Frontline Myeloma Therapies Undergoing Dramatic Transformation

Shaji Kumar, MD

The high level of efficacy observed with the combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone in the phase III SWOG S0777 study significantly changed the frontline treatment paradigm for patients with multiple myeloma, according to Shaji Kumar, MD, at the20th AnnualInternational Congress on Hematologic Malignancies^®.

“This is the first time in the newly diagnosed setting that we’ve been able to show an improved overall survival, and I think that is very important,” said Kumar, professor of Medicine, Mayo Clinic. “The SWOG study showed that there was an overall survival improvement seen using the triplet, and I think increasingly the field is moving toward that being the defacto combination for initial treatment.”

The phase III study randomized 473 patients with untreated multiple myeloma to receive bortezomib plus lenalidomide and dexamethasone (n = 243) or lenalidomide and dexamethasone alone (n = 230). Those enrolled did not intend to receive immediate autologous stem cell transplant following progression.

Median progression-free survival (PFS) with the bortezomib triplet was 43 months versus 30 months with lenalidomide and dexamethasone alone (HR, 0.712; 96% CI, 0.560-0.906; one-sidedP= .0018). The median overall survival (OS) was 75 months in the bortezomib arm compared with 64 months for the doublet (HR, 0.709; one-sided P= .0125).

After more than 72 months of follow-up in some cases, 72.3% of patients remained alive in the bortezomib arm versus 58.6% with the doublet. The complete response (CR) rates were 15.7% and 8.4%, with bortezomib and without, respectively. The overall response rate (ORR) was 81.5% with the triplet and 71.5% for the doublet.

The triplet is associated with peripheral neuropathy and cytopenia, which were expected with the addition of bortezomib, says Kumar. Dose modification should be considered, if toxicities become unmanageable, he advised.

Overall, the addition of bortezomib was shown to cause grade &ge;3 neuropathy in 24% of patients versus 5% with the doublet (P<.0001). The most frequently occurring grade &ge;3 hematologic adverse events (AEs) with and without bortezomib, respectively, were lymphopenia (23% vs 18%), neutropenia (19% vs 21%), thrombocytopenia (18% vs 14%), leukopenia (14% vs 16%), and low hemoglobin (13% vs 16%).

&ldquo;With the triplet combination, obviously there is more toxicity, but it seems to be easily managed,&rdquo; says Kumar &ldquo;The benefits far out weigh the risks associated with it.&rdquo;

Future of Frontline Therapy

Now that the groundwork has been laid, other proteasome inhibitor (PI)-based triplet therapies could be utilized in the frontline setting. Recently, the oral PI ixazomib (Ninlaro) gained FDA approval in combination with lenalidomide and dexamethasone as a second-line option for patients with multiple myeloma. Additionally, the PI carfilzomib (Kyprolis) is approved in the relapsed/refractory setting.

The phase III ENDURANCE trial is currently enrolling participants to partially answer the question of which PI to use in the frontline setting. In this trial, the carfilzomib triplet will be compared with the bortezomib triplet for newly diagnosed patients. The study plans to enroll 756 participants with an estimated primary completion date of May 2016. This study will also examine whether limited or indefinite maintenance therapy with lenalidomide is superior (NCT01863550).

&ldquo;I think by using combinations of these novel agents we can achieve very deep remissions, deeper than what we have seen in the past,&rdquo; Kumar said. &ldquo;We can control the disease much faster. We have decreased the proportion of patients who die very early after prognosis because of complications. Overall we&rsquo;ve improved better overall survival by maintaining better performance status. Patients are living longer than they used to.&rdquo;

In addition to the SWOG S0777 study and frontline triplet therapy, Kumar also mentioned the potential impact of novel agents in the frontline setting, such as the monoclonal antibodies daratumumab (Darzalex) and elotuzumab (Empliciti). Both of these agents were approved in late 2015, and each has a different mechanism of action. Clinical trials are currently accruing patients to investigate these therapies in the frontline setting, said Kumar.

&ldquo;All of these new drugs are going to find their way up to the newly diagnosed patient population,&rdquo; he said.

Despite so many new agents on the horizon, many challenges still remain in multiple myeloma, Kumar said. The length of maintenance therapy, optimal agents for consolidation, and the role of stem cell transplant still needs to be further evaluated, along with a growing need for biomarkers to determine which patients will benefit from treatment. Despite the already accelerated pace, Kumar expects advancement in myeloma to continue as rapidly as they have in the past few years.

&ldquo;I think we will continue to make good progress,&rdquo; he said. &ldquo;Patients are getting deep responses and living longer and longer. I think we will start looking at even more individualized therapy as we continue to better understand the biology of this disease.&rdquo;

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.