New Myeloma Guideline Expands Diagnostic Criteria, Adds Novel Agents

In the relapsed/refractory setting, 8 new options appear in the most recent update to the guideline. In newly diagnosed patients, primary therapy now includes lenalidomide plus dexamethasone in combination with bortezomib (preferred) or the ixazomib. Additionally, the “active” myeloma category was expanded through an adjustment in the diagnostic criteria, to make more patients eligible for therapy.

“In the guidelines this year, the criteria for treatment of multiple myeloma have changed,” said Anderson, director of the Multiple Myeloma Center at Dana-Farber Cancer Institute. “Previously, treatment has demanded abnormalities in calcium, renal function, anemia, and bone disease [the so-called CRAB features]. However, that is no longer true.”

Even without CRAB features, the following are sufficient to define active multiple myeloma in asymptomatic patients, and qualify such patients for treatment, according to the NCCN:

• Bone marrow plasmacytosis ≥60%
• Abnormal free light chain ratio &ge;100 (involved kappa) or <0.01 (involved lambda)
• Focal bone marrow lesions detected by functional imaging

The new iteration of the multiple myeloma guidelines includes a revised International Staging System that incorporates cytogenetics for the first time, in order to define prognosis following treatment. Moreover, more stringent measures of complete response (CR) were included, with a molecular CR now defined as <1 myeloma cell per 1 million normal cells by sequencing or immunophenotypic CR by multicolor flow cytometry, the most sensitive of which can detect <1 myeloma per 1 million normal cells.

FRONTLINE THERAPY FOR TRANSPLANT CANDIDATES

In bone marrow transplant candidates, primary treatment options in the most recent guideline include a proteasome inhibitor plus lenalidomide and dexamethasone. The recommendation for the use of triplet combination therapy in newly diagnosed multiple myeloma is based on synergies in activity in preclinical models and in the clinic, said Anderson. The 3 primary proteasome inhibitors available include bortezomib, carfilzomib, and the oral agent ixazomib, which was most recently introduced. These agents have shown varying levels of evidence in the frontline setting.

In the phase III SWOG S0777 trial, the triplet of bortezomib plus lenalidomide and dexamethasone demonstrated improvements in CR rates (including molecular CR), progression-free survival (PFS), and overall survival (OS) compared with lenalidomide/dexamethasone alone.²

The complete response rates were 15.7% and 8.4%, with bortezomib and without. Median PFS with bortezomib was 43 versus 30 months with lenalidomide and dexamethasone alone (HR, 0.712; 96% CI, 0.560-0.906; one-sided P = .0018). The median OS was 75 months in the bortezomib arm compared with 64 months for the doublet (HR, 0.709; one-sided P = .0125).

Ixazomib and carfilzomib were not listed under the preferred regimens, but were identified as other options. Carfilzomib plus lenalidomide and dexamethasone was included in the new guideline as a category 2A therapy in the frontline setting, based on a phase I/II study showing a response rate of 100%, with a near CR rate of 87% and a stringent CR rate of 65%. The 3-year PFS rate was 79.6%.³

Ixazomib, which is approved in the relapsed/refractory setting, has also been explored as an upfront therapy, with a phase III currently ongoing. In a phase II study,⁴induction therapy with the all-oral regimen of ixazomib plus lenalidomide/dexamethasone produced a 90% response rate, including a 59% very good partial response or better.

Following induction, ixazomib was continued as single agent maintenance therapy. In the maintenance arm, 11 patients experienced a CR with continuous ixazomib (52%), 4 of which were stringent CRs (19%). Overall, 33% of patients had an improvement in their response during maintenance treatment.

The recommendation to use triplet therapy upfront applies to transplant candidates and very fit nontransplant candidates. Following induction regardless of transplant, maintenance therapy &ldquo;is a standard of practice in multiple myeloma,&rdquo; Anderson said.

Preferred maintenance regimens in the new guideline are bortezomib, lenalidomide, and thalidomide. PFS is approximately doubled with the use of lenalidomide maintenance post-transplant. In North America, maintenance until progression is recommended. Subcutaneous bortezomib every other week as maintenance has also conferred a PFS and 5-year OS advantage versus no maintenance, whether or not the patient undergoes transplant.⁵

UPFRONT THERAPY FOR NONTRANSPLANT CANDIDATES

In newly diagnosed nontransplant candidates with multiple myeloma, primary therapy now includes the triplet therapy of lenalidomide plus bortezomib and dexamethasone (category 1) or ixazomib plus lenalidomide and dexamethasone, which is listed as an &ldquo;other&rdquo; regimen. Adding a proteasome inhibitor or immunomodulatory agent to melphalan and prednisone in this setting has translated into improvement in PFS and OS.

Continuous lenalidomide plus dexamethasone was incorporated into the guideline following the demonstration of superiority to melphalan, prednisone, and thalidomide in newly diagnosed transplant-ineligible patients with multiple myeloma.⁶Findings from this study established the lenalidomide regimen as a new standard of care, said Anderson.

In the study, median PFS with continuous lenalidomide/dexamethasone was 25.5 months compared with 21.2 months with melphalan, prednisone, and thalidomide (HR, 0.72). Additionally, continuous lenalidomide/dexamethasone was superior to the melphalan-containing regimen for OS. The 4-year OS rate was 59% with lenalidomide versus 51% for the melphalan group.

RELAPSED/REFRACTORY MULTIPLE MYELOMA

A number of the preferred regimens listed in the new guideline for pretreated patients included triplet combinations, specifically those that build upon lenalidomide and dexamethasone, which are recommended alone or in combination with carfilzomib, elotuzumab, ixazomib, cyclophosphamide, or panobinostat. Additionally, the latest guideline elevated the combination of pomalidomide and low-dose dexamethasone to category 1 regimen for patients with relapsed/refractory multiple myeloma.

Data supporting the carfilzomib triplet regimen come from the phase III ASPIRE trial, which compared the triplet to lenalidomide and dexamethasone alone.⁷The median PFS with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR, 0.69; 95% CI, 0.57- 0.83; P <.0001).

Additionally, carfilzomib plus dexamethasone was superior to bortezomib plus dexamethasone in the phase III ENDEAVOR trial for patients with relapsed multiple myeloma.⁸In the study, the median PFS with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53, 95% CI, 0.44-0.65; P <.0001). Median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib group (HR, 0.79; P = .066).

For the antibodies, the SLAMF7 inhibitor elotuzumab in combination lenalidomide and dexamethasone showed sustained improvements in PFS and OS over lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma.⁹The addition of the antibody to the doublet reduced the risk of progression or death by 27% and improved OS by 4.1 months. The agent received a category 1 listing as a preferred regimen in the pretreated setting.

For daratumumab, the phase II MMY2002 study demonstrated a 65% one-year OS rate and a 29.2% response rate for the anti—CD38 antibody. Moreover, in the phase I/II GEN501 study, the response rate was 36%, median PFS was 5.6 months (95% CI, 4.2-8.1), and the 1-year OS rate was 77% (95% CI, 58-88).^10,11Phase III findings from CASTOR study exploring daratumumab will be presented at the 2016 ASCO Annual Meeting. The agent is currently recommended following 3 prior regimens.

In addition to the antibodies, the first HDAC inhibitor, panobinostat, showed sustained improvements in PFS, warranting a category 1 listing. In the phase III PANORAMA-1 trial,12 treatment with the 3-drug panobinostat regimen improved the primary endpoint of PFS by 3.9 months compared with bortezomib and dexamethasone alone.

The agent is specifically indicated for those who have received at least 2 prior regimens. Specifically in this population, the addition of panobinostat to bortezomib and dexamethasone improved PFS by 7.8 months in a subgroup of 147 patients with multiple myeloma who had received at least 2 prior treatments, including bortezomib and an immunomodulatory agent.

&ldquo;It&rsquo;s been a truly remarkable year in multiple myeloma, we&rsquo;ve had 16 new FDA approved treatments in the last 12 years and last year alone we had 7 new FDA approved treatments, so the 2016 version of the NCCN guidelines is completely revised,&rdquo; concluded Anderson.

References

1. Anderson KC. Updates on diagnostic criteria and management of multiple myeloma. Presented at: 21st NCCN Annual Conference, March 30-April 2, 2016; Hollywood, FL.
2. Durie B, Hoering A, Rajkumar SV, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): Results of the randomized phase III Trial SWOG S0777. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 25.
3. Dytfeld D, Jasielec J, Griffith KA, et al. Carfilzomib, lenalidomide, and low-dose dexamethasone in elderly patients with newly diagnosed multiple myeloma.Haematologica. 2014; 99(9): e162—e164.
4. Kumar S, Berdeja JG, Niesviky R, et al. Long-term ixazomib maintenance is tolerable and improves depth of response following ilxazomib-lenalidomide-dexamethasone induction in patients (pts) with previously untreated multiple myeloma (multiple myeloma): Phase 2 study results. Presented at 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 82.
5. Cerrato C, Gay F, Petrucci MT, et al. Significant survival improvement with maintenance in patients achieving a complete response: pooled analysis of 4 Italian phase III trials in newly diagnosed multiple myeloma patients. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 1974.
6. Benhoubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014;271:906-917.
7. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.N Engl J Med. 2015;372:142-152.
8. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study [published online December 5, 2015].Lancet Oncol. DOI: 10.1016/S1470-2045(15)00464-7.
9. Dimopoulos MA, Lonial S, White D, et al. Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma - 3-Year Safety and Efficacy Follow-up. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 28.
10. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with &ge; 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).J Clin Oncol. 2015;33 (suppl; abstr LBA8512).
11. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myelomaN Engl J Med. 2015;373:1207-1219.
12. Einsele H, Richardson P, Hungria V, et al. Subgroup Analysis by Prior Treatment Among Patients with Relapsed or Relapsed and Refractory Multiple Myeloma in the PANORAMA 1 Study of Panobinostat or Placebo Plus Bortezomib and Dexamethasone. Presented at: 20th Congress of the European Hematology Association (EHA) Vienna, Austria, 2015. Abstract #S102.