomide + low-dose dexamethasone: MM-003. Haematologica. 2013;13(suppl 1):S134. Abstract P-189.
29. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract LBA-6.
30. Jagannath S, Richardson PG, Hofmeister C, et al. Pomalidomide with or without low-dose dexamethasone in relapsed and refractory multiple myeloma: updated analysis. Haematologica. 2013;13(suppl 1):S143-S144. Poster P-210.
31. Richardson PG, Hofmeister CC, Siegel DS, et al. Ph 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma. Haematologica. 2013;13(suppl 1):S128-S129. Poster P-178.
32. Kumar S, Niesvizky R, Berdeja JG, et al. Safety and pharmacokinetics of weekly MLN9708, an investigational oral proteasome inhibitor, alone and in combination. Haematologica. 2013;13(suppl 1):S154. Abstract P-230.
33. Kumar S, Bensinger WI, Craig B, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: results from a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 816.
34. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 332.

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