In the past, single agent and double agent regimens have been a mainstay in the treatment of multiple myeloma, yet the five year survival rate has remained steadfastly low around 3-4 years, on average. Typically, younger and fitter patients do better than elderly patients with a poorer performance status, yet the majority of new diagnoses are found in the elderly. Finding new treatment approaches is therefore a key imperative.
2009 has seen the advent of new triple, and even quadruple, combinations in an effort to improve efficacy and survival, hopefully not at the expense of increased side effects. Two of the most commonly used drugs, bortezomib and
lenalidomide, for example, differ in their side effect profile with an increased
tendency to peripheral neuropathy and deep venous thrombosis,
respectively. New dosing regimens have begun to look at new strategies in the form of modified dosing regimens, which are potentially more patient friendly, without compromising efficacy.
Important trial results from two European groups at this American Society of Hematology (ASH) meeting, for example, demonstrated that a four
drug combination improved durable responses and progression-free survival in
elderly patients. Both studies showed that a
weekly schedule of bortezomib (Velcade) maintained efficacy with fewer toxic side effects (i.e. significantly decreased the incidence of grade 3-4 peripheral neuropathy) compared to the standard
twice weekly schedule.
newly diagnosed myeloma patients the combination of bortezomib with
melphalan-prednisone (VMP) has been previously shown to be superior to MP, while in relapsed-refractory patients the four drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high
proportion of complete responses (CR).
An Italian phase III study therefore looked at the four drug combination in the upfront setting and showed that induction therapy with a four drug combination of bortezomib,
melphalan, prednisone, and thalidomide (VMPT) followed by maintenance
therapy with bortezomib and thalidomide (VT) achieved superior response rates and PFS compared to VMP.
A Spanish study noted that previously in elderly patients with newly diagnosed myeloma, the
melphalan – prednisone (VMP) is significantly superior to MP alone.
However, it is unclear which agent is the optimal partner
for bortezomib: an alkylating agent or an immunomodulatory drug, so they set out to answer this critical question by comparing VMP to VTP, where T is thalidomide.
The results indicated that:
"1. Both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a
clear different toxicity profile (more neutropenia, but less cardiac
toxicity and peripheral neuropathy with VMP)
2. Maintenance therapy with either VT and
VP markedly improve the quality of responses with a good safety
3. The combination of these induction and
maintenance schedules seems to overcome the poor prognosis of high-risk cytogenetic abnormalities in elderly MM patients"
It should be noted that while melphalan causes more neutropenia, the cardiac toxicity seen with thalidomide is more difficult to manage, so the VMP combination is likely to be more suitable going forward in newly diagnosed elderly patients with myeloma.
One triple combination that garnered a lot of interest earlier this year at ASCO, was a trial looking at combining lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone (RVD) in relapsed or refractory myeloma patients, with overall response rates (ORR) of 69%, including 26% complete/near complete responses (CR/nCR) and manageable toxicities Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed myeloma patients to be lenalidomide (25 mg/day), bortezomib (1.3 mg/m2), and dexamethasone (20 mg). In all phase I patients, the ORR was 100%, including 31% CR, 9% nCR, and 75% very good PR (VGPR).
At this ASH meeting, we heard results reported for patients treated in the phase II portion of the study as conditioning prior to autologous stem cell transplantation (ASCT) by Dr Richardson, who concluded that:
"These phase II results suggest that RVD is a highly
effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD
was well tolerated, with limited rates of grade 3 peripheral neuropathy and DVT/PE despite
prolonged use of bortezomib and lenalidomide."
The data are summarised in the table below, based on all patients (n=35):
Response at cycle 4 (n=31)
Response at cycle 8 (n=24)
Some of the most exciting new developments in myeloma could be found in both the oral and poster sessions.
A new generation proteasome inhibitor, carfilzomib (PX-171), has been generating consistent results in the bortezomib refractory setting. An ongoing phase II study presented at ASH looked at carfilzomib monotherapy in myeloma patients with relapsed or refractory disease following 1–3 prior therapies, ie a heavily pre-treated population. Updated data for the bortezomib-treated cohort were reported at ASH and the authors concluded that:
"18% ORR (CBR 30%) is notable for this steroid- and
anthracycline-sparing regimen. Single-agent carfilzomib is well tolerated, even
in patients with renal insufficiency, and both myelosuppression and peripheral neuropathy
Carfilzomib was originally developed by Proteolix, who have just been acquired by Onyx. This should ensure more solid funding for the development of the phase III program, which looks promising in the relapsed, refractory setting.
Perifosine (Keryx) modulates Akt, and a number of other signal transduction pathways,
including the JNK and MAPK, all of which are associated with programmed cell death, cell growth, cell
differentiation and cell survival. Updated data from a phase I/II study in 84 patients who were heavily pre-treated with a median of 5 prior lines of therapy (range 1-13), showed that the overall response rate (ORR) was 41%, for the bortezomib relapsed group, 65%, and for the bortezomib refractory group, 43%.
Approximately 60% of patients
demonstrated progression (or stable disease (SD) for 4 cycles) at some point in their
treatment and received 20 mg dexamethasone, four times per week, in
addition to perifosine plus bortezomib. Responses occurred both with
patients taking perifosine in combination with bortezomib and with
patients receiving the combination plus dexamethasone. The ORR for the perifosine plus bortezomib arm was 25%, with an increase to 38% when dexamethasone was added. Survival data in the 73 evaluable patients was 6.4 months for PFS and 25 moths for overall survival (OS).
Another exciting new compound in development is MLN4924 from Millennium, the novel mechanism of which was recently described in detail (see article below) and was the also subject of a Nature article. The compound works very differently from proteasome inhibitors, which target the proteasome substrate. MLN4924 is involved with neddylation rather than direct ubiquination.
Neddylation activating enzyme (NAE) is the E1-activating enzyme for the ubiquitin-like protein Nedd8.
NAE catalyzes the first step in the neddylation cascade leading to
modification of cullin-based ubiquitin ligase activity. This results in
specific protein substrates, with important roles in cancer cell
survival, being targeted for degradation as shown the diagram below:
The end result is that MLN4924 inhibits neddylation by disrupting the cullin-RING ligase-mediated protein turnover, leading
to apoptotic death in human tumour cells by a new mechanism of action,
the deregulation of S-phase DNA synthesis.
A phase I dose escalation study in myeloma and NHL patients with MLN4924 was reported at ASH. The primary objectives were to determine the maximum
tolerated dose (MTD) and safety profile of MLN4924, as well as describe the
pharmacokinetics (PK) and pharmacodynamics (PD) in blood. Among the 22 patients enrolled to date, the median age was 65 years, 14 had myeloma and 8 had NHL.
The results showed that NEDD8-Cullin levels in peripheral blood myeloma cells (PBMCs) were inhibited and Nrf-2 target gene
transcripts in whole blood were higher vs. baseline after MLN4924
administration, which is indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the
second dose of MLN4924, which is indicative of NAE inhibition in peripheral
tissue. These results are promising and provide early proof of concept for the role of neddylation in myeloma.
Overall, this was a good meeting on the myeloma front with lots of promise for triple and quadruple combinations, as well as new agents being developed in both the newly diagnosed and refractory settings that augers well for the future, both in terms of improved survival and also more tolerable regimens.
Soucy, T., Smith, P., & Rolfe, M. (2009). Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer Clinical Cancer Research, 15 (12), 3912-3916 DOI: 10.1158/1078-0432.CCR-09-0343
Soucy, T., Smith, P., Milhollen, M., Berger, A., Gavin, J., Adhikari, S., Brownell, J., Burke, K., Cardin, D., Critchley, S., Cullis, C., Doucette, A., Garnsey, J., Gaulin, J., Gershman, R., Lublinsky, A., McDonald, A., Mizutani, H., Narayanan, U., Olhava, E., Peluso, S., Rezaei, M., Sintchak, M., Talreja, T., Thomas, M., Traore, T., Vyskocil, S., Weatherhead, G., Yu, J., Zhang, J., Dick, L., Claiborne, C., Rolfe, M., Bolen, J., & Langston, S. (2009). An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer Nature, 458 (7239), 732-736 DOI: 10.1038/nature07884