The results of an important Ninlaro ^[1] (ixazomib) clin­i­cal trial have been published in a leading medical journal.

The "TOURMALINE-MM1" trial was instrumental in gaining Ninlaro ap­proval in the United States as a new treat­ment for multiple myeloma. The Phase 3 trial tested whether adding Ninlaro to Revlimid ^[2] (lena­lido­mide) and dexa­metha­sone ^[3] is safe and im­proves treat­ment out­comes in patients with re­lapsed multiple myeloma

Up until now, only limited results of the TOURMALINE-MM1 trial have been publicly avail­able. Some can be found in Ninlaro's pre­scrib­ing in­­for­ma­tion ^[4]. Summaries of the results also have been presented at con­fer­ences.

Yesterday, however, the researchers who led the TOURMALINE-MM1 trial published a detailed article about the trial results in the New England Journal of Medicine.

Dr. Edward Libby, a myeloma specialist at the University of Washington and Fred Hutchinson Cancer Center in Seattle, summarized the results for The Beacon. He said, “The TOURMALINE-MM1 results dem­onstrate that an all-oral triplet regi­men of ixazomib, lena­lido­mide, and dexa­metha­sone has sig­nif­i­cantly im­proved pro­gres­sion-free survival versus the standard com­bi­na­tion of lena­lido­mide and dexa­metha­sone in re­lapsed / refractory multiple myeloma,”

Dr. Libby, who was not involved in the study, added that “the three-drug regi­men has acceptable toxicity that is similar to that of lena­lido­mide and dexa­metha­sone alone.” He also called attention to the fact that “patients with high-risk cytogenetics also benefited from the triplet com­bi­na­tion.”

Highlights Of The Trial Results

Based on the findings published yesterday, the key results of the TOURMALINE-MM1 appear to be as follows:

• Adding Ninlaro to Revlimid and dexa­metha­sone improves progression-free survival. Patients in the trial who were given Ninlaro, Revlimid, and dexa­metha­sone relapsed a median of six months later than patients who were treated with just Revlimid and dexa­metha­sone (20.6 months versus 14.7 months, respectively).
• The improvement in progression-free survival seen in the TOURMALINE-MM1 study is in line with what has been seen in recent studies that have added either Kyprolis ^[5] (carfilzomib) or Empliciti ^[6] (elotuzumab) to Revlimid and dexa­metha­sone in relapsed myeloma patients. Some might say that Ninlaro is a bit less effective than Kyprolis or Empliciti when combined with Revlimid and dexa­metha­sone, but that might be debated.
• Ninlaro's results in patients with high-risk disease are especially noteworthy. Patients in the trial who were treated with Ninlaro had the same progression-free survival regardless of whether they had standard-risk or high-risk chromosomal abnormalities.
• Ninlaro does not seem to have any troublesome side effect issues. It does not cause much peripheral neuropathy. However, it can cause low platelet levels and rashes, and patients taking Ninlaro appear to be more likely to have mild gastrointestinal issues such as diarrhea, constipation, nausea, and vomiting.
• For reasons that are not yet clear, the progression-free survival benefit for Ninlaro was seen particularly in patients under the age of 65. There was only a muted improvement in progression-free survival in patients over the age of 65.

Background

Ninlaro belongs to the class of drugs known as pro­te­a­some inhibitors, which in­cludes Velcade ^[7] (bor­tez­o­mib) and Kyprolis. Proteasome inhibitors work by preventing the breakdown of protein in cancer cells, triggering their death.

Unlike Velcade and Kyprolis, which are admin­istered by injection or infusion, Ninlaro is given orally as a capsule. Another orally-administered pro­te­a­some inhibitor, oprozomib ^[8], is being in­ves­ti­gated as a poten­tial myeloma ther­apy, but it is still relatively early in the devel­op­ment process.

Ninlaro shares some chemical similarities to Velcade. However, the two myeloma ther­a­pies are distinctly different drugs, much as Revlimid and thalidomide ^[9] (Thalidomide) are different drugs despite being chem­i­cally similar.

The U.S. Food and Drug Admin­istra­tion in November last year approved Ninlaro for use in com­bi­na­tion with Revlimid and dexa­metha­sone in multiple myeloma patients who have received at least one prior ther­apy (see related Beacon  ^[10]news).

Ninlaro also has been submitted for approval in Europe.

Design Of The TOURMALINE-MM1 Study

The TOURMALINE-MM1 trial is a double-blind, placebo-controlled trial. It in­cluded 722 multiple myeloma patients who had received one to three prior ther­a­pies. The trial had few re­stric­tions on specific pre­vi­ous treat­ments patients could have if they wanted to take part in the trial. Patients could not join the trial, however, if their disease was resistant (refractory) to either Revlimid or a pro­te­a­some inhibitor.

Patients were ran­domized to receive either Revlimid and dexa­metha­sone plus a placebo (sugar pill), or Revlimid and dexa­metha­sone in com­bi­na­tion with Ninlaro.

Ninlaro was admin­istered  as one 4 mg capsule per week for three weeks, followed by a week off. In addi­tion, patients received 25 mg of Revlimid on days 1 to 21 of each 28-day treat­ment cycle, plus 40 mg of oral dexa­metha­sone weekly. Treatment was con­tinued until a patient’s disease progressed, or until side effects or toler­abil­ity required dis­con­tinu­a­tion

The median follow-up time was 23 months.

Study Results - Efficacy

More patients who received Ninlaro in com­bi­na­tion with Revlimid and dexa­metha­sone achieved at least a partial response to treat­ment compared to patients who received the placebo with Revlimid and dexa­metha­sone (78 per­cent versus 72 per­cent, re­spec­tive­ly).

The median time to response was 1.1 months for patients receiving the Ninlaro com­bi­na­tion, compared to 1.9 months for patients receiving Revlimid and dexa­metha­sone alone. The median duration of response for the treat­ment groups was 20.5 versus 15.0 months, re­spec­tive­ly.

Progression-free survival was longer in the Ninlaro-treated patients versus patients receiving Revlimid and dexa­metha­sone (a median of 20.6 months versus 14.7 months).

The median over­all survival has not been reached yet in either treat­ment arm.

Impact Of Patient Risk Status

One of the particularly noteworthy findings reported by the TOURMALINE-MM1 investigators is that Ninlaro may yield the same pro­gres­sion-free survival in both standard-risk and high-risk myeloma patients.

The researchers classified patients in the trial as having high-risk multiple myeloma if one or more of the fol­low­ing chromosomal ab­nor­mal­i­ties were found in the patient's myeloma cells (based on FISH testing): del(17p), t(4;14), or t(14;16). Patients were classified as having standard-risk disease if they did not have any high-risk chromosomal ab­nor­mal­ity.

Progression-free survival among the Ninlaro-treated patients was 20.6 months in standard-risk patients and 21.4 months in high-risk patients.

In other words, high-risk patients treated with Ninlaro actually had slightly higher – albeit not statistically different – pro­gres­sion-free survival than standard-risk patients.

Risk status did affect pro­gres­sion-free survival in the ex­pec­ted way, however, in the patients who did not receive treat­ment with Ninlaro. Standard-risk patients treated with just Revlimid and dexa­metha­sone had pro­gres­sion-free survival of 15.6 months, while the high-risk patients treated with Revlimid and dexa­metha­sone had pro­gres­sion-free survival of 9.7 months.

Impact of Patient Age

Patients under the age of 65 seemed to benefit in particular from treat­ment with the Ninlaro, Revlimid, dexa­metha­sone triplet. In these patients, pro­gres­sion-free survival was 20.6 months in patients treated with Ninlaro, Revlimid, and dexa­metha­sone, compared to 14.1 months in patients treated with just Revlimid and dexa­metha­sone.

For patients 65 to 75 years of age, the same survival numbers were 17.5 and 17.6 months, re­spec­tive­ly. Likewise, the survival results were 18.5 and 13.1 months, re­spec­tive­ly, for patients over 75.

The muted benefit of Ninlaro in older patients may be due to challenges in managing the side effects of a three-drug regi­men. This may have been made more difficult in the context of a clin­i­cal trial, where explicit protocols related to dose reductions had to be followed.

Comparisons With Results Of Other Important Trials

The authors note that the im­prove­ment in treat­ment out­comes seen with Ninlaro in the TOURMALINE-MM1 study are in line with what has been seen for Kyprolis in the ASPIRE trial and Empliciti in the ELOQUENT-2 trial. They also recognize, however, that cross-trial comparisons should be made with care, due to "differences in study designs, methods, and patient pop­u­la­tions".

In both of the other two trials – ASPIRE and ELOQUENT-2 – a third drug was added to a base of Revlimid and dexa­metha­sone to see whether there was an im­prove­ment in pro­gres­sion-free survival, and whether the three-drug regi­men was safe.

In the ASPIRE trial, pro­gres­sion-free survival was 26.3 months in the patients treated with Kyprolis, Revlimid, and dexa­metha­sone, and 17.6 months in the patients who received only Revlimid and dexa­metha­sone.

In the ELOQUENT-2 trial, pro­gres­sion-free survival was 19.4 months in the patients treated with Empliciti, Revlimid, and dexa­metha­sone, and 14.9 months in the patients who received only Revlimid and dexa­metha­sone.

Progression-free survival hazard ratios in the three trials were 0.74 (TOURMALINE-MM1), 0.69 (ASPIRE), and 0.70 (ELOQUENT-2).

Study Results - Safety and Tolerability

The over­all rate of severe side effects was similar between the two treat­ment groups in the TOURMALINE-MM1 trial (74 per­cent for patients receiving the Ninlaro, versus 69 per­cent of patients receiving Revlimid and dexa­metha­sone).

However, the rate of severe low platelet counts and severe rash were higher among Ninlaro-treated patients (19 per­cent versus 9 per­cent for severe low platelet counts and 36 per­cent versus 23 per­cent for rash).

Ninlaro was not asso­ci­ated with a noticeable increase in periph­eral neu­rop­athy. Just over a quarter (27 per­cent) of the patients treated with Ninlaro, Revlimid, and dexa­metha­sone ex­peri­enced some degree of periph­eral neu­rop­athy, compared to 22 per­cent of the patients treated with just Revlimid and dexa­metha­sone.

Only 2 per­cent of the patients in both treat­ment groups, however, ex­peri­enced severe (Grade 3 or 4) periph­eral neu­rop­athy.

Ninlaro did seem to be asso­ci­ated with a somewhat higher rate of gastro­in­tes­ti­nal-related side effects. There were slightly higher rates of mild diarrhea, con­sti­pa­tion, nausea, and vomiting. There did not seem to be a discrepancy in how often severe cases of such side effects occurred.

Of note, there were at least two side effects – insomnia and muscle spasms – that were reported less frequently by patients treated with Ninlaro, Revlimid, and dexa­metha­sone than patients treated with just Revlimid and dexa­metha­sone.

Treatment dis­con­tinu­a­tion due to severe side effects was 17 per­cent in the Ninlaro-treated group of patients and 14 per­cent in the patients treated with just Revlimid and dexa­metha­sone. On-study death rates were similar between the two treat­ment groups: 4 per­cent for Ninlaro-treated patients versus 6 per­cent for patients receiving Revlimid and dexa­metha­sone.

For more in­­for­ma­tion, please see Moreau, P. et al, "Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma," in The New England Journal of Medicine, April 27, 2016 (abstract ^[11]).

In addi­tion, Takeda Oncology, the com­pany that developed and markets Ninlaro, has issued a press release ^[12] regarding the publication of the TOURMALIN-MM1 trial results.