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Myeloma: Building on Len-Dex for Relapsed/Refractory Disease

Carlson, Robert H.

doi: 10.1097/01.COT.0000387938.47501.fc

CHICAGO—Despite improved outcomes with novel therapeutic drug combinations, multiple myeloma remains incurable, but research goes forward seeking an ideal partner for the very active lenalidomide-dexamethasone regimen.

If the ultimate goal is personalized therapy for relapsed/refractory multiple myeloma then there may have to be more than one possibility for the third drug.

Proteosome inhibitors, histone deacetylase inhibitors and mTOR inhibitors all have promise depending on the patient subtype, said Robert Z. Orlowski, MD, PhD, Associate Professor in the Departments of Lymphoma/Myeloma and Experimental Therapeutics at the University of Texas MD Anderson Cancer Center, speaking in a poster-discussion session on Lymphoma and Plasma Cell Disorders here at the ASCO Annual Meeting.



Dr. Orlowski said that several new drugs added to the lenalidomide-dexamethasone platform in Phase I and II trials described at the meeting had good response rates and tolerable side effects. “But we don’t really know if patients who responded are in some subgroup of chemotherapy-sensitive patients who will do well with whatever combination they receive, or whether we can match some of these three-drug regimens to specific patient subsets defined by proteomic and genomic studies.

“What we need is an integrated approach to identify biomarkers and mediators of sensitivity and resistance.”

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Pandeacetylase Inhibitor

Dr. Orlowski reviewed a Phase Ib study by Maria-Victoria Mateos, MD, PhD, Attending Physician in the Hematology Department of Hospital Universitario Salamanca in Spain, of the orally bioavailable pandeacetylase inhibitor panobinostat, combined with lenalidomide and high-dose dexamethasone.

The 46 patients in the study, which was sponsored by Novartis Pharma AG, had relapsed or relapsed/refractory disease, but not primary refractory. Among those who were refractory, only 17% had prior lenalidomide.

This study sought the maximum tolerated dose, with patients receiving panobinostat at 5 mg, 10 mg, 20 mg or 25 mg.

The rate of responses considered better than just minor was 48% (22 of 46 patients) including one stringent complete response, two complete responses, and seven very good partial responses, although none of these were in the lenalidomide-refractory patients.

In the intent-to-treat population the partial response or better rate was 43%, which Dr. Orlowski said could be compared with 63% in the Phase III 009 lenalidomide-dexamethasone trial (Weber et al: NEJM 2007;357:2133).

Dose-limiting toxicities were seen in nine of 36 evaluable patients, including three of seven at the 25 mg panobinostat dose, and six patients required at least one dose reduction of that drug.

Seven deaths were recorded, four related to therapy, which Dr. Orlowski considered a high rate compared with the mortality rates in Phase III lenalidomide-dexamethasone trials.

“This speaks to the fact that lenalidomide and high-dose dexamethasone is quite a toxic combination,” he said.

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Histone Deacetylase Inhibitor

Another Phase I study took a similar route, but used the oral histone deacetylase inhibitor vorinostat in combination with lenalidomide and low-dose dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma.

Preliminary results suggest that vorinostat-lenalidomide-dexamethasone may be a convenient, effective, and generally well-tolerated oral regimen in these patients.

Principal investigator was Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. This ongoing multicenter trial enrolled patients into one of five escalating doses of the combination regimen. Most patients had received prior bortezomib (65%), thalidomide (68%), or lenalidomide (45%).

Patients had received a median of four prior lines of therapy.

Of 30 patient evaluable for efficacy, 87% (26) experienced stable disease or better at varying doses, including two complete responses, two very good partial and 10 partial responses, five minimal responses, and seven with stable disease. Four of the 20 patients had progressive disease.

“The intent-to-treat response rate of 52% is encouraging,” Dr. Orlowski said.

The response rate for minimal response or better was 63%.

Of 13 evaluable patients who received prior lenalidomide, stable or greater response was seen in nine patients (69%), with one very good partial, three partials, one minimal response, and four with stable disease, for a minimal-or-better response rate of 39%.

The only dose-limiting toxicity was Grade 3 diarrhea at the highest dose level. Other Grade 3/4 toxicities were a drop in absolute neutrophil count in 26%, drop in platelets in 17%, diarrhea in 13%, and fatigue and anemia in 10% each.

No treatment-related deaths were reported, and no maximally tolerated dose had been reached.

“Additional study data showed that 69% of lenalidomide-exposed patients had a clinical benefit, and in lenalidomide-refractory patients there was a hint that the addition of vorinostat may overcome lenalidomide resistance,” Dr. Orlowski said.

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PAD in 1q21 Amplification

Current therapy for younger newly diagnosed multiple myeloma patients involves induction chemotherapy followed by high-dose therapy and autologous stem cell transplantation, but patients usually relapse within one to three years.

To address this, Australian researchers led by Douglas Joshua, MD, Professor of Hematology at the

University of Sydney and the Royal Prince Alfred Hospital, conducted a combination regimen trial of bortezomib-doxorubicin-dexamethasone (PAD) as induction therapy in 108 patients with newly diagnosed myeloma with 1q21 amplification.

In a preliminary analysis they reported no evidence that the adverse prognostic impact of 1q21 amplification decreased response to four cycles of PAD induction therapy.

This is despite the 1q21-amplified patient subgroup containing a higher proportion of patients with Stage 2 and 3 disease at diagnosis, the researchers said.

The researchers concluded that further follow-up of patients in this trial is required to determine if patients with 1q21 amplification have shorter progression-free survival after PAD induction, as has been suggested in other studies

“This study showed good response rate in both groups, a 92% overall response rate in patients who did not have amplified 1q21 and 100% response in patient who did have 1q21 amplification,” Dr. Orlowski said. “This suggests that bortezomib-containing regimens will be the preferred induction, but of course this needs further follow-up.”

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Proteosome Inhibitors Top Partner

In an interview after the session, Dr. Orlowski said that the studies were small and so it is difficult to make comparisons—”But it seems that the best partner for lenalidomide-dexamethasone is still a proteosome inhibitor.”

He said the histone deacetylase combinations may have some role to play, “but the point I wanted to make was that we have to identify subsets of patients who would do well with one three-drug regimen versus another, rather than randomly trying different combinations on everybody.

“We may find that one three-drug regimen is good for one subtype, let’s say with an HDAC inhibitor, and a different subtype of patients may respond to a proteosome inhibitor.”

Even after Phase III trials it may be difficult to “pick a winner,” he said, without head-to-head comparisons trials.

“That’s why we have to figure out our patients’ subgroups to get response rates to 80% and 100%, even in the relapse/refractory setting.”

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Dr. Orlowski explained how the bortezomib-doxorubicin-dexamethasone regimen in the Australian trial arrived at the acronym PAD: “Dr. Jamie Cavanagh of St. Bartholomew’s Hospital, London, was the first to use that combination, and the P then stood for PS-341, the original name for bortezomib. Adriamycin, of course, is the brand name for doxorubicin. Using V for Velcade would be VAD, which we already have with vincristine,” Dr. Orlowski continued, “and if they used B for bortezomib, that would be…BAD.”

© 2010 Lippincott Williams & Wilkins, Inc.
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