Triplet Therapy, ASCT Frontline Standard for Multiple Myeloma

George Somlo, MD

The preferred primary therapy for patients with multiple myeloma is induction therapy with a triplet regimen containing a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and dexamethasone followed by autologous stem cell transplantation (ASCT), consolidation, and maintenance, according to George Somlo, MD, at the 2016 NCCN Annual Congress on Hematologic Malignancies.

"Stem cell transplant is still an option but the new paradigm is to include novel agents in the induction followed by autologous stem cell transplantation for appropriate patients," said Somlo, from the City of Hope Comprehensive Cancer Center. "The question of consolidation or maintenance could be semantics but there is a need for some sort of maintenance therapy. Essentially, we're trying to treat myeloma now closer to leukemia, we don't fool ourselves into thinking that induction will keep a patient in remission."

The ultimate goal of primary therapy is to induce a very good partial response (VGPR) or better. In the latest NCCN criteria, a VGPR is defined as serum and urine M-protein levels that are detectable only when using immunofixation and not by electrophoresis or represented by a 90% reduction in serum M protein and a urine level of <100 mg per 24 hour.

The probability of survival is significantly better in those who achieve a VGPR or complete remission (CR), when compared with those who achieve a PR (P = .0017). Moreover, patients achieving a stringent CR have a significantly better 5-year overall survival (OS) rate (80%) versus those who achieve a CR (53%) or a near CR (47%).

"Initiate the therapy that you think has the highest likelihood of inducing a patient to at least a very good partial response but ideally a complete remission," said Somlo. In many instances, this will involve the continued use of ASCT, he noted. "I think it is fair to say, at least for the time being, ASCT is here to stay."

A phase III study conducted by the IFM and Dana-Farber that was presented at the 2015 ASH Annual Meeting¹ assessed upfront therapy with the IMiD lenalidomide (Revlimid), PI bortezomib (Velcade), and dexamethasone (RVd) with or without ASCT for younger patients with multiple myeloma. Maintenance lenalidomide was administered in both arms for 1 year. Overall, there was a 31% reduction in the risk of progression or death with the use of transplant.

In the study, the 4-year progression-free survival (PFS) rate with ASCT was 47% compared with 35% for RVd alone (HR, 0.69; 95% CI, 0.56-0.84; P ≤.001). The VGPR or better rate was 88% with ASCT and 78% with RVd alone (P = .001). The 4-year OS rate was 81% with ASCT and 83% with RVd alone (HR, 1.2; 95% CI, 0.7-1.8).

"This, as well as many other studies, are difficult to interpret when it comes to overall survival, because in this case those patients who progressed after just standard consolidation therapy were allowed to undergo ASCT," said Somlo. "We have so many new drugs now that to have a study where after progression these patients aren't getting treatment in salvage would probably now be considered unethical."

Another phase III study, reported at the 2016 ASCO Annual Meeting,² compared upfront ASCT with triplet therapy for patients with myeloma. This study included 1266 patients with newly diagnosed multiple myeloma who received induction therapy with the triplet regimen of bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCD) and then were randomly assigned to receive bortezomib, melphalan, and prednisone (VMP) or high-dose melphalan followed by either a single or double ASCT.

The median PFS was 44 months in the VMP arm and was not reached in the ASCT group. The 3-year PFS rates were 57.5% and 66.1%, for the VMP versus ASCT group, respectively (HR, 0.73; 95% CI, 0.59-0.90; P = .003). This benefit remained consistent in those with high- and standard-risk cytogenetics. The VGPR or better rates were 73.8% versus 88.5%, for the VMP and ASCT arms, respectively.

"Like many other studies, VGPR is higher in those who underwent ASCT," said Somlo. Following triplet therapy and ASCT, there remains a consistent and important role for maintenance therapy, he added.

At this point, the maintenance regimen of choice is lenalidomide, following a 40% reduction in the risk of death with the agent compared with placebo in the CALGB100104 study (HR, 0.60; P = .001).³ Median time to progression was 53 months with lenalidomide versus 26 months for placebo (HR, 0.54; P <.001).

This was also seen for maintenance lenalidomide following high-dose melphalan and ASCT in a meta-analysis presented at the 2016 ASCO Annual Meeting.⁴ In this study, the 7-year OS rate was 62% with the lenalidomide versus 50% with placebo. Median OS was not yet estimable in the lenalidomide arm versus 86.0 months in the control group.

In most cases, maintenance therapy is continued beyond 1 year, with many stopping after 18 to 24 months or not until progression. In the IFM study maintenance therapy was given for 25 months and in the CALGB study treatment lasted for 30 months.

One concern with lenalidomide is the incidence of secondary primary malignancies, both hematologic and solid tumors. "This is countered by the fact that the survival benefit was significant with maintenance lenalidomide," Somlo noted.

Bortezomib represents another potentially effective maintenance option, although there is not yet enough data for this option to give it a category 1 recommendation in the NCCN guideline.

In the 827-patient HOVON-65 study,⁵ the CR and near CR rates were superior with bortezomib, doxorubicin, and dexamethasone (PAD) compared with vincristine, doxorubicin, and dexamethasone (VAD). The CR/nCR rate were 49% with PAD versus 35% with VAD. The risk of death was reduced by 22% with PAD versus VAD (HR, 0.78; 95% CI, 0.64-0.90; P = .01).

"This is an intriguing strategy, and bortezomib is listed in the NCCN guidelines as an alternative," said Somlo.

With a broad frontline paradigm established, the focus switches toward various populations, specifically which regimen should be used in an older population. In most cases, the benefits of triplet therapy remain consistent, even in older patients, Somlo noted, although comorbidities and not age should be the deciding factor.

In the SWOG S0777 study,⁶ which included patients aged ≥65 years, RVd was compared with Rd as induction therapy for newly diagnosed patients with multiple myeloma. The CR rates were 15.7% and 8.4%, with RVd and Rd, respectively. The VGPR rate with RVd was 27.8% versus 23.4% with the doublet alone.

Median PFS with RVd was 43 versus 30 months with Rd (HR, 0.712; 96% CI, 0.560-0.906; one-sided P = .0018). The median OS was 75 months with RVd compared with 64 months for the doublet (HR, 0.709; 95% CI, 0.516-0.973; one-sided P = .0125).

When treating patients with renal impairment, bone disease, infection, or other risk factors it is important to follow NCCN guidelines for adjunctive treatment. For those with bone disease, this typically involves the addition of a bisphosphonate. This is most important for older patients, Somlo noted.

"Patients who get a complete or very good partial response will do better, regardless of their age," said Somlo. "It is important to treat patients aggressively, but it is just as important to pay attention to bone disease and hypercalcemia. I will refer you to the NCCN guidelines. The recommendations are really important to follow for patients getting any therapy."

There are many agents recently approved that are making their way toward the frontline, including daratumumab (Darzalex), panobinostat (Farydak), and elotuzumab (Empliciti). There are also other PIs available, including carfilzomib (Kyprolis) and ixazomib (Ninlaro). A number of promising therapies are also in development, including new PIs, HDAC and KSP inhibitors, new monoclonal antibodies, and checkpoint inhibitors.

"There are still serious unmet needs—plasma cell leukemia and p17 deletion come to mind," said Somlo. "There are still questions out there. My goal here is to go for a cure."

References:

1. Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida. Abstract 391.
2. Cavo, M Palumbo A, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). J Clin Oncol. 2016 (suppl; abstr 8000).
3. Holstein SA, Owzar K, Richardson PG, et al. Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM). J Clin Oncol. 2015;33 (suppl; abstr 8523).
4. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). J Clin Oncol. 2016;34 (suppl; abstr 8001).
5. Sonnevald P, Scheid C, van der Hold B, et al. Bortezomib Induction and Maintenance Treatment Improves Survival In Patients With Newly Diagnosed Multiple Myeloma:Extended Follow-Up Of The HOVON-65/GMMG-HD4 Trial. Blood. 2013;122(21):404.
6. Durie B, Hoering A, Rajkumar V, 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: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 25.

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