Co-authored by Mara Jeffress, Ph.D.
The number of agents available to treat relapsed/refractory myeloma has expanded rapidly over the past three years, with the launch of next-generation proteasome inhibitor Kyprolis® (carfilzomib, Onyx /Amgen, accelerated FDA approval July 2012) and the next-generation immunomodulator Pomalyst® (pomalidomide, Celgene, FDA approved February 2013) as monotherapies, and the HDAC inhibitor Farydak® (panobinostat, Novartis, accelerated FDA approval February 2015) for use in combination with bortezomib + dexamethasone (VelDex). These three agents add to the long-established standards of care, Velcade® (bortezomib, Millennium/Takeda) and Revlimid® (lenalidomide, Celgene), which are used in both newly diagnosed and relapsed/refractory patients. Pivotal data for Kyprolis and two new agents ― elotuzumab (AbbVie/Bristol-Myers Squibb) and daratumumab (Genmab/Janssen) ― were presented on Tuesday at the Myeloma Oral Session of the American Society of Clinical Oncology (ASCO) annual meeting.
Based on the results of a large Phase II program, Kyprolis was granted FDA accelerated approval as a monotherapy for myeloma patients who have received prior therapy with an immunomodulatory agent and proteasome inhibitor. It is now the most commonly used third-line agent, used in one-third of patients.1 As a second-generation proteasome inhibitor, the ability of Kyprolis to gain use in earlier lines of therapy will hinge on demonstrating benefit in comparison with the entrenched first-generation proteasome inhibitor, Velcade. The Phase III ENDEAVOR trial compared Kyprolis (at a dose of 56 mg/m2, twice the currently approved monotherapy dose of 27 mg/m2) plus dexamethasone (KypDex) versus VelDex in 929 patients who have received one to three prior lines of therapy (50% were second-line, 33% were third-line and 17% were fourth-line). Progression-free survival (PFS) was significantly improved, with the KypDex arm doubling PFS at the median compared to VelDex (median PFS 18.7 versus 9.4 months, HR=0.53, p< 0.0001).2 Overall survival (OS) data were immature; however, a slight trend to benefit was suggested in the data presented (HR=0.79, p=0.66). Overall response rates (ORR) also favored Kyprolis: 77% versus 63% (p< 0.0001); 54% versus 29% had a very good partial response or better, and 13% versus 6% of patients had a complete response. Responses were robust even in patients treated with prior Velcade. Treatment discontinuation (14.0% vs. 15.7%) and on study death (3.9% vs. 3.4%) due to an adverse event (AE) occurred at similar frequencies in each arm. Grade 3/4 hypertension (8.9% vs. 2.6%), dyspnea (5.6% vs. 2.2%), cardiac failure (4.8% vs. 1.8%) and acute renal failure (4.1% vs. 2.6%) were all increased in the KypDex arm. Considering the fact that patients in this trial were receiving double the approved monotherapy dose, the AEs perhaps aren’t unexpected, although they are still concerning when considering the use of this regimen in the general population of myeloma patients outside of a highly selected clinical trial. These increased toxicities were balanced by a significant decrease in Grade 2 or higher peripheral neuropathy (6.3% vs. 32.0%, p< .0001), which is all the more encouraging considering that the majority (79%) of patients in the control arm received subcutaneous (SC) Velcade, which has lower rates of neuropathy compared to the intravenous (IV) formulation.
The near doubling of PFS over VelDex will establish KypDex as a new standard of care, especially if OS data is positive. The positive results from ENDEAVOR should only serve to strengthen Kyprolis’ share in third-line and help it gain share in second-line, where VelDex is currently utilized in one-third of patients.1 The positive results of ENDEAVOR come just six months after another positive Phase III trial for Kyprolis – the ASPIRE trial, which showed that patients receiving Kyprolis combined with lenalidomide + dexamethasone (RevDex) had a median PFS of 26.3 months compared to a median PFS of 17.6 months for patients treated with RevDex alone (HR=0.69; p=0.0001).3 Together, these two trials raise questions about where Kyprolis will fit in the treatment paradigm – as a doublet or a triplet, and in which line of therapy?
While Kyprolis, at least in ENDEAVOR, is challenging Velcade head-to-head, elotuzumab is choosing to combine with one of the current standard-of-care treatment regimens, RevDex. Elotuzumab is an anti-SLAMF7 monoclonal antibody that has FDA Breakthrough Therapy Designation for relapsed/refractory multiple myeloma and is being studied in two Phase III trials, both in combination with RevDex, in the front-line and relapsed/refractory settings. In the relapsed setting, the results of the ELOQUENT-2 trial compared elotuzumab in combination with RevDex versus RevDex alone in 646 patients who had received a median of two prior therapies, including Velcade (70%), thalidomide (48%) and Revlimid (6%). Revlimid-refractory patients were excluded from enrollment. Elotuzumab given with RevDex extended PFS by a median of 4.5 months compared with RevDex alone (median PFS 19.4 vs. 14.9 months, HR = 0.70, p = 0.0004). In addition, one-year PFS was 68% versus 57% and two-year PFS was 41% versus 27%. ORR also favored the addition of elotuzumab (79% vs. 66%, p = 0.0002).4 OS is still immature and was not reported, but the presenter, Dr. Lonial, suggested the results, which will be available in the fourth quarter of 2015, were trending toward the positive. There were no significant increases in toxicity except for Grade 3/4 lymphopenia (77% vs. 49%) and increased incidence of Grade 1-3 infusion reactions (10% vs. 0%); Grade 3/4 neutropenia was lower in the elotuzumab arm (34% vs. 44%). A large number of high-risk patients were enrolled in the trial (32% del17p and 10% t(4;14)), and subgroup analysis showed that PFS was robust even in these subgroups (HR=0.65 for del17p and HR=0.53 for t(4;14)). While important to understand that the regimen provides benefit in these subsets, it does create difficulties for cross-trial comparisons.
Acknowledging the trial demographic differences, a comparison of ELOQUENT-2 with outcomes for KypDex and Kyprolis + RevDex suggests that elotuzumab + RevDex might provide a comparable median PFS and ORR as is achieved with KypDex (although the Hazard Ratio was better for KypDex), and inferior median PFS and ORR compared to KypRevDex (comparison is difficult here as fewer patients (12.6%) in ASPIRE were high-risk, which may have boosted the mPFS); however, the AE profile appears most benign for elotuzumab in combination with RevDex. A key advantage of elotuzumab is its novel mechanism of action and its combinability with other agents due to its relative mild toxicity profile. While these advantages may give elotuzumab a strong positioning stance in newly diagnosed patients, competitive pressures are stronger in relapsed myeloma. Most significant may be the changing backbone of care across the lines of therapy (choice of immunomodulator or proteasome inhibitor or both), which may leave fewer opportunities for use of elotuzumab if its approval in the relapsed/refractory setting is tied to the RevDex combination.
Elotuzumab is aiming to be the first monoclonal antibody used to treat multiple myeloma. Competition will come quickly from another antibody known as daratumumab. Daratumumab is a human monoclonal antibody directed against CD38, which is highly expressed on the surface of multiple myeloma cells. Daratumumab has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Based on promising early data, the FDA granted Breakthrough Therapy Status to daratumumab for treatment of double-refractory multiple myeloma.
Daratumumab, at least initially, is taking a slightly different development tactic than either Kyprolis or elotuzumab and is hoping to enter the myeloma market initially by targeting fourth-line or later patients.5 An open-label, two-part Phase II study (Sirius, MMY2002, NCT01985126) evaluated daratumumab monotherapy in its FDA breakthrough therapy designation population: double-refractory myeloma patients with at least three prior lines of therapy. In part 1, 34 patients were randomized to daratumumab 8 mg/kg (n = 18) or 16 mg/kg (n = 16) to determine the most effective dose. In part 2, 90 additional patients were given the 16 mg/kg dose. Data for 106 heavily pretreated (median five prior lines, including 95% double refractory and 66% refractory to three of four approved agents (Revlimid, Velcade, Pomalyst and/or Kyprolis)) patients were reported. After a median follow-up of 9.3 months, 29% of patients responded to daratumumab, including three complete responses, 10 very good partial responses, and 18 partial responses. Responses to daratumumab were rapid and durable, lasting on average 7.4 months. Response was consistent across all subgroups including the most refractory patients. Median PFS was 3.7 months. Median OS has not been reached, and the estimated one-year OS rate is 65%, which is remarkable in such a refractory population. Common all-grade AE (≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%) and cough (20.8%). Infusion-related reactions were common (43%) but mainly Grade 1/2 (5% Grade 3; 0% Grade 4). J&J intends to seek accelerated approval for daratumumab later this year6 and already has plans to enter the ranks of emerging triplet therapies in myeloma, by initiating two Phase III trials in relapsed/refractory patients combining daratumumab with VelDex (NCT02136134) or with RevDex (NCT02076009). The discussant, Dr. Lentzsch, enthusiastically reviewed the Phase I/II data showing that daratumumab plus RevDex had an impressive 87% ORR with responses that deepened over time.
Given the increasingly crowded relapsed/refractory setting, companies that plan to bring more agents to multiple myeloma will need to go head-to-head against or combine with RevDex, VelDex, KypDex or the various established and emerging triplet regimens. As we have seen in other crowded markets such as renal cell carcinoma, even existing approved agents may be forced into head-to-head trials to establish dominance and win a significant portion of the market. As of now, there is no clear winner, and the influx of new agents will only confuse matters more with the lack of understanding of whether triplets are better than doublets, if quadruplets are better than triplets (this is sure to be explored in the near future), which regimen is superior and how to sequence the drugs. Furthermore, across all scenarios also exists the question of cost of care. Can the market (and patients) afford combination therapies that continue to push the boundaries of affordability? The price may be justified if the new combination therapies can provide a long-term survival benefit, but for now the regimens reported here have only firmly established a PFS benefit.
1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.
2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. J Clin Oncol. 2015;33(suppl; abstr 8509)
3. Stuart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. NEJM, 372(2): 142-52, 2015.
4. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(suppl; abstr 8508)
5. Lonial S, Weiss BM, Usmani SZ et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33(suppl; abstr LBA8512)
6. Johnson & Johnson press release, May 20, 2015.